Mukozitis – Patofizjologia i mechanizm

Mukozitis
Patofizjologia i mechanizm

Mukozitis to złożone, wielofazowe powikłanie leczenia przeciwnowotworowego, szczególnie radioterapii głowy i szyi oraz chemioterapii, charakteryzujące się uszkodzeniem DNA komórek nabłonka jamy ustnej i generacją reaktywnych form tlenu (ROS). Proces patogenetyczny obejmuje pięć faz: inicjacji (uszkodzenie DNA i ROS), upregulacji (aktywacja NF-κB i produkcja cytokin prozapalnych TNF-α, IL-1β, IL-6), amplifikacji (sprzężenia zwrotne nasilające uszkodzenia), owrzodzenia (kliniczne objawy, ból, kolonizacja bakteryjna) oraz gojenia (proliferacja i różnicowanie nabłonka). Kluczową rolę odgrywają ROS, które przy nadmiarze powodują uszkodzenia oksydacyjne, oraz cytokiny prozapalne, które nasilają stan zapalny i apoptozę. Mikrobiom jamy ustnej i wrodzony układ odpornościowy, w tym makrofagi i receptory Toll-podobne (TLR), modulują przebieg mukozitis, co wskazuje na dwukierunkową interakcję między mikroorganizmami a odpowiedzią immunologiczną gospodarza.

Patogeneza mukozitis

Faza inicjacji
Faza upregulacji i generacji przekaźników
Faza sygnalizacji i amplifikacji
Faza owrzodzenia
Faza gojenia

Molekularne mechanizmy uszkodzenia w mukozitis

Rola reaktywnych form tlenu (ROS)
Rola cytokin prozapalnych
Rola czynnika jądrowego kappa B (NF-κB)

Rola mikrobioty w patogenezie mukozitis

Rola wrodzonej odpowiedzi immunologicznej

Nowe podejścia terapeutyczne bazujące na mechanizmach mukozitis

Terapie celowane na szlaki molekularne
Fotobiomodulacja (PBM)
Inne podejścia terapeutyczne

Podsumowanie nowych kierunków badań

Kolejne rozdziały

Patogeneza mukozitis

Mukozitis (zapalenie błony śluzowej) to powszechne powikłanie występujące u pacjentów poddawanych leczeniu przeciwnowotworowemu, szczególnie w przypadku radioterapii okolicy głowy i szyi, chemioterapii oraz kombinacji obu tych metod, jak to ma miejsce w schematach kondycjonujących przed przeszczepem komórek macierzystych szpiku kostnego. Patogeneza mukozitis jest złożonym, dynamicznym procesem, który na poziomie molekularnym charakteryzuje się pięcioma nakładającymi się fazami.¹²

Faza inicjacji

Pierwsza faza rozwoju mukozitis, zwana fazą inicjacji, rozpoczyna się natychmiast po podaniu chemioterapii lub radioterapii. W tej fazie dochodzi do bezpośredniego uszkodzenia DNA komórek, a także – co jest częstszym mechanizmem – pośredniego uszkodzenia poprzez powstawanie reaktywnych form tlenu (ROS).¹² Promieniowanie jonizujące powoduje bezpośrednie uszkodzenie DNA komórek znajdujących się w polu napromieniania, prowadząc do pęknięć pojedynczych nici DNA i usunięcia zasad w niektórych miejscach, co przyczynia się do destabilizacji DNA.³ Wielokrotne uszkodzenia DNA hamują transkrypcję i replikację komórkową, co w trakcie kilkutygodniowego cyklu radioterapii prowadzi do śmierci tkanek prawidłowych.⁴

Na poziomie komórkowym, uszkodzenie dotyczy przede wszystkim szybko dzielących się komórek warstwy podstawnej nabłonka jamy ustnej.¹ Metotreksat, będący antagonistą kwasu foliowego, hamuje reduktazę dihydrofolianową (DHFR), enzym redukujący kwas foliowy do kwasu tetrahydrofoliowego. Zahamowanie DHFR przez metotreksat powoduje niedobór tymidylanu i puryn, a następnie zmniejszenie syntezy kwasów nukleinowych, co prowadzi do zahamowania podziału komórek.¹

Faza upregulacji i generacji przekaźników

Druga faza, nazywana fazą upregulacji z generacją przekaźników, charakteryzuje się aktywacją czynników transkrypcyjnych, przede wszystkim czynnika jądrowego kappa B (NF-κB).¹ NF-κB działa jako główny mediator transkrypcyjny, regulujący ponad 200 genów związanych z cytokinami prozapalnymi (czynnik martwicy nowotworów α/TNF-α, interleukina-6/IL-6, interleukina-1β/IL-1β), cząsteczkami adhezji komórkowej, odpowiedzią na stres i modulatorami cytokin.¹

W tej fazie dochodzi do aktywacji czynników transkrypcyjnych w śródbłonku, fibroblastach, makrofagach i nabłonku, co prowadzi do produkcji cytokin prozapalnych, takich jak TNF-α, IL-1β, IL-6 oraz enzymów, które pośredniczą w serii zdarzeń biologicznych prowadzących do apoptozy i amplifikacji uszkodzeń.² Obecność cytokin prozapalnych w błonie śluzowej powoduje wczesne uszkodzenie tkanki łącznej i śródbłonka, a także hamuje utlenowanie tkanki i sprzyja śmierci komórek podstawnych nabłonka.²

Faza sygnalizacji i amplifikacji

Trzecia faza, zwana fazą sygnalizacji i amplifikacji, charakteryzuje się dodatnimi sprzężeniami zwrotnymi, które nasilają i przedłużają uszkodzenia tkanek.¹ Uwolniony TNF-α inicjuje aktywację kinazy MAP (MAPK) w komórkach docelowych i jednocześnie podtrzymuje aktywność NF-κB.¹ Ten mechanizm dodatniego sprzężenia zwrotnego prowadzi do amplifikacji pierwotnego uszkodzenia.²

W tej fazie produkcja mediatorów zapalnych, takich jak TNF-α, prostaglandyny, NF-κB oraz interleukiny, wzrasta. Wzmacniają one uszkodzenia błony śluzowej wywołane promieniowaniem i ROS poprzez rekrutację dodatkowych monocytów i neutrofili oraz zwiększenie przepuszczalności śródbłonka naczyniowego dla tych komórek zapalnych.¹ Zmiany w ekspresji białek macierzy pozakomórkowej (ECM) tkanek jamy ustnej, takich jak fibronektyna i kolagen, w odpowiedzi na uszkodzenia tkanek spowodowane radioterapią i chemioterapią, dodatkowo nasilają fazę zapalną.²

Faza owrzodzenia

Czwarta faza, zwana fazą owrzodzenia, to moment, w którym kliniczne objawy mukozitis stają się widoczne.¹ W ciągu pierwszych 12 tygodni radioterapii, cytotoksyczne efekty promieniowania jonizującego, zapalenie i uszkodzenia DNA spowodowane przez ROS prowadzą do stopniowej apoptozy komórek nabłonka błony śluzowej w obrębie nabłonka wielowarstwowego płaskiego i warstwy blaszki właściwej.¹ Rezultatem jest owrzodzenie błony śluzowej i tworzenie się pseudobłon, co stanowi charakterystyczny obraz mukozitis.²

Faza owrzodzenia jest najbardziej bolesna ze względu na utratę nabłonka pokrywającego zakończenia nerwowe w warstwie blaszki właściwej.³ W tej fazie, integralność błony śluzowej i podśluzowej jest naruszona, pacjenci odczuwają ból i mogą wymagać opieki.² Obecność przerwania ciągłości w błonie podśluzowej pozwala licznym mikroorganizmom, symbiotycznym mieszkańcom zdrowej błony śluzowej, na inwazję tej okolicy tkankowej, prowadząc do zapalenia mediowanego przez komórki jednojadrowe, co sprzyja uwalnianiu nowych cytokin prozapalnych, które wzmacniają ekspresję mediatorów proapoptotycznych i zwiększają uszkodzenie tkanek.³

Bakterie kolonizują owrzodzenia, a produkty ich ścian komórkowych infiltrują błonę podśluzową. Prowadzi to do aktywacji makrofagów tkankowych, co powoduje dalszą produkcję cytokin prozapalnych.¹ Dodatkowo, bakteryjne sygnały immunologiczne za pośrednictwem receptorów Toll-podobnych (TLR) niejednoznacznie kształtują uszkodzenia genotoksyczne indukowane chemioterapią w przewodzie pokarmowym.²

Faza gojenia

Ostatnia faza, zwana fazą gojenia, występuje po zakończeniu terapii przeciwnowotworowej.⁴ Gojenie trwa kilka tygodni do miesięcy po usunięciu pierwotnego czynnika uszkadzającego w postaci promieniowania, a komórki w warstwie podstawnej otrzymują sygnały do proliferacji i różnicowania się w zdrowy nabłonek wielowarstwowy płaski.⁴

W tej fazie sygnalizacja z macierzy pozakomórkowej (ECM) błony podśluzowej prowadzi do proliferacji i różnicowania nabłonka, a tym samym do pogrubienia nabłonka.³ Lokalna flora jamy ustnej zostaje przywrócona.⁴ Mukozitis jest zdarzeniem ostrym, które w większości przypadków samoistnie ustępuje po zakończeniu leczenia przeciwnowotworowego.⁵

Molekularne mechanizmy uszkodzenia w mukozitis

Rola reaktywnych form tlenu (ROS)

Reaktywne formy tlenu odgrywają kluczową rolę w patogenezie mukozitis. ROS działają jako wtórne przekaźniki w sygnalizacji komórkowej i są niezbędne do różnych procesów biologicznych w normalnych komórkach.¹ Jednak nadmierne ilości ROS mogą indukować uszkodzenia oksydacyjne cząsteczek komórkowych, w tym lipidów, białek i DNA, przyczyniając się do śmierci komórek.²

Poziom komórkowy ROS jest kontrolowany przez równowagę między generowaniem ROS a ich eliminacją przez systemy antyoksydacyjne składające się z enzymów antyoksydacyjnych i endogennych przeciwutleniaczy.¹ Wiele badań wykazało, że wzmocnienie aktywności antyoksydacyjnej chroni przed zapaleniem błony śluzowej wywołanym promieniowaniem.² Dlatego badania wykorzystujące enzymy antyoksydacyjne lub drobnocząsteczkowe zmiatacze ROS wzmocniły koncepcję, że ROS są ważnym wczesnym wyzwalaczem prowadzącym do mukozitis.³

Na poziomie molekularnym, uszkodzenie błony śluzowej jamy ustnej i jelit indukowane chemioterapią jest związane z produkcją reaktywnych form tlenu (ROS) we wczesnych przedklinicznych stadiach.¹ Biorąc pod uwagę istotną rolę, jaką ROS odgrywają w patogenezie mukozitis, hamowanie tego szlaku może być ważną strategią terapeutyczną.¹

Rola cytokin prozapalnych

Cytokiny prozapalne są uważane za kluczowe w rozwoju mukozitis indukowanego przez chemioterapię i radioterapię.⁴ Badania wykazały również zastosowanie powszechnie stosowanych leków farmakologicznych w leczeniu mukozitis ze względu na ich hamujący wpływ na produkcję i/lub wydzielanie cytokin.⁵

Produkcja ROS pośredniczy w aktywacji inflamasomu podczas zapalenia błony śluzowej przewodu pokarmowego poprzez zwiększone rozszczepianie kaspazy-1, a następnie uwalnianie IL-1β i IL-18.¹ Badania na zwierzętach obejmujące manipulację IL-1, IL-18 lub kaspazą-1 dodatkowo potwierdzają rolę inflamasomu w pośredniczeniu w uszkodzeniu tkanek podczas leczenia chemioterapią.¹

Biorąc pod uwagę krytyczną rolę IL-1β w rekrutacji neutrofili i innych konsekwencjach mukozitis przewodu pokarmowego, inflamasom stanowi przekonujący cel do dalszych badań.² Anakinra, antagonista receptora IL-1 (IL-1RA), wykazała łagodzenie zapalenia błony śluzowej jelit w różnych modelach przedklinicznych.³

Rola czynnika jądrowego kappa B (NF-κB)

NF-κB jest centralnym regulatorem genów indukowanych przez 5-FU, a ekspresja genów regulowanych przez NF-κB koreluje ze zjawiskiem związanym z mukozitis.¹ Dlatego celowanie w NF-κB może być dobrą strategią leczenia komórek nowotworowych i ochrony komórek normalnych przed leczeniem nowotworowym.²

Wykazano, że apoptoza ma kluczowe znaczenie dla rozwoju mukozitis.³ Dlatego środki opracowane do zapobiegania mukozitis powinny chronić normalne komórki przed śmiercią apoptotyczną wywołaną terapią przeciwnowotworową, nie hamując przy tym apoptozy wywołanej terapią przeciwnowotworową w komórkach nowotworowych.⁴

Rola mikrobioty w patogenezie mukozitis

Mikrobiom jamy ustnej ulega zmianom pod wpływem chemioterapii i radioterapii, przyczyniając się do nasilenia uszkodzenia błony śluzowej, i może być czynnikiem prognostycznym ryzyka rozwoju mukozitis.¹ Mechanizmy, za pomocą których mikrobiom wywiera ten wpływ, nie zostały jeszcze w pełni odkryte; jednak dowody potwierdzają dwukierunkową relację między tymi społecznościami mikroorganizmów jamy ustnej a wrodzonym układem odpornościowym.²

Wprowadzenie myszy wolnych od drobnoustrojów w badaniach eksperymentalnych elegancko potwierdziło kluczową rolę drobnoustrojów zarówno w rozwoju mukozitis, jak i kształtowaniu wrodzonego układu odpornościowego.³ Wyniki tego badania nie mogą potwierdzić, która społeczność mikroorganizmów jest odpowiedzialna, przy czym zarówno mikrobiom jamy ustnej, jak i jelitowy są postulowane jako odgrywające rolę w rozwoju mukozitis, niezależnie od siebie i wspólnie.⁴

Ryzyko związane z ogólnym zmniejszeniem ilości drobnoustrojów jako strategii poprawy mukozitis polega na zakłóceniu działania drobnoustrojów komensalnych, które są niezbędne do utrzymania homeostazy i wspomagania procesów naprawy błony śluzowej poprzez sygnalizację wrodzoną układu odpornościowego.¹

Rola wrodzonej odpowiedzi immunologicznej

Wrodzony układ odpornościowy obejmuje bariery, komórki i czynniki humoralne, które są odpowiedzialne za kontrolę homeostastycznej tolerancji wobec drobnoustrojów komensalnych, a także za nieswoiste odpowiedzi gospodarza na potencjalne zagrożenia fizjologiczne.¹ Stałe zagrożenie przełamaniem nabłonka przez drobnoustroje sprawia, że odporność wrodzona jest wysoce rozwinięta na styku drobnoustrojów i gospodarza w jamie ustnej.²

Wyrafinowana sieć interakcji między wrodzonym układem odpornościowym a mikrobiotą jamy ustnej tworzy dwukierunkową relację w celu utrzymania optymalnej fizjologii dla obu systemów.³ W przypadku utraty przestrzennego oddzielenia między czynnikami mikrobiologicznymi powierzchni a blaszką właściwą, rezultatem jest aktywacja właściwych komórek odporności wrodzonej błony śluzowej jamy ustnej, w tym makrofagów, komórek dendrytycznych, neutrofili i wrodzonych komórek limfoidalnych.⁴

W szczególności makrofagi typu I zostały powiązane z progresją mukozitis ze względu na podśluzowe uwalnianie szeregu cytokin i chemokin prozapalnych, w tym TNFα, IL-1β, IL-6, CXCL8 i MIP.⁵

Receptory TLR (Toll-like receptors) są coraz częściej uznawane za ważne w patogenezie mukozitis, co zostało ustalone w szeregu badań koncentrujących się głównie na uszkodzeniach dolnego odcinka przewodu pokarmowego.⁵ Wszystkie receptory TLR są ekspresjonowane w błonie śluzowej jamy ustnej i wydają się być nadregulowane w okresach zapalenia, ustalając ich potencjalną rolę w patologii mukozitis jamy ustnej.⁶

Nowe podejścia terapeutyczne bazujące na mechanizmach mukozitis

Terapie celowane na szlaki molekularne

Zastosowanie nowych spostrzeżeń na temat roli odpowiedzi immunologicznej wrodzonej w rozwoju mukozitis jamy ustnej polega na skierowaniu badań w kierunku nowych skutecznych interwencji.¹ Biorąc pod uwagę nieodłączne podobieństwa w patofizjologii, badanie skuteczności leków, które wykazały obiecujące wyniki w leczeniu zapalenia błony śluzowej jelit w kontekście mukozitis jamy ustnej, stanowi ważny kierunek przyszłych badań.²

Biorąc to pod uwagę, wraz z wiedzą, że uszkodzenie bariery nabłonkowej indukowane przez IL-1β w błonie śluzowej jamy ustnej jest kluczowym czynnikiem rozwoju i progresji mukozitis jamy ustnej, anakinra może być obiecująca w leczeniu mukozitis jamy ustnej.³

Pierwszy w swojej klasie inhibitor fosforylazy urydyny TK-90 prawie całkowicie wyeliminował ciężkie zapalenie błony śluzowej jamy ustnej u pacjentów z niezaawansowanym rakiem płaskonabłonkowym głowy i szyi, którzy przeszli radioterapię, jak wykazało małe randomizowane badanie.¹ „Urydyna jest niezbędna do zachowania zdrowia prawidłowej błony śluzowej”, wyjaśnił Saba. „Poprzez hamowanie fosforylazy urydyny, poziomy urydyny są przywracane w błonie śluzowej, zasadniczo zmniejszając wyciek w mitochondriach i, dzięki temu, chroniąc błonę śluzową przed skutkami promieniowania i chemioterapii.”²

Jeśli chodzi o mechanizm działania w porównaniu z innymi środkami oszczędzającymi błonę śluzową, Saba zwrócił uwagę, że dysmutaza ponadtlenkowa „gasi jeden rodzaj wolnych rodników tlenowych, ale kiedy podaje się TK-90, gasi on 20 do 30 różnych podtypów form tlenu. […] „Założenie jest takie, że trzeba ugasić wszystkie te podtypy, aby odnieść sukces”, powiedział.³

Fotobiomodulacja (PBM)

PBM jest definiowana jako mechanizm, w którym niejonizujące promieniowanie optyczne w zakresie spektralnym światła widzialnego lub bliskiej podczerwieni jest absorbowane przez endogenne chromofory w celu wywołania zdarzeń fotofizycznych i fotochemicznych bez powodowania uszkodzeń termicznych, co prowadzi do zmian fizjologicznych i korzyści terapeutycznych.¹

Fala światła czerwonego lub podczerwonego jest absorbowana przez mitochondria. Prowadzi to do stymulacji cytochromu C, zwiększenia produkcji adenozynotrifosforanu (ATP) i tlenku azotu (NO), co skutkuje poprawą perfuzji tkanek, jak również czynników wzrostu komórek.² Ostatecznie PBM zmniejsza nocycepcję wtórnie do eliminacji mediatorów ostrego zapalenia i zwiększonej aktywności aksonalnej.³

PBM jest interesująca w zapobieganiu lub leczeniu mukozitis i doświadcza rosnącego rozkwitu w onkologii.¹ Kilka badań wykorzystało PBM, zarówno profilaktycznie, jak i terapeutycznie. Wyniki wykazały wyższość profilaktycznego (zapobiegawczego) zastosowania PBM nad podejściem terapeutycznym.² Pomimo licznych dowodów na skuteczność PBM, jej miejsce jest nadal przedmiotem dyskusji w postępowaniu terapeutycznym, szczególnie ze względu na niejednorodność protokołów i brak danych dozymetrycznych.³

W literaturze wyróżniono cztery możliwe mechanizmy działania komórkowego PBM. Istnieje wiele dowodów sugerujących, że PBM stymuluje aktywność mitochondrialną i wzmacnia różne procesy komórkowe łańcucha oddechowego.¹ Ogólnie rzecz biorąc, PBM zwiększała produkcję NO, który wiązał się z Cco; ale także dysocjował Cco i NO.²

Po trzecie, wysunięto hipotezę, że PBM może mieć antagonistyczne działanie na tworzenie ROS.¹ Wewnątrzkomórkowe odpowiedzi niższego rzędu są napędzane przez transdukcję fotosygnału i amplifikację w odpowiedzi głównie na zmianę stężenia ATP, ROS i NO.² AP-1 jest głównym szlakiem sygnałowym generowanym po wzroście ATP.³ Aktywacja tych szlaków sygnałowych prowadzi do czynników transkrypcyjnych regulujących ekspresję genów. NF-κB jest głównym szlakiem sygnałowym spowodowanym stresem oksydacyjnym.⁴

Na poziomie tkankowym, PBM w przypadku mukozitis stosuje się w celu przyspieszenia i zapewnienia każdej fazy procesu gojenia ran.⁵ Krótko mówiąc, PBM w bliskiej podczerwieni może prowadzić do zmniejszenia stanu zapalnego poprzez markery zapalne i waskularyzację.⁶

Inne podejścia terapeutyczne

Mukozitis można hamować poprzez modulację szlaków indukowanych przez radioterapię lub chemioterapię niezależnie od leczenia nowotworowego, co stwarza możliwość opracowania bardziej ukierunkowanych terapii i interwencji.⁵

Daikenchuto (DKT) ma pozytywne efekty terapeutyczne w poprawie różnych zaburzeń żołądkowo-jelitowych.¹ Obecne badanie sprawdziło, czy DKT ma potencjalny efekt terapeutyczny w chemioterapią indukowanym ostrym zapaleniu błony śluzowej jelita cienkiego (CIM) w modelu szczurów.² Efekt przeciwzapalny DKT przypisuje się faktowi, że DKT zarządza zmniejszeniem regulacji cyklooksygenazy 2 (COX-2), zwiększeniem regulacji endogennej adrenomedulliny (ADM) i tłumieniem infiltracji eozynofilowej.³ DKT chronił przed CIM indukowanym metotreksatem w modelu szczurów poprzez zmniejszenie zapalenia, stymulację proliferacji komórek i stabilizację bariery śluzówkowej.⁴

Palifermin – czynnik wzrostu keratynocytów, który zwiększa grubość nabłonka śluzówki – jest zatwierdzony przez FDA do zmniejszania częstości występowania i czasu trwania ciężkiego zapalenia błony śluzowej jamy ustnej związanego z nowotworami hematologicznymi u pacjentów, którzy otrzymują terapię mielotoksyczną wymagającą wsparcia komórkami macierzystymi hematopoetycznymi.¹

Krioterapia polega na tym, że pacjenci trzymają w ustach kawałki lodu nieprzerwanie podczas chemioterapii. Nie znaleziono badań naukowych potwierdzających skuteczność tej metody w leczeniu metotreksatem, ale kilka prac badawczych wykazało jej skuteczność w stosunku do innych chemioterapeutyków, takich jak 5-FU lub mephalan, oraz podczas kondycjonowania przed HSCT. Zakłada się, że lód powoduje miejscowy skurcz naczyń, co zmniejsza dostarczanie leku do tkanek błony śluzowej jamy ustnej, a tym samym zmniejsza ryzyko mukozitis.¹

Wysoko molekularny kwas hialuronowy (H-MW-HA) drastycznie zmniejsza zapalenie błony śluzowej wywołane chemioterapią i apoptotyczną śmierć komórek.¹ Nasze dane sugerują, że H-MW-HA łagodzi wywołane przez 5-FU zapalenie błony śluzowej jamy ustnej i jelit, przynajmniej częściowo, poprzez hamowanie apoptozy, hamowanie stresu oksydacyjnego i tłumienie cytokin zapalnych.²

Podsumowanie nowych kierunków badań

Badania nad mukozitis i jego leczeniem to szybko rozwijająca się dziedzina, dostarczająca nieustannie nowych kierunków badań i potencjalnych terapii.¹ Impet badawczy przyspiesza w zakresie patogenezy mukozitis, a wraz z tym nastąpiło wykorzystanie nowych modeli i interwencji, które są ukierunkowane na konkretne mechanizmy uszkodzeń.²

Postępy technologiczne mają potencjał zrewolucjonizowania dziedziny badań nad mukozitis, chociaż potrzebny jest skoncentrowany wysiłek, aby przenieść racjonalnie ukierunkowane interwencje do środowiska klinicznego.³ Badania nad mikrobiomem jamy ustnej, rolą wrodzonej odpowiedzi immunologicznej oraz nowymi terapiami celowanymi molekularnie, takimi jak inhibitory fosforylazy urydyny, stwarzają obiecujące perspektywy dla lepszego zrozumienia i leczenia mukozitis.¹

Trwające badania prowadzą do kompleksowego zrozumienia biologii mukozitis, co zaowocowało opracowaniem nowych interwencji.¹ Fakt, że pierwszy zarejestrowany środek przeciw zapaleniu błony śluzowej jamy ustnej czerpał swoją skuteczność z działań plejotropowych, był koncepcyjnie demonstracyjny dla potencjału terapeutycznego leków, które selektywnie ingerują w patogenezę mukozitis.² Szereg eklektycznych cząsteczek, wszystkie zaprojektowane do ingerowania w szlaki prowadzące do uszkodzenia, znajduje się w fazie przedklinicznej i klinicznej.³

Kolejne rozdziały

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Materiały źródłowe

#1 Oral Mucositis: understanding the pathology and management
https://pmc.ncbi.nlm.nih.gov/articles/PMC3738725/
Oral mucositis is a common complication of radiotherapy to the head and neck region, chemotherapy and the combination of the two such as seen in conditioning regiments for homologous stem cell transplantation (HSCT). […] On a molecular pathology level mucositis is characterized as having five phases: initiation, upregulation with messenger generation, signaling and amplification, ulceration and inflammation and finally healing. […] There are five steps in the pathogenesis of oral mucositis. The first is the initiation phase which involves the initial injury to cells by radiotherapy and chemotherapy either by direct DNA damage or more commonly indirectly via reactive oxygen species. This leads to a series of enzyme and transcription factor activation which eventually leads to upregulation of genes coding for inflammatory cytokines such as TNF-, IL-1 and IL-6 which target the submucosa and basal epithelium resulting in tissue damage. The resulting inflammation and tissue damage leads to ulceration and subsequent bacterial colonization further feeding a vicious cycle of inflammatory cytokine mediated damage. The final healing phase involves signaling via the extracellular matrix resulting in epithelial proliferation and epithialization reastablishing the mucosal barrier.
#1 Radiation-induced oral mucositis â radiation-induced oral mucositis: pathogenesis, risk factors, clinical manifestations, prevention, and treatment – Legeza – Bulletin of the Russian Military Medical Academy
https://journals.eco-vector.com/1682-7392/article/view/65173
This study presents the modern concepts of pathogenesis, risk factors, etiology, clinical manifestations, prevention, and treatment of oropharyngeal mucositis, one of the main complications of radiation therapy for head and neck region cancer. […] The leading role in the mechanisms of disease development belongs to rapidly dividing cells of the basal layer of the oropharyngeal mucous membrane. […] This damage is due to both direct (excitation and ionization) and indirect (accumulation of active oxygen and nitrogen compounds, activation of transcription factors, hyperfunction of pro-inflammatory cytokines, etc.) action of ionizing radiation on the most important biological molecules and supramolecular structures (polynucleotides, nucleoproteins, phospholipids, etc.). […] The main risk factors for mucositis include the localization and size of the tumor, the amount of radiation dose to the oral region, and individual body characteristics (young age, pernicious habits, metal structures of dentures, a history of periodontal disease, etc.). […] The most important components of the etiopathogenetic therapy of the disease include antiviral drugs (acyclovir and valacyclovir) and fungicides (clotrimazole, fluconazole, and itraconazole).
#1 Methotrexate-associated oral mucositis in children with acute lymphoblastic leukemia | Pustelnik | Nowotwory. Journal of Oncology
https://journals.viamedica.pl/nowotwory_journal_of_oncology/article/view/96144
Methotrexate is a folate antagonist it inhibits dihydrofolate reductase (DHFR). This enzyme reduces folic acid to tetrahydrofolic acid. Tetrahydrofolate has to be built up by a DHFR-catalyzed reaction. Inhibition of DHFR by methotrexate results in a deficiency of thymidylate and purines and then a decrease in nucleic acid synthesis, which leads to inhibited cells division. Methotrexate acts mainly in the S phase in a cell cycle, and is therefore appropriate for leukemias and lymphomas. Cytotoxic MTX occurs mainly in rapidly multiplying cells such as epithelial. These cells are susceptible to the effects of cytotoxic therapy because they undergo rapid turnover, usually every 7 to 14 days. […] In pathogenesis, methotrexate-induced oral mucositis is thought to develop through epithelial damage by reactive oxygen species, disruption of cell growth and apoptosis or necrosis. This exposes the mucous membranes to oral infections caused by bacteria and fungi. The administration of MTX leads to an increase in oxidative stress and, consequently, cytotoxicity.
#1 Mucositis in patients with hematologic malignancies: an overview | Haematologica
https://haematologica.org/article/view/4328
In the setting of allogeneic stem cell transplantation (SCT), mucositis plays a contributing role in the development and maintenance of acute graft-versus-host disease (GVHD) through the overproduction of inflammatory cytokines. […] The pathobiology of mucositis, including the gastrointestinal forms, is currently defined as a five-phase process: initiation, signaling with generation of messengers, amplification, ulceration, and, finally, healing. […] At the beginning DNA damage, generation of reactive oxygen species (ROS), and the coincident activation of other pathways occur. […] During the upregulation and message generation phase, transcription factors, such as nuclear factor Îº-B (NF Îº-B) are activated to upregulate genes in the endothelium, fibroblasts, macrophages, and epithelium; this process is followed by the production of pro-inflammatory cytokines, such as tumor necrosis factor Î± (TNF-Î±), interleukin-1 Î² (IL-1Î²), interleukin-6 (IL-6), and enzymes, which mediate a series of biological events leading to apoptosis and amplification of the injury, loss of epithelial integrity and the development of ulceration.
#1 Oral mucositis: the hidden side of cancer therapy | Journal of Experimental & Clinical Cancer Research | Full Text
https://jeccr.biomedcentral.com/articles/10.1186/s13046-020-01715-7
During this stage cells of the injured mucosa promote the transcription of several genes involved in the mucositis process. […] In this molecular scenario, the nuclear factor-ÎºB (NF-ÎºB) represents the main transcriptional mediator modulating over 200 genes associated with pro-inflammatory cytokines (tumor necrosis factor Î±/TNF-Î±; interleukin-6/IL-6; interleukin-1Î²/IL-1Î²), cell adhesion molecules, stress responders and cytokine modulators. […] The presence of pro-inflammatory cytokines is, also, reported within the mucosa, where they seem to induce early damage of connective tissue and endothelium, as well as to inhibit tissue oxygenations and to favor epithelial basal cell death. […] Concurrently with the activation of other pathways the primary damage is amplified through positive-feedback loop mechanisms.
#1 Mucositis – Wikipedia
https://en.wikipedia.org/wiki/Mucositis
The pathophysiology of mucositis is complex and multifactorial. Currently, Sonis’ five phase model is the accepted explanation for the process. The 5 stages are: […] Free radicals are produced due to DNA damage caused by chemo- or radiotherapy. […] Chemotherapy, radiotherapy and free radicals all contribute to the activation of transcription factors, such as NF-B. This results in the upregulation of pro-inflammatory cytokines, ceramide, nitric oxide and matrix metalloproteinases. The consequence of this is mucosal destruction, caused by thinning of the epithelium due to tissue injury and cell death. […] Positive or negative feedback loops involving some of the molecules in the previous phase can exacerbate or prolong tissue injury. For example, the pro-inflammatory cytokine TNF- can positively feedback on NF-B thus inducing more pro-inflammatory cytokine production.
#1 Oral mucositis: the hidden side of cancer therapy | Journal of Experimental & Clinical Cancer Research | Full Text
https://jeccr.biomedcentral.com/articles/10.1186/s13046-020-01715-7
The released TNF-Î±, indeed, initiates the activation of the mitogen activated protein kinase (MAPK) on target cells and, in the same time, sustains NF-ÎºB activity. […] Clinical manifestations of mucositis are appreciable at the fourth stage of the inflammation process, the ulceration phase. […] During this stage, mucosa and sub mucosal integrity is compromised, patients complain of pain and may need caregivers management. […] The presence of breaks in the submucosa, allows several microorganisms, symbiotic inhabitant of the healthy mucosa, to invade this tissue district leading to mononucler-infiltrating cells-mediated inflammation response, thus promoting new pro-inflammatory cytokines release that amplify expression of pro-apoptotic mediators and increase tissue damage. […] Mucositis is an acute event that mostly self-resolves as the anticancer treatment ends.
#1 Pathogenesis and Amelioration of Radiation-Induced Oral Mucositis
https://pmc.ncbi.nlm.nih.gov/articles/PMC8931694/
A host of reactions with the bases and phosphate groups in DNA can occur with ROS, resulting in alteration of DNA structure and single and double strand breaks. […] Additionally, inflammatory signaling pathways are upregulated during high ROS states which further contribute to cytotoxicity. […] In this inflammatory phase, cytokines including tissue necrosis factor alpha (TNF-), prostaglandins, NF-, and interleukin (IL) 1, are released. […] It is believed their mechanism of enhancing RT and ROS-mediated mucosal damage is by recruiting additional monocytes and neutrophils and increasing vascular endothelial permeability to these inflammatory cells. […] Changes in expression of extracellular matrix (ECM) proteins of oral cavity tissues such as fibronectin and collagen in response to tissue injury from RT and CHT further enhance the inflammatory phase.
#1 Pathogenesis and Amelioration of Radiation-Induced Oral Mucositis
https://pmc.ncbi.nlm.nih.gov/articles/PMC8931694/
Over the first 12 weeks of RT, the cytotoxic effects of ionizing radiation, inflammation, and ROS-mediated DNA damage result in gradual apoptosis of mucosal epithelial cells within the stratified squamous epithelium and lamina propria layers. […] The outcome is mucosal ulceration and formation of pseudomembranes which marks the characteristic appearance of OM. […] The ulceration stage is the most painful due to loss of the epithelium covering the nerve endings in the lamina propria layer. […] Healing takes place over the course of weeks to months once the initial insult from radiation is removed and cells in the basal layer are signaled to proliferate and differentiate into healthy stratified squamous epithelium.
#1 Mucositis – Wikipedia
https://en.wikipedia.org/wiki/Mucositis
Bacteria colonise ulcers and their cell wall products infiltrate the submucosa. This leads to activation of tissue macrophages, which causes further production of pro-inflammatory cytokines. In addition, bacteria-mediated immune signalling via Toll-like receptors (TLRs) ambiguously shapes chemotherapy-induced genotoxic damage in the gastrointestinal tract. […] Signalling from the extracellular matrix of the submucosa results in epithelial proliferation and differentiation, and thus a thickening of the epithelium. The local oral flora are reinstated.
#1 Mechanism-based management for mucositis: option for treating side eff | OTT
https://www.dovepress.com/mechanism-based-management-for-mucositis-option-for-treating-side-effe-peer-reviewed-fulltext-article-OTT
In the ulceration stage, clinical manifestations of mucositis become apparent as mucosal integrity is lost and painful lesions are formed. […] The final healing phase occurs after the cessation of cancer therapy. […] These pathways exist in early events during the pathogenesis of mucositis, and thus provide good opportunities to prevent and inhibit the development of mucositis. […] ROS act as secondary messengers in cell signaling, and are required for various biological processes in normal cells. […] However, excessive amounts of ROS can induce oxidative damage to cellular molecules, including lipids, proteins, and DNA, contributing to cell death. […] Therefore, scavenging of the ROS induced by chemotherapy or radiotherapy could effectively prevent the initial step of the tissue-damage event.
#1 Mechanism-based management for mucositis: option for treating side eff | OTT
https://www.dovepress.com/mechanism-based-management-for-mucositis-option-for-treating-side-effe-peer-reviewed-fulltext-article-OTT
The cellular ROS level is controlled by a balance between ROS generation and their elimination by antioxidant systems consisting of antioxidant enzymes and endogenous antioxidants. […] Many studies demonstrated that the enhancement of antioxidative activity protects against radiation-induced mucositis. […] Therefore, studies using antioxidant enzymes or small-molecule ROS scavengers have reinforced the idea that ROS are an important early trigger leading to mucositis. […] Inflammatory cytokines have been considered to play a critical role in the development of mucositis induced by chemotherapy and radiotherapy. […] Studies have also reported the application of commonly utilized pharmacological agents to treat mucositis, due to their inhibitory effects on cytokine production and/or secretion.
#1 High molecular weight hyaluronic acid drastically reduces chemotherapy-induced mucositis and apoptotic cell death | Cell Death & Disease
https://www.nature.com/articles/s41419-023-05934-6
Oral and intestinal mucositis (OIM) are debilitating inflammatory diseases initiated by oxidative stress, resulting in epithelial cell death and are frequently observed in cancer patients undergoing chemo-radiotherapy. […] The protective effects of HA in chemotherapy-induced mucositis and their underlying mechanisms remain to be fully elucidated. […] Our data suggest that H-MW-HA attenuates 5-FU-induced OIM, at least partly, by impeding apoptosis, inhibiting of oxidative stress and suppressing inflammatory cytokines. […] An understanding of the pathophysiology of chemotherapy-induced mucositis is instrumental for the development of novel mechanism-based drugs for this condition. […] At the molecular level, oral and intestinal chemotherapy-induced mucosal injury is associated with the production of reactive oxygen species (ROS) at early preclinical stages.
#1 High molecular weight hyaluronic acid drastically reduces chemotherapy-induced mucositis and apoptotic cell death | Cell Death & Disease
https://www.nature.com/articles/s41419-023-05934-6
Given the vital role played by ROS in mucositis pathogenesis, inhibition of this pathway could be a valid therapeutic strategy. […] Importantly, our data demonstrates that these types of injury to the tongue and intestine induced by 5-FU were ameliorated by co-administration of H-MW-HA. […] Molecularly, it is well-established that oxidative stress, inflammation, and apoptosis are major contributors to the development of mucositis induced by 5-FU treatment. […] We have demonstrated that the protective effects of H-MW-HA correlated with a significant reduction in mucosal apoptotic cells and COX-2 expression.
#1
https://journals.lww.com/co-supportiveandpalliativecare/fulltext/2024/06000/gastrointestinal_mucositis__a_sign_of_a__systemic_.4.aspx
Rapidly dividing enterocytes are vulnerable to apoptosis and pyroptosis induced by cytotoxic drugs and irradiation, which, combined with ROS, upregulation of numerous proinflammatory cytokines, and microbiome disturbances, leads to excessive local inflammation and destruction of intestinal mucosa. […] Changes in gut microbiota composition and increased permeability contribute to systemic inflammation and an increased risk of bloodstream infections, but predicting these infections using inflammatory markers remains challenging. […] Therapeutic interventions targeting inflammatory pathways, microbiome modulation, and mucosal repair show promise in mitigating mucosal damage and systemic inflammation associated with GIM. […] Production of ROS mediates activation of the inflammasome during GIM by increased cleavage of caspase-1 and subsequently IL-1 and IL-18 release.
#1
https://journals.lww.com/co-supportiveandpalliativecare/fulltext/2024/06000/gastrointestinal_mucositis__a_sign_of_a__systemic_.4.aspx
Animal studies involving manipulation of IL-1, IL-18, or caspase-1 provide further support for a role of the inflammasome in mediating tissue injury during chemotherapy treatment. […] The gut microbiome is known to be altered by chemotherapy and radiotherapy, contributing to the severity of mucosal injury, and may be a predictive factor for risk of GIM development. […] It is evident and will not be discussed further that bloodstream infections (BSIs) especially during neutropenia can induce sepsis, a form of severe SIR. […] Given the critical role of IL-1 in neutrophil recruitment and other consequences of GIM, the inflammasome presents a compelling target for further research. […] Anakinra is a recombinant human IL-1 receptor antagonist (IL-1RA), which has been shown to alleviate intestinal mucositis in various preclinical models. […] A change of perspective based on cellular, animal, and clinical studies proposes that mucosal damage is largely the consequence of cumulative chemo/radiotherapy-induced biological mucosal changes overwhelming physiologic self-protective mechanisms.
#1 Mechanism-based management for mucositis: option for treating side eff | OTT
https://www.dovepress.com/mechanism-based-management-for-mucositis-option-for-treating-side-effe-peer-reviewed-fulltext-article-OTT
NF-B is a central regulator of genes induced by 5-FU, and the expression of NF-B-regulated genes correlates with a mucositis-related phenomenon. […] Therefore, targeting NF-B could be a good strategy to treat cancer cells and protect normal cells from cancer treatment. […] It has been demonstrated that apoptosis is critical for the development of mucositis. […] Therefore, agents developed for the prevention of mucositis should protect normal cells from cancer therapy-induced apoptotic cell death without impeding cancer therapy-induced apoptosis in cancer cells. […] Mucositis can be inhibited by the modulation of radiotherapy- or chemotherapy-induced pathways independently of cancer treatment, which provides an opportunity for the development of more targeted therapies and interventions.
#1 The Role of the Innate Immune Response in Oral Mucositis Pathogenesis
https://www.mdpi.com/1422-0067/24/22/16314
TLRs have been increasingly recognized as being important in mucositis pathogenesis, established through a range of studies focusing predominantly on lower gastrointestinal tract injury. […] All TLRs are expressed in the oral mucosa and appear to be upregulated during periods of inflammation, establishing their potential role in OM pathology. […] The oral microbiome is known to be altered by chemotherapy and radiotherapy, contributes to the severity of oral injury, and may be a predictive factor for risk of OM development. […] The mechanisms by which the microbiome exerts this influence have yet to be fully uncovered; however, evidence supports a bidirectional relationship between these oral microbial communities and the innate immune system. […] The introduction of germ-free mice in experimental research has elegantly confirmed the critical role of microbes in both OM development and shaping the innate immune system. […] The results of this study cannot confirm the microbial community responsible, with both the oral and gut microbiome hypothesized to play a role in OM development in isolation to one another and collectively.
#1 The Role of the Innate Immune Response in Oral Mucositis Pathogenesis
https://www.mdpi.com/1422-0067/24/22/16314
The application of new insights into the role of innate immune responses on OM development is to direct research towards novel effective interventions. […] The risk with general depletion of microbes as a strategy to improve OM is the disruption to commensals that are required to maintain homeostasis and assist with mucosal repair processes through innate immune signaling. […] Given the inherent similarities in pathophysiology, investigating the efficacy of drugs that have shown promise in the treatment of intestinal mucositis in the context of OM represents an important avenue for future research. […] Considering this, along with the knowledge that IL-1Î²-induced epithelial barrier injury in the oral mucosa is a critical driver of OM development and progression, anakinra may hold promise in the treatment of OM.
#1 The Role of the Innate Immune Response in Oral Mucositis Pathogenesis
https://www.mdpi.com/1422-0067/24/22/16314
The innate immune system comprises barriers, cells, and humoral factors, which are responsible for control of homeostatic tolerance to commensal microbes as well as indiscriminate host responses to potential physiological threats. […] The constant threat of microbial breaches across the epithelium ensures that innate immunity is highly developed at the oral microbeâhost interface. […] A sophisticated network of interactions between the innate immune system and the oral microbiota creates a bidirectional relationship to maintain optimal physiology for both systems. […] Where there is a loss of spatial separation between surface microbial factors and the lamina propria, the result is activation of oral mucosal innate immune cells proper, including macrophages, dendritic cells, neutrophils, and innate lymphoid cells. […] In particular, type I macrophages have been associated with OM progression due to submucosal release of a range of proinflammatory cytokines and chemokines, including TNFÎ±, IL-1Î², IL-6, CXCL8, and MIP.
#1 Novel Therapy Promising for Radiation-Induced Oral Mucositis | MedPage Today
https://www.medpagetoday.com/meetingcoverage/mhncs/109010
The first-in-class uridine phosphorylase inhibitor TK-90 almost completely eliminated severe oral mucositis (SOM) in patients with non-metastatic squamous cell carcinoma of the head and neck who underwent radiation therapy, a small randomized study showed. […] „Uridine is essential to the preservation of the health of the normal mucosa,” Saba explained. „By inhibiting uridine phosphorylase, uridine levels are restored in the mucosa, basically reducing the leakage in the mitochondria and, by doing that, protecting the mucosa from the effects of radiation and chemotherapy.” […] As for its mechanism of action compared with other mucositis-sparing agents, Saba pointed out that superoxide dismutase „quenches one type of free radical oxygen species, but when you give TK-90 it quenches the 20 to 30 different subtypes of oxygen species. […] „The premise is that you need to quench all of these subtypes in order to be successful,” he said. […] In the case of antibiotics, Saba observed that they act in the later stages of mucositis progression, whereas restoring uridine levels with TK-90 acts earlier.
#1 Implementation of Photobiomodulation for Radio or Chemo-Induced Mucositis – Clinical Oncology Journal (ISSN 2766-9882)
https://clinicaloncologyjournal.com/article/1000164/implementation-of-photobiomodulation-for-radio-or-chemo-induced-mucositis
PBM is defined as a mechanism, by which non-ionizing optical radiation in the spectral range of the visible or near infrared is absorbed by endogenous chromophores to trigger photo physical and photochemical events without causing thermal damage, resulting in physiological changes and therapeutic benefits. […] The wave of red or infrared light is absorbed by the mitochondria. This results in stimulation of cytochrome C, an increase in the production of Adenosine Triphosphate (ATP) and of Nitric Oxide (NO) with the consequence of an improvement of tissue perfusion, as well as in cell growth factors. […] Finally, PBM, reduces nociception secondary to the elimination of mediators of acute inflammation and increased axonal activity. […] Mucositis is described as erythema and painful ulcerative lesions of the oral mucosa observed in cancer patients treated with chemotherapy and/or radiotherapy.
#1 Implementation of Photobiomodulation for Radio or Chemo-Induced Mucositis – Clinical Oncology Journal (ISSN 2766-9882)
https://clinicaloncologyjournal.com/article/1000164/implementation-of-photobiomodulation-for-radio-or-chemo-induced-mucositis
Mucositis is a common side effect of chemotherapy and/or radiation therapy that causes pain, difficulty eating, salivation and eating disorders, oral ulcerations and even discontinuation of treatments. Its etiopathological origin is complex and multifactorial. […] PBM is interesting to prevent or treat mucositis, it is experiencing a growing boom in oncology. […] Several studies have used PBM, both preventive and therapeutic. The results showed the superiority of the prophylactic (preventive) application of PBM over the therapeutic approach. […] Despite ample evidence of the effectiveness of PBM, its place is still under discussion in therapeutic management, particularly because of the heterogeneity of protocols and lack of dosimetric data. […] The review by Zadik et al. established recommendations for PBM protocols in the prevention of oral mucositis in patients treated with hematology (transplantation), radiotherapy or radio chemotherapy for head and neck cancer.
#1 Mechanisms of PhotoBioModulation (PBM) focused on oral mucositis prevention and treatment: a scoping review | BMC Oral Health | Full Text
https://bmcoralhealth.biomedcentral.com/articles/10.1186/s12903-021-01574-4
Oral mucositis (OM) is a severe complication cancer patients undergo when treated with chemoradiotherapy. The aim of this review is to discuss the mechanisms of photobiomodulation (PBM) regarding OM prevention and treatment, and more precisely to focus on the effect of PBM on tumor and healthy cells. […] PBM interactions with the tissue and additional mechanism in OM therapy were detailed in this review. […] Inflammation is mostly induced by the formation of excessive Reactive Oxygen Species (ROS) and activation of nuclear factor kappa B (NF-B). […] The literature reported four possible mechanisms for PBM cellular actions. Indeed, several pieces of evidence suggested that PBM stimulated mitochondrial activity and enhanced various cellular processes of the respiratory chain. […] Overall, PBM enhanced an increase in NO production that binded to Cco; but also dissociated Cco and NO.
#1 Mechanisms of PhotoBioModulation (PBM) focused on oral mucositis prevention and treatment: a scoping review | BMC Oral Health | Full Text
https://bmcoralhealth.biomedcentral.com/articles/10.1186/s12903-021-01574-4
Thirdly, it was hypothesized that PBM could have antagonist effects on ROS formation. […] The downstream intracellular responses are driven by photosignal transduction and amplification in response mostly to ATP, ROS and NO concentration change. […] AP-1 is the main signalling pathway generated after ATP increase. […] The activation of these signalling pathway results in transcription factors upregulating genes. NF-B is the main signalling pathway due to oxidative stress. […] At the tissue level, PBM for OM is used in order to accelerate and ensure each phase of the wound healing process. […] In short, PBM in near infra-red can lead to a reduction in inflammation through inflammatory markers and vascularisation. […] The effect of PBM on cancer cells is a controversial issue in the literature. Many studies found that PBM could enhance malignant cell proliferation; and biostimulation, suggesting that PBM had no protection effects.
#1 Therapeutic effect and mechanism of Daikenchuto in a model of methotrexate-induced acute small intestinal mucositis | PLOS One
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0283626
Daikenchuto (DKT) has positive therapeutic effects on improving various gastrointestinal disorders. […] The present study investigated whether or not DKT has a potential therapeutic effect on chemotherapy-induced acute small intestinal mucositis (CIM) in a rat model. […] Methotrexate (MTX) causes inhibition of growth and repair activities of epithelium and mucosa where the dividing and proliferating activities are increased, inducing CIM, which is the main reason for limiting further use of this drug or prompting its use. […] The anti-inflammatory effect of DKT are attributed to the fact that DKT manages the downregulation of cyclooxygenase 2 (COX-2), the upregulation of endogenous adrenomedullin (ADM), and the suppression of eosinophil infiltration. […] DKT protected against MTX-induced CIM in a rat model by reducing inflammation, stimulating cell proliferation, and stabilizing the mucosal barrier.
#1 Mucositis in Cancer Patients: A Review
https://www.uspharmacist.com/article/mucositis-in-cancer-patients-a-review
The goal of such therapy is vasoconstriction of the vessels in the mouth, which decreases the delivery of cytotoxic chemotherapy to sensitive areas of the oral mucosa. […] Paliferminâa keratinocyte growth factor that increases mucosal epithelium thicknessâis FDA-approved to decrease the incidence and duration of severe oral mucositis associated with hematologic malignancies in patients who are receiving myelotoxic therapy requiring hematopoietic stem cell support. […] The main focus of mucositis treatment, however, should be adequate pain control and palliation of symptoms. […] If topical therapies fail, systemic analgesia should be added. […] Mucositis is a common and painful side effect of treatment for many cancer patients.
#1 Methotrexate-associated oral mucositis in children with acute lymphoblastic leukemia | Pustelnik | Nowotwory. Journal of Oncology
https://journals.viamedica.pl/nowotwory_journal_of_oncology/article/view/96144
The last preventive method suggested will be cryotherapy, which involves patients holding ice-chips in their mouths continuously during chemotherapy. No scientific studies have been found proving the efficacy of this method for MTX treatment, but several research papers have demonstrated its effectiveness against other chemotherapeutics, such as 5-FU or mephalan, and during conditioning before HSCT. It is assumed that ice causes local vasoconstriction, which reduces drug delivery to the oral mucosa tissues and therefore reduces the risk of OM.
#1
https://link.springer.com/article/10.1007/s00520-019-04893-z
Mucositis research and treatment are a rapidly evolving field providing constant new avenues of research and potential therapies. […] Research momentum is accelerating for mucositis pathogenesis, and with this has come utilization of new models and interventions that target specific mechanisms of injury. […] Technological advances have the potential to revolutionize the field of mucositis research, although focused effort is needed to move rationally targeted interventions to the clinical setting.
#1 The Role of the Innate Immune Response in Oral Mucositis Pathogenesis
https://www.mdpi.com/1422-0067/24/22/16314
The innate immune response provides both protective and injury signals within the oral cavity depending on the context. […] The increasing appreciation of innate immunity and interactions with resident microbes during OM development has created opportunities to target specific features of early signaling cascades.
#1 Mucositis: The Impact, Biology and Therapeutic Opportunities of Oral Mucositis – BioModels
https://biomodels.com/publication/mucositis-the-impact-biology-and-therapeutic-opportunities-of-oral-mucositis/
Mucositis: The Impact, Biology and Therapeutic Opportunities of Oral Mucositis […] Despite being regularly reported and documented as one of the worst side effects of cancer therapy, relatively little was appreciated about the complexities of mucositis pathogenesis until relatively recently. […] ongoing research is leading to a comprehensive understanding of the biology of mucositis, which has resulted in the development of novel interventions. […] the fact that the first registered anti-OM agent derived its efficacy from its pleotropic activities was conceptually demonstrative of the therapeutic potential of drugs that selectively interfere with mucositis pathogenesis. […] A number of eclectic molecules, all designed to interfere with pathways that lead to injury are in pre-clinical and clinical development.
#2 Oral mucositis: the hidden side of cancer therapy | Journal of Experimental & Clinical Cancer Research | Full Text
https://jeccr.biomedcentral.com/articles/10.1186/s13046-020-01715-7
Inflammation response of epithelial mucosa to chemo- radiotherapy cytotoxic effects leads to mucositis, a painful side effect of antineoplastic treatments. […] Mucositis development consists of a cascade of events that can be divided in five stages occurring consecutively and mechanistically linked. The injury of mucosa membranes, named mucositis initiation phase, is caused by either radio- and/or chemotherapy. […] Systemic chemotherapy and radiotherapy induce tissue damage causing reactive oxygen species (ROS) release, DNA damage thereby leading to cell death of the basal and suprabasal epithelial cells. […] In particular, DNA strands breaks lead to the activation of the apoptotic process which is regulated by p53 activation and increased caspase 3. […] As a direct consequence of it, dead cells release endogenous damage-associated pattern molecules (DAMPs).
#2 Pathogenesis and Amelioration of Radiation-Induced Oral Mucositis
https://pmc.ncbi.nlm.nih.gov/articles/PMC8931694/
A multiphase process underlies the development of mucositis of the upper aerodigestive tract, beginning with cytotoxicity induced directly by ionizing radiation. […] Ionizing radiation results in direct DNA damage to cells within the RT field. […] Other effects of ionizing radiation include single strand breaks and elimination of bases at certain sites which contribute to DNA destabilization. […] Nevertheless, repeated insult to DNA inhibits cellular transcription and replication which over a multi-week course of RT, results in death of normal tissues. […] The second step in RT-mediated OM involves potentiation of cytotoxicity by reactive oxygen species (ROS). […] Under exogenous stress, high levels of ROS are produced which overcome cellular antioxidizing capabilities and perpetuates DNA damage.
#2 Mucositis in patients with hematologic malignancies: an overview | Haematologica
https://haematologica.org/article/view/4328
In the setting of allogeneic stem cell transplantation (SCT), mucositis plays a contributing role in the development and maintenance of acute graft-versus-host disease (GVHD) through the overproduction of inflammatory cytokines. […] The pathobiology of mucositis, including the gastrointestinal forms, is currently defined as a five-phase process: initiation, signaling with generation of messengers, amplification, ulceration, and, finally, healing. […] At the beginning DNA damage, generation of reactive oxygen species (ROS), and the coincident activation of other pathways occur. […] During the upregulation and message generation phase, transcription factors, such as nuclear factor Îº-B (NF Îº-B) are activated to upregulate genes in the endothelium, fibroblasts, macrophages, and epithelium; this process is followed by the production of pro-inflammatory cytokines, such as tumor necrosis factor Î± (TNF-Î±), interleukin-1 Î² (IL-1Î²), interleukin-6 (IL-6), and enzymes, which mediate a series of biological events leading to apoptosis and amplification of the injury, loss of epithelial integrity and the development of ulceration.
#2 Oral mucositis: the hidden side of cancer therapy | Journal of Experimental & Clinical Cancer Research | Full Text
https://jeccr.biomedcentral.com/articles/10.1186/s13046-020-01715-7
During this stage cells of the injured mucosa promote the transcription of several genes involved in the mucositis process. […] In this molecular scenario, the nuclear factor-ÎºB (NF-ÎºB) represents the main transcriptional mediator modulating over 200 genes associated with pro-inflammatory cytokines (tumor necrosis factor Î±/TNF-Î±; interleukin-6/IL-6; interleukin-1Î²/IL-1Î²), cell adhesion molecules, stress responders and cytokine modulators. […] The presence of pro-inflammatory cytokines is, also, reported within the mucosa, where they seem to induce early damage of connective tissue and endothelium, as well as to inhibit tissue oxygenations and to favor epithelial basal cell death. […] Concurrently with the activation of other pathways the primary damage is amplified through positive-feedback loop mechanisms.
#2 Mucositis – Wikipedia
https://en.wikipedia.org/wiki/Mucositis
The pathophysiology of mucositis is complex and multifactorial. Currently, Sonis’ five phase model is the accepted explanation for the process. The 5 stages are: […] Free radicals are produced due to DNA damage caused by chemo- or radiotherapy. […] Chemotherapy, radiotherapy and free radicals all contribute to the activation of transcription factors, such as NF-B. This results in the upregulation of pro-inflammatory cytokines, ceramide, nitric oxide and matrix metalloproteinases. The consequence of this is mucosal destruction, caused by thinning of the epithelium due to tissue injury and cell death. […] Positive or negative feedback loops involving some of the molecules in the previous phase can exacerbate or prolong tissue injury. For example, the pro-inflammatory cytokine TNF- can positively feedback on NF-B thus inducing more pro-inflammatory cytokine production.
#2 Pathogenesis and Amelioration of Radiation-Induced Oral Mucositis
https://pmc.ncbi.nlm.nih.gov/articles/PMC8931694/
A host of reactions with the bases and phosphate groups in DNA can occur with ROS, resulting in alteration of DNA structure and single and double strand breaks. […] Additionally, inflammatory signaling pathways are upregulated during high ROS states which further contribute to cytotoxicity. […] In this inflammatory phase, cytokines including tissue necrosis factor alpha (TNF-), prostaglandins, NF-, and interleukin (IL) 1, are released. […] It is believed their mechanism of enhancing RT and ROS-mediated mucosal damage is by recruiting additional monocytes and neutrophils and increasing vascular endothelial permeability to these inflammatory cells. […] Changes in expression of extracellular matrix (ECM) proteins of oral cavity tissues such as fibronectin and collagen in response to tissue injury from RT and CHT further enhance the inflammatory phase.
#2 Pathogenesis and Amelioration of Radiation-Induced Oral Mucositis
https://pmc.ncbi.nlm.nih.gov/articles/PMC8931694/
Over the first 12 weeks of RT, the cytotoxic effects of ionizing radiation, inflammation, and ROS-mediated DNA damage result in gradual apoptosis of mucosal epithelial cells within the stratified squamous epithelium and lamina propria layers. […] The outcome is mucosal ulceration and formation of pseudomembranes which marks the characteristic appearance of OM. […] The ulceration stage is the most painful due to loss of the epithelium covering the nerve endings in the lamina propria layer. […] Healing takes place over the course of weeks to months once the initial insult from radiation is removed and cells in the basal layer are signaled to proliferate and differentiate into healthy stratified squamous epithelium.
#2 Oral mucositis: the hidden side of cancer therapy | Journal of Experimental & Clinical Cancer Research | Full Text
https://jeccr.biomedcentral.com/articles/10.1186/s13046-020-01715-7
The released TNF-Î±, indeed, initiates the activation of the mitogen activated protein kinase (MAPK) on target cells and, in the same time, sustains NF-ÎºB activity. […] Clinical manifestations of mucositis are appreciable at the fourth stage of the inflammation process, the ulceration phase. […] During this stage, mucosa and sub mucosal integrity is compromised, patients complain of pain and may need caregivers management. […] The presence of breaks in the submucosa, allows several microorganisms, symbiotic inhabitant of the healthy mucosa, to invade this tissue district leading to mononucler-infiltrating cells-mediated inflammation response, thus promoting new pro-inflammatory cytokines release that amplify expression of pro-apoptotic mediators and increase tissue damage. […] Mucositis is an acute event that mostly self-resolves as the anticancer treatment ends.
#2 Mucositis – Wikipedia
https://en.wikipedia.org/wiki/Mucositis
Bacteria colonise ulcers and their cell wall products infiltrate the submucosa. This leads to activation of tissue macrophages, which causes further production of pro-inflammatory cytokines. In addition, bacteria-mediated immune signalling via Toll-like receptors (TLRs) ambiguously shapes chemotherapy-induced genotoxic damage in the gastrointestinal tract. […] Signalling from the extracellular matrix of the submucosa results in epithelial proliferation and differentiation, and thus a thickening of the epithelium. The local oral flora are reinstated.
#2 Mechanism-based management for mucositis: option for treating side eff | OTT
https://www.dovepress.com/mechanism-based-management-for-mucositis-option-for-treating-side-effe-peer-reviewed-fulltext-article-OTT
In the ulceration stage, clinical manifestations of mucositis become apparent as mucosal integrity is lost and painful lesions are formed. […] The final healing phase occurs after the cessation of cancer therapy. […] These pathways exist in early events during the pathogenesis of mucositis, and thus provide good opportunities to prevent and inhibit the development of mucositis. […] ROS act as secondary messengers in cell signaling, and are required for various biological processes in normal cells. […] However, excessive amounts of ROS can induce oxidative damage to cellular molecules, including lipids, proteins, and DNA, contributing to cell death. […] Therefore, scavenging of the ROS induced by chemotherapy or radiotherapy could effectively prevent the initial step of the tissue-damage event.
#2 Mechanism-based management for mucositis: option for treating side eff | OTT
https://www.dovepress.com/mechanism-based-management-for-mucositis-option-for-treating-side-effe-peer-reviewed-fulltext-article-OTT
The cellular ROS level is controlled by a balance between ROS generation and their elimination by antioxidant systems consisting of antioxidant enzymes and endogenous antioxidants. […] Many studies demonstrated that the enhancement of antioxidative activity protects against radiation-induced mucositis. […] Therefore, studies using antioxidant enzymes or small-molecule ROS scavengers have reinforced the idea that ROS are an important early trigger leading to mucositis. […] Inflammatory cytokines have been considered to play a critical role in the development of mucositis induced by chemotherapy and radiotherapy. […] Studies have also reported the application of commonly utilized pharmacological agents to treat mucositis, due to their inhibitory effects on cytokine production and/or secretion.
#2
https://journals.lww.com/co-supportiveandpalliativecare/fulltext/2024/06000/gastrointestinal_mucositis__a_sign_of_a__systemic_.4.aspx
Animal studies involving manipulation of IL-1, IL-18, or caspase-1 provide further support for a role of the inflammasome in mediating tissue injury during chemotherapy treatment. […] The gut microbiome is known to be altered by chemotherapy and radiotherapy, contributing to the severity of mucosal injury, and may be a predictive factor for risk of GIM development. […] It is evident and will not be discussed further that bloodstream infections (BSIs) especially during neutropenia can induce sepsis, a form of severe SIR. […] Given the critical role of IL-1 in neutrophil recruitment and other consequences of GIM, the inflammasome presents a compelling target for further research. […] Anakinra is a recombinant human IL-1 receptor antagonist (IL-1RA), which has been shown to alleviate intestinal mucositis in various preclinical models. […] A change of perspective based on cellular, animal, and clinical studies proposes that mucosal damage is largely the consequence of cumulative chemo/radiotherapy-induced biological mucosal changes overwhelming physiologic self-protective mechanisms.
#2 Mechanism-based management for mucositis: option for treating side eff | OTT
https://www.dovepress.com/mechanism-based-management-for-mucositis-option-for-treating-side-effe-peer-reviewed-fulltext-article-OTT
NF-B is a central regulator of genes induced by 5-FU, and the expression of NF-B-regulated genes correlates with a mucositis-related phenomenon. […] Therefore, targeting NF-B could be a good strategy to treat cancer cells and protect normal cells from cancer treatment. […] It has been demonstrated that apoptosis is critical for the development of mucositis. […] Therefore, agents developed for the prevention of mucositis should protect normal cells from cancer therapy-induced apoptotic cell death without impeding cancer therapy-induced apoptosis in cancer cells. […] Mucositis can be inhibited by the modulation of radiotherapy- or chemotherapy-induced pathways independently of cancer treatment, which provides an opportunity for the development of more targeted therapies and interventions.
#2 The Role of the Innate Immune Response in Oral Mucositis Pathogenesis
https://www.mdpi.com/1422-0067/24/22/16314
TLRs have been increasingly recognized as being important in mucositis pathogenesis, established through a range of studies focusing predominantly on lower gastrointestinal tract injury. […] All TLRs are expressed in the oral mucosa and appear to be upregulated during periods of inflammation, establishing their potential role in OM pathology. […] The oral microbiome is known to be altered by chemotherapy and radiotherapy, contributes to the severity of oral injury, and may be a predictive factor for risk of OM development. […] The mechanisms by which the microbiome exerts this influence have yet to be fully uncovered; however, evidence supports a bidirectional relationship between these oral microbial communities and the innate immune system. […] The introduction of germ-free mice in experimental research has elegantly confirmed the critical role of microbes in both OM development and shaping the innate immune system. […] The results of this study cannot confirm the microbial community responsible, with both the oral and gut microbiome hypothesized to play a role in OM development in isolation to one another and collectively.
#2 The Role of the Innate Immune Response in Oral Mucositis Pathogenesis
https://www.mdpi.com/1422-0067/24/22/16314
The innate immune system comprises barriers, cells, and humoral factors, which are responsible for control of homeostatic tolerance to commensal microbes as well as indiscriminate host responses to potential physiological threats. […] The constant threat of microbial breaches across the epithelium ensures that innate immunity is highly developed at the oral microbeâhost interface. […] A sophisticated network of interactions between the innate immune system and the oral microbiota creates a bidirectional relationship to maintain optimal physiology for both systems. […] Where there is a loss of spatial separation between surface microbial factors and the lamina propria, the result is activation of oral mucosal innate immune cells proper, including macrophages, dendritic cells, neutrophils, and innate lymphoid cells. […] In particular, type I macrophages have been associated with OM progression due to submucosal release of a range of proinflammatory cytokines and chemokines, including TNFÎ±, IL-1Î², IL-6, CXCL8, and MIP.
#2 The Role of the Innate Immune Response in Oral Mucositis Pathogenesis
https://www.mdpi.com/1422-0067/24/22/16314
The application of new insights into the role of innate immune responses on OM development is to direct research towards novel effective interventions. […] The risk with general depletion of microbes as a strategy to improve OM is the disruption to commensals that are required to maintain homeostasis and assist with mucosal repair processes through innate immune signaling. […] Given the inherent similarities in pathophysiology, investigating the efficacy of drugs that have shown promise in the treatment of intestinal mucositis in the context of OM represents an important avenue for future research. […] Considering this, along with the knowledge that IL-1Î²-induced epithelial barrier injury in the oral mucosa is a critical driver of OM development and progression, anakinra may hold promise in the treatment of OM.
#2 Novel Therapy Promising for Radiation-Induced Oral Mucositis | MedPage Today
https://www.medpagetoday.com/meetingcoverage/mhncs/109010
The first-in-class uridine phosphorylase inhibitor TK-90 almost completely eliminated severe oral mucositis (SOM) in patients with non-metastatic squamous cell carcinoma of the head and neck who underwent radiation therapy, a small randomized study showed. […] „Uridine is essential to the preservation of the health of the normal mucosa,” Saba explained. „By inhibiting uridine phosphorylase, uridine levels are restored in the mucosa, basically reducing the leakage in the mitochondria and, by doing that, protecting the mucosa from the effects of radiation and chemotherapy.” […] As for its mechanism of action compared with other mucositis-sparing agents, Saba pointed out that superoxide dismutase „quenches one type of free radical oxygen species, but when you give TK-90 it quenches the 20 to 30 different subtypes of oxygen species. […] „The premise is that you need to quench all of these subtypes in order to be successful,” he said. […] In the case of antibiotics, Saba observed that they act in the later stages of mucositis progression, whereas restoring uridine levels with TK-90 acts earlier.
#2 Implementation of Photobiomodulation for Radio or Chemo-Induced Mucositis – Clinical Oncology Journal (ISSN 2766-9882)
https://clinicaloncologyjournal.com/article/1000164/implementation-of-photobiomodulation-for-radio-or-chemo-induced-mucositis
PBM is defined as a mechanism, by which non-ionizing optical radiation in the spectral range of the visible or near infrared is absorbed by endogenous chromophores to trigger photo physical and photochemical events without causing thermal damage, resulting in physiological changes and therapeutic benefits. […] The wave of red or infrared light is absorbed by the mitochondria. This results in stimulation of cytochrome C, an increase in the production of Adenosine Triphosphate (ATP) and of Nitric Oxide (NO) with the consequence of an improvement of tissue perfusion, as well as in cell growth factors. […] Finally, PBM, reduces nociception secondary to the elimination of mediators of acute inflammation and increased axonal activity. […] Mucositis is described as erythema and painful ulcerative lesions of the oral mucosa observed in cancer patients treated with chemotherapy and/or radiotherapy.
#2 Implementation of Photobiomodulation for Radio or Chemo-Induced Mucositis – Clinical Oncology Journal (ISSN 2766-9882)
https://clinicaloncologyjournal.com/article/1000164/implementation-of-photobiomodulation-for-radio-or-chemo-induced-mucositis
Mucositis is a common side effect of chemotherapy and/or radiation therapy that causes pain, difficulty eating, salivation and eating disorders, oral ulcerations and even discontinuation of treatments. Its etiopathological origin is complex and multifactorial. […] PBM is interesting to prevent or treat mucositis, it is experiencing a growing boom in oncology. […] Several studies have used PBM, both preventive and therapeutic. The results showed the superiority of the prophylactic (preventive) application of PBM over the therapeutic approach. […] Despite ample evidence of the effectiveness of PBM, its place is still under discussion in therapeutic management, particularly because of the heterogeneity of protocols and lack of dosimetric data. […] The review by Zadik et al. established recommendations for PBM protocols in the prevention of oral mucositis in patients treated with hematology (transplantation), radiotherapy or radio chemotherapy for head and neck cancer.
#2 Mechanisms of PhotoBioModulation (PBM) focused on oral mucositis prevention and treatment: a scoping review | BMC Oral Health | Full Text
https://bmcoralhealth.biomedcentral.com/articles/10.1186/s12903-021-01574-4
Oral mucositis (OM) is a severe complication cancer patients undergo when treated with chemoradiotherapy. The aim of this review is to discuss the mechanisms of photobiomodulation (PBM) regarding OM prevention and treatment, and more precisely to focus on the effect of PBM on tumor and healthy cells. […] PBM interactions with the tissue and additional mechanism in OM therapy were detailed in this review. […] Inflammation is mostly induced by the formation of excessive Reactive Oxygen Species (ROS) and activation of nuclear factor kappa B (NF-B). […] The literature reported four possible mechanisms for PBM cellular actions. Indeed, several pieces of evidence suggested that PBM stimulated mitochondrial activity and enhanced various cellular processes of the respiratory chain. […] Overall, PBM enhanced an increase in NO production that binded to Cco; but also dissociated Cco and NO.
#2 Mechanisms of PhotoBioModulation (PBM) focused on oral mucositis prevention and treatment: a scoping review | BMC Oral Health | Full Text
https://bmcoralhealth.biomedcentral.com/articles/10.1186/s12903-021-01574-4
Thirdly, it was hypothesized that PBM could have antagonist effects on ROS formation. […] The downstream intracellular responses are driven by photosignal transduction and amplification in response mostly to ATP, ROS and NO concentration change. […] AP-1 is the main signalling pathway generated after ATP increase. […] The activation of these signalling pathway results in transcription factors upregulating genes. NF-B is the main signalling pathway due to oxidative stress. […] At the tissue level, PBM for OM is used in order to accelerate and ensure each phase of the wound healing process. […] In short, PBM in near infra-red can lead to a reduction in inflammation through inflammatory markers and vascularisation. […] The effect of PBM on cancer cells is a controversial issue in the literature. Many studies found that PBM could enhance malignant cell proliferation; and biostimulation, suggesting that PBM had no protection effects.
#2 Therapeutic effect and mechanism of Daikenchuto in a model of methotrexate-induced acute small intestinal mucositis | PLOS One
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0283626
Daikenchuto (DKT) has positive therapeutic effects on improving various gastrointestinal disorders. […] The present study investigated whether or not DKT has a potential therapeutic effect on chemotherapy-induced acute small intestinal mucositis (CIM) in a rat model. […] Methotrexate (MTX) causes inhibition of growth and repair activities of epithelium and mucosa where the dividing and proliferating activities are increased, inducing CIM, which is the main reason for limiting further use of this drug or prompting its use. […] The anti-inflammatory effect of DKT are attributed to the fact that DKT manages the downregulation of cyclooxygenase 2 (COX-2), the upregulation of endogenous adrenomedullin (ADM), and the suppression of eosinophil infiltration. […] DKT protected against MTX-induced CIM in a rat model by reducing inflammation, stimulating cell proliferation, and stabilizing the mucosal barrier.
#2 High molecular weight hyaluronic acid drastically reduces chemotherapy-induced mucositis and apoptotic cell death | Cell Death & Disease
https://www.nature.com/articles/s41419-023-05934-6
Oral and intestinal mucositis (OIM) are debilitating inflammatory diseases initiated by oxidative stress, resulting in epithelial cell death and are frequently observed in cancer patients undergoing chemo-radiotherapy. […] The protective effects of HA in chemotherapy-induced mucositis and their underlying mechanisms remain to be fully elucidated. […] Our data suggest that H-MW-HA attenuates 5-FU-induced OIM, at least partly, by impeding apoptosis, inhibiting of oxidative stress and suppressing inflammatory cytokines. […] An understanding of the pathophysiology of chemotherapy-induced mucositis is instrumental for the development of novel mechanism-based drugs for this condition. […] At the molecular level, oral and intestinal chemotherapy-induced mucosal injury is associated with the production of reactive oxygen species (ROS) at early preclinical stages.
#2
https://link.springer.com/article/10.1007/s00520-019-04893-z
Mucositis research and treatment are a rapidly evolving field providing constant new avenues of research and potential therapies. […] Research momentum is accelerating for mucositis pathogenesis, and with this has come utilization of new models and interventions that target specific mechanisms of injury. […] Technological advances have the potential to revolutionize the field of mucositis research, although focused effort is needed to move rationally targeted interventions to the clinical setting.
#2 Mucositis: The Impact, Biology and Therapeutic Opportunities of Oral Mucositis – BioModels
https://biomodels.com/publication/mucositis-the-impact-biology-and-therapeutic-opportunities-of-oral-mucositis/
Mucositis: The Impact, Biology and Therapeutic Opportunities of Oral Mucositis […] Despite being regularly reported and documented as one of the worst side effects of cancer therapy, relatively little was appreciated about the complexities of mucositis pathogenesis until relatively recently. […] ongoing research is leading to a comprehensive understanding of the biology of mucositis, which has resulted in the development of novel interventions. […] the fact that the first registered anti-OM agent derived its efficacy from its pleotropic activities was conceptually demonstrative of the therapeutic potential of drugs that selectively interfere with mucositis pathogenesis. […] A number of eclectic molecules, all designed to interfere with pathways that lead to injury are in pre-clinical and clinical development.
#3 Pathogenesis and Amelioration of Radiation-Induced Oral Mucositis
https://pmc.ncbi.nlm.nih.gov/articles/PMC8931694/
A multiphase process underlies the development of mucositis of the upper aerodigestive tract, beginning with cytotoxicity induced directly by ionizing radiation. […] Ionizing radiation results in direct DNA damage to cells within the RT field. […] Other effects of ionizing radiation include single strand breaks and elimination of bases at certain sites which contribute to DNA destabilization. […] Nevertheless, repeated insult to DNA inhibits cellular transcription and replication which over a multi-week course of RT, results in death of normal tissues. […] The second step in RT-mediated OM involves potentiation of cytotoxicity by reactive oxygen species (ROS). […] Under exogenous stress, high levels of ROS are produced which overcome cellular antioxidizing capabilities and perpetuates DNA damage.
#3 Pathogenesis and Amelioration of Radiation-Induced Oral Mucositis
https://pmc.ncbi.nlm.nih.gov/articles/PMC8931694/
Over the first 12 weeks of RT, the cytotoxic effects of ionizing radiation, inflammation, and ROS-mediated DNA damage result in gradual apoptosis of mucosal epithelial cells within the stratified squamous epithelium and lamina propria layers. […] The outcome is mucosal ulceration and formation of pseudomembranes which marks the characteristic appearance of OM. […] The ulceration stage is the most painful due to loss of the epithelium covering the nerve endings in the lamina propria layer. […] Healing takes place over the course of weeks to months once the initial insult from radiation is removed and cells in the basal layer are signaled to proliferate and differentiate into healthy stratified squamous epithelium.
#3 Oral mucositis: the hidden side of cancer therapy | Journal of Experimental & Clinical Cancer Research | Full Text
https://jeccr.biomedcentral.com/articles/10.1186/s13046-020-01715-7
The released TNF-Î±, indeed, initiates the activation of the mitogen activated protein kinase (MAPK) on target cells and, in the same time, sustains NF-ÎºB activity. […] Clinical manifestations of mucositis are appreciable at the fourth stage of the inflammation process, the ulceration phase. […] During this stage, mucosa and sub mucosal integrity is compromised, patients complain of pain and may need caregivers management. […] The presence of breaks in the submucosa, allows several microorganisms, symbiotic inhabitant of the healthy mucosa, to invade this tissue district leading to mononucler-infiltrating cells-mediated inflammation response, thus promoting new pro-inflammatory cytokines release that amplify expression of pro-apoptotic mediators and increase tissue damage. […] Mucositis is an acute event that mostly self-resolves as the anticancer treatment ends.
#3 Mucositis – Wikipedia
https://en.wikipedia.org/wiki/Mucositis
Bacteria colonise ulcers and their cell wall products infiltrate the submucosa. This leads to activation of tissue macrophages, which causes further production of pro-inflammatory cytokines. In addition, bacteria-mediated immune signalling via Toll-like receptors (TLRs) ambiguously shapes chemotherapy-induced genotoxic damage in the gastrointestinal tract. […] Signalling from the extracellular matrix of the submucosa results in epithelial proliferation and differentiation, and thus a thickening of the epithelium. The local oral flora are reinstated.
#3 Mechanism-based management for mucositis: option for treating side eff | OTT
https://www.dovepress.com/mechanism-based-management-for-mucositis-option-for-treating-side-effe-peer-reviewed-fulltext-article-OTT
The cellular ROS level is controlled by a balance between ROS generation and their elimination by antioxidant systems consisting of antioxidant enzymes and endogenous antioxidants. […] Many studies demonstrated that the enhancement of antioxidative activity protects against radiation-induced mucositis. […] Therefore, studies using antioxidant enzymes or small-molecule ROS scavengers have reinforced the idea that ROS are an important early trigger leading to mucositis. […] Inflammatory cytokines have been considered to play a critical role in the development of mucositis induced by chemotherapy and radiotherapy. […] Studies have also reported the application of commonly utilized pharmacological agents to treat mucositis, due to their inhibitory effects on cytokine production and/or secretion.
#3
https://journals.lww.com/co-supportiveandpalliativecare/fulltext/2024/06000/gastrointestinal_mucositis__a_sign_of_a__systemic_.4.aspx
Animal studies involving manipulation of IL-1, IL-18, or caspase-1 provide further support for a role of the inflammasome in mediating tissue injury during chemotherapy treatment. […] The gut microbiome is known to be altered by chemotherapy and radiotherapy, contributing to the severity of mucosal injury, and may be a predictive factor for risk of GIM development. […] It is evident and will not be discussed further that bloodstream infections (BSIs) especially during neutropenia can induce sepsis, a form of severe SIR. […] Given the critical role of IL-1 in neutrophil recruitment and other consequences of GIM, the inflammasome presents a compelling target for further research. […] Anakinra is a recombinant human IL-1 receptor antagonist (IL-1RA), which has been shown to alleviate intestinal mucositis in various preclinical models. […] A change of perspective based on cellular, animal, and clinical studies proposes that mucosal damage is largely the consequence of cumulative chemo/radiotherapy-induced biological mucosal changes overwhelming physiologic self-protective mechanisms.
#3 Mechanism-based management for mucositis: option for treating side eff | OTT
https://www.dovepress.com/mechanism-based-management-for-mucositis-option-for-treating-side-effe-peer-reviewed-fulltext-article-OTT
NF-B is a central regulator of genes induced by 5-FU, and the expression of NF-B-regulated genes correlates with a mucositis-related phenomenon. […] Therefore, targeting NF-B could be a good strategy to treat cancer cells and protect normal cells from cancer treatment. […] It has been demonstrated that apoptosis is critical for the development of mucositis. […] Therefore, agents developed for the prevention of mucositis should protect normal cells from cancer therapy-induced apoptotic cell death without impeding cancer therapy-induced apoptosis in cancer cells. […] Mucositis can be inhibited by the modulation of radiotherapy- or chemotherapy-induced pathways independently of cancer treatment, which provides an opportunity for the development of more targeted therapies and interventions.
#3 The Role of the Innate Immune Response in Oral Mucositis Pathogenesis
https://www.mdpi.com/1422-0067/24/22/16314
TLRs have been increasingly recognized as being important in mucositis pathogenesis, established through a range of studies focusing predominantly on lower gastrointestinal tract injury. […] All TLRs are expressed in the oral mucosa and appear to be upregulated during periods of inflammation, establishing their potential role in OM pathology. […] The oral microbiome is known to be altered by chemotherapy and radiotherapy, contributes to the severity of oral injury, and may be a predictive factor for risk of OM development. […] The mechanisms by which the microbiome exerts this influence have yet to be fully uncovered; however, evidence supports a bidirectional relationship between these oral microbial communities and the innate immune system. […] The introduction of germ-free mice in experimental research has elegantly confirmed the critical role of microbes in both OM development and shaping the innate immune system. […] The results of this study cannot confirm the microbial community responsible, with both the oral and gut microbiome hypothesized to play a role in OM development in isolation to one another and collectively.
#3 The Role of the Innate Immune Response in Oral Mucositis Pathogenesis
https://www.mdpi.com/1422-0067/24/22/16314
The innate immune system comprises barriers, cells, and humoral factors, which are responsible for control of homeostatic tolerance to commensal microbes as well as indiscriminate host responses to potential physiological threats. […] The constant threat of microbial breaches across the epithelium ensures that innate immunity is highly developed at the oral microbeâhost interface. […] A sophisticated network of interactions between the innate immune system and the oral microbiota creates a bidirectional relationship to maintain optimal physiology for both systems. […] Where there is a loss of spatial separation between surface microbial factors and the lamina propria, the result is activation of oral mucosal innate immune cells proper, including macrophages, dendritic cells, neutrophils, and innate lymphoid cells. […] In particular, type I macrophages have been associated with OM progression due to submucosal release of a range of proinflammatory cytokines and chemokines, including TNFÎ±, IL-1Î², IL-6, CXCL8, and MIP.
#3 The Role of the Innate Immune Response in Oral Mucositis Pathogenesis
https://www.mdpi.com/1422-0067/24/22/16314
The application of new insights into the role of innate immune responses on OM development is to direct research towards novel effective interventions. […] The risk with general depletion of microbes as a strategy to improve OM is the disruption to commensals that are required to maintain homeostasis and assist with mucosal repair processes through innate immune signaling. […] Given the inherent similarities in pathophysiology, investigating the efficacy of drugs that have shown promise in the treatment of intestinal mucositis in the context of OM represents an important avenue for future research. […] Considering this, along with the knowledge that IL-1Î²-induced epithelial barrier injury in the oral mucosa is a critical driver of OM development and progression, anakinra may hold promise in the treatment of OM.
#3 Novel Therapy Promising for Radiation-Induced Oral Mucositis | MedPage Today
https://www.medpagetoday.com/meetingcoverage/mhncs/109010
The first-in-class uridine phosphorylase inhibitor TK-90 almost completely eliminated severe oral mucositis (SOM) in patients with non-metastatic squamous cell carcinoma of the head and neck who underwent radiation therapy, a small randomized study showed. […] „Uridine is essential to the preservation of the health of the normal mucosa,” Saba explained. „By inhibiting uridine phosphorylase, uridine levels are restored in the mucosa, basically reducing the leakage in the mitochondria and, by doing that, protecting the mucosa from the effects of radiation and chemotherapy.” […] As for its mechanism of action compared with other mucositis-sparing agents, Saba pointed out that superoxide dismutase „quenches one type of free radical oxygen species, but when you give TK-90 it quenches the 20 to 30 different subtypes of oxygen species. […] „The premise is that you need to quench all of these subtypes in order to be successful,” he said. […] In the case of antibiotics, Saba observed that they act in the later stages of mucositis progression, whereas restoring uridine levels with TK-90 acts earlier.
#3 Implementation of Photobiomodulation for Radio or Chemo-Induced Mucositis – Clinical Oncology Journal (ISSN 2766-9882)
https://clinicaloncologyjournal.com/article/1000164/implementation-of-photobiomodulation-for-radio-or-chemo-induced-mucositis
PBM is defined as a mechanism, by which non-ionizing optical radiation in the spectral range of the visible or near infrared is absorbed by endogenous chromophores to trigger photo physical and photochemical events without causing thermal damage, resulting in physiological changes and therapeutic benefits. […] The wave of red or infrared light is absorbed by the mitochondria. This results in stimulation of cytochrome C, an increase in the production of Adenosine Triphosphate (ATP) and of Nitric Oxide (NO) with the consequence of an improvement of tissue perfusion, as well as in cell growth factors. […] Finally, PBM, reduces nociception secondary to the elimination of mediators of acute inflammation and increased axonal activity. […] Mucositis is described as erythema and painful ulcerative lesions of the oral mucosa observed in cancer patients treated with chemotherapy and/or radiotherapy.
#3 Implementation of Photobiomodulation for Radio or Chemo-Induced Mucositis – Clinical Oncology Journal (ISSN 2766-9882)
https://clinicaloncologyjournal.com/article/1000164/implementation-of-photobiomodulation-for-radio-or-chemo-induced-mucositis
Mucositis is a common side effect of chemotherapy and/or radiation therapy that causes pain, difficulty eating, salivation and eating disorders, oral ulcerations and even discontinuation of treatments. Its etiopathological origin is complex and multifactorial. […] PBM is interesting to prevent or treat mucositis, it is experiencing a growing boom in oncology. […] Several studies have used PBM, both preventive and therapeutic. The results showed the superiority of the prophylactic (preventive) application of PBM over the therapeutic approach. […] Despite ample evidence of the effectiveness of PBM, its place is still under discussion in therapeutic management, particularly because of the heterogeneity of protocols and lack of dosimetric data. […] The review by Zadik et al. established recommendations for PBM protocols in the prevention of oral mucositis in patients treated with hematology (transplantation), radiotherapy or radio chemotherapy for head and neck cancer.
#3 Mechanisms of PhotoBioModulation (PBM) focused on oral mucositis prevention and treatment: a scoping review | BMC Oral Health | Full Text
https://bmcoralhealth.biomedcentral.com/articles/10.1186/s12903-021-01574-4
Thirdly, it was hypothesized that PBM could have antagonist effects on ROS formation. […] The downstream intracellular responses are driven by photosignal transduction and amplification in response mostly to ATP, ROS and NO concentration change. […] AP-1 is the main signalling pathway generated after ATP increase. […] The activation of these signalling pathway results in transcription factors upregulating genes. NF-B is the main signalling pathway due to oxidative stress. […] At the tissue level, PBM for OM is used in order to accelerate and ensure each phase of the wound healing process. […] In short, PBM in near infra-red can lead to a reduction in inflammation through inflammatory markers and vascularisation. […] The effect of PBM on cancer cells is a controversial issue in the literature. Many studies found that PBM could enhance malignant cell proliferation; and biostimulation, suggesting that PBM had no protection effects.
#3 Therapeutic effect and mechanism of Daikenchuto in a model of methotrexate-induced acute small intestinal mucositis | PLOS One
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0283626
Daikenchuto (DKT) has positive therapeutic effects on improving various gastrointestinal disorders. […] The present study investigated whether or not DKT has a potential therapeutic effect on chemotherapy-induced acute small intestinal mucositis (CIM) in a rat model. […] Methotrexate (MTX) causes inhibition of growth and repair activities of epithelium and mucosa where the dividing and proliferating activities are increased, inducing CIM, which is the main reason for limiting further use of this drug or prompting its use. […] The anti-inflammatory effect of DKT are attributed to the fact that DKT manages the downregulation of cyclooxygenase 2 (COX-2), the upregulation of endogenous adrenomedullin (ADM), and the suppression of eosinophil infiltration. […] DKT protected against MTX-induced CIM in a rat model by reducing inflammation, stimulating cell proliferation, and stabilizing the mucosal barrier.
#3
https://link.springer.com/article/10.1007/s00520-019-04893-z
Mucositis research and treatment are a rapidly evolving field providing constant new avenues of research and potential therapies. […] Research momentum is accelerating for mucositis pathogenesis, and with this has come utilization of new models and interventions that target specific mechanisms of injury. […] Technological advances have the potential to revolutionize the field of mucositis research, although focused effort is needed to move rationally targeted interventions to the clinical setting.
#3 Mucositis: The Impact, Biology and Therapeutic Opportunities of Oral Mucositis – BioModels
https://biomodels.com/publication/mucositis-the-impact-biology-and-therapeutic-opportunities-of-oral-mucositis/
Mucositis: The Impact, Biology and Therapeutic Opportunities of Oral Mucositis […] Despite being regularly reported and documented as one of the worst side effects of cancer therapy, relatively little was appreciated about the complexities of mucositis pathogenesis until relatively recently. […] ongoing research is leading to a comprehensive understanding of the biology of mucositis, which has resulted in the development of novel interventions. […] the fact that the first registered anti-OM agent derived its efficacy from its pleotropic activities was conceptually demonstrative of the therapeutic potential of drugs that selectively interfere with mucositis pathogenesis. […] A number of eclectic molecules, all designed to interfere with pathways that lead to injury are in pre-clinical and clinical development.
#4 Pathogenesis and Amelioration of Radiation-Induced Oral Mucositis
https://pmc.ncbi.nlm.nih.gov/articles/PMC8931694/
A multiphase process underlies the development of mucositis of the upper aerodigestive tract, beginning with cytotoxicity induced directly by ionizing radiation. […] Ionizing radiation results in direct DNA damage to cells within the RT field. […] Other effects of ionizing radiation include single strand breaks and elimination of bases at certain sites which contribute to DNA destabilization. […] Nevertheless, repeated insult to DNA inhibits cellular transcription and replication which over a multi-week course of RT, results in death of normal tissues. […] The second step in RT-mediated OM involves potentiation of cytotoxicity by reactive oxygen species (ROS). […] Under exogenous stress, high levels of ROS are produced which overcome cellular antioxidizing capabilities and perpetuates DNA damage.
#4 Oral mucositis: the hidden side of cancer therapy | Journal of Experimental & Clinical Cancer Research | Full Text
https://jeccr.biomedcentral.com/articles/10.1186/s13046-020-01715-7
The released TNF-Î±, indeed, initiates the activation of the mitogen activated protein kinase (MAPK) on target cells and, in the same time, sustains NF-ÎºB activity. […] Clinical manifestations of mucositis are appreciable at the fourth stage of the inflammation process, the ulceration phase. […] During this stage, mucosa and sub mucosal integrity is compromised, patients complain of pain and may need caregivers management. […] The presence of breaks in the submucosa, allows several microorganisms, symbiotic inhabitant of the healthy mucosa, to invade this tissue district leading to mononucler-infiltrating cells-mediated inflammation response, thus promoting new pro-inflammatory cytokines release that amplify expression of pro-apoptotic mediators and increase tissue damage. […] Mucositis is an acute event that mostly self-resolves as the anticancer treatment ends.
#4 Pathogenesis and Amelioration of Radiation-Induced Oral Mucositis
https://pmc.ncbi.nlm.nih.gov/articles/PMC8931694/
Over the first 12 weeks of RT, the cytotoxic effects of ionizing radiation, inflammation, and ROS-mediated DNA damage result in gradual apoptosis of mucosal epithelial cells within the stratified squamous epithelium and lamina propria layers. […] The outcome is mucosal ulceration and formation of pseudomembranes which marks the characteristic appearance of OM. […] The ulceration stage is the most painful due to loss of the epithelium covering the nerve endings in the lamina propria layer. […] Healing takes place over the course of weeks to months once the initial insult from radiation is removed and cells in the basal layer are signaled to proliferate and differentiate into healthy stratified squamous epithelium.
#4 Mucositis – Wikipedia
https://en.wikipedia.org/wiki/Mucositis
Bacteria colonise ulcers and their cell wall products infiltrate the submucosa. This leads to activation of tissue macrophages, which causes further production of pro-inflammatory cytokines. In addition, bacteria-mediated immune signalling via Toll-like receptors (TLRs) ambiguously shapes chemotherapy-induced genotoxic damage in the gastrointestinal tract. […] Signalling from the extracellular matrix of the submucosa results in epithelial proliferation and differentiation, and thus a thickening of the epithelium. The local oral flora are reinstated.
#4 Mechanism-based management for mucositis: option for treating side eff | OTT
https://www.dovepress.com/mechanism-based-management-for-mucositis-option-for-treating-side-effe-peer-reviewed-fulltext-article-OTT
The cellular ROS level is controlled by a balance between ROS generation and their elimination by antioxidant systems consisting of antioxidant enzymes and endogenous antioxidants. […] Many studies demonstrated that the enhancement of antioxidative activity protects against radiation-induced mucositis. […] Therefore, studies using antioxidant enzymes or small-molecule ROS scavengers have reinforced the idea that ROS are an important early trigger leading to mucositis. […] Inflammatory cytokines have been considered to play a critical role in the development of mucositis induced by chemotherapy and radiotherapy. […] Studies have also reported the application of commonly utilized pharmacological agents to treat mucositis, due to their inhibitory effects on cytokine production and/or secretion.
#4 Mechanism-based management for mucositis: option for treating side eff | OTT
https://www.dovepress.com/mechanism-based-management-for-mucositis-option-for-treating-side-effe-peer-reviewed-fulltext-article-OTT
NF-B is a central regulator of genes induced by 5-FU, and the expression of NF-B-regulated genes correlates with a mucositis-related phenomenon. […] Therefore, targeting NF-B could be a good strategy to treat cancer cells and protect normal cells from cancer treatment. […] It has been demonstrated that apoptosis is critical for the development of mucositis. […] Therefore, agents developed for the prevention of mucositis should protect normal cells from cancer therapy-induced apoptotic cell death without impeding cancer therapy-induced apoptosis in cancer cells. […] Mucositis can be inhibited by the modulation of radiotherapy- or chemotherapy-induced pathways independently of cancer treatment, which provides an opportunity for the development of more targeted therapies and interventions.
#4 The Role of the Innate Immune Response in Oral Mucositis Pathogenesis
https://www.mdpi.com/1422-0067/24/22/16314
TLRs have been increasingly recognized as being important in mucositis pathogenesis, established through a range of studies focusing predominantly on lower gastrointestinal tract injury. […] All TLRs are expressed in the oral mucosa and appear to be upregulated during periods of inflammation, establishing their potential role in OM pathology. […] The oral microbiome is known to be altered by chemotherapy and radiotherapy, contributes to the severity of oral injury, and may be a predictive factor for risk of OM development. […] The mechanisms by which the microbiome exerts this influence have yet to be fully uncovered; however, evidence supports a bidirectional relationship between these oral microbial communities and the innate immune system. […] The introduction of germ-free mice in experimental research has elegantly confirmed the critical role of microbes in both OM development and shaping the innate immune system. […] The results of this study cannot confirm the microbial community responsible, with both the oral and gut microbiome hypothesized to play a role in OM development in isolation to one another and collectively.
#4 The Role of the Innate Immune Response in Oral Mucositis Pathogenesis
https://www.mdpi.com/1422-0067/24/22/16314
The innate immune system comprises barriers, cells, and humoral factors, which are responsible for control of homeostatic tolerance to commensal microbes as well as indiscriminate host responses to potential physiological threats. […] The constant threat of microbial breaches across the epithelium ensures that innate immunity is highly developed at the oral microbeâhost interface. […] A sophisticated network of interactions between the innate immune system and the oral microbiota creates a bidirectional relationship to maintain optimal physiology for both systems. […] Where there is a loss of spatial separation between surface microbial factors and the lamina propria, the result is activation of oral mucosal innate immune cells proper, including macrophages, dendritic cells, neutrophils, and innate lymphoid cells. […] In particular, type I macrophages have been associated with OM progression due to submucosal release of a range of proinflammatory cytokines and chemokines, including TNFÎ±, IL-1Î², IL-6, CXCL8, and MIP.
#4 Mechanisms of PhotoBioModulation (PBM) focused on oral mucositis prevention and treatment: a scoping review | BMC Oral Health | Full Text
https://bmcoralhealth.biomedcentral.com/articles/10.1186/s12903-021-01574-4
Thirdly, it was hypothesized that PBM could have antagonist effects on ROS formation. […] The downstream intracellular responses are driven by photosignal transduction and amplification in response mostly to ATP, ROS and NO concentration change. […] AP-1 is the main signalling pathway generated after ATP increase. […] The activation of these signalling pathway results in transcription factors upregulating genes. NF-B is the main signalling pathway due to oxidative stress. […] At the tissue level, PBM for OM is used in order to accelerate and ensure each phase of the wound healing process. […] In short, PBM in near infra-red can lead to a reduction in inflammation through inflammatory markers and vascularisation. […] The effect of PBM on cancer cells is a controversial issue in the literature. Many studies found that PBM could enhance malignant cell proliferation; and biostimulation, suggesting that PBM had no protection effects.
#4 Therapeutic effect and mechanism of Daikenchuto in a model of methotrexate-induced acute small intestinal mucositis | PLOS One
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0283626
Daikenchuto (DKT) has positive therapeutic effects on improving various gastrointestinal disorders. […] The present study investigated whether or not DKT has a potential therapeutic effect on chemotherapy-induced acute small intestinal mucositis (CIM) in a rat model. […] Methotrexate (MTX) causes inhibition of growth and repair activities of epithelium and mucosa where the dividing and proliferating activities are increased, inducing CIM, which is the main reason for limiting further use of this drug or prompting its use. […] The anti-inflammatory effect of DKT are attributed to the fact that DKT manages the downregulation of cyclooxygenase 2 (COX-2), the upregulation of endogenous adrenomedullin (ADM), and the suppression of eosinophil infiltration. […] DKT protected against MTX-induced CIM in a rat model by reducing inflammation, stimulating cell proliferation, and stabilizing the mucosal barrier.
#5 Oral mucositis: the hidden side of cancer therapy | Journal of Experimental & Clinical Cancer Research | Full Text
https://jeccr.biomedcentral.com/articles/10.1186/s13046-020-01715-7
The released TNF-Î±, indeed, initiates the activation of the mitogen activated protein kinase (MAPK) on target cells and, in the same time, sustains NF-ÎºB activity. […] Clinical manifestations of mucositis are appreciable at the fourth stage of the inflammation process, the ulceration phase. […] During this stage, mucosa and sub mucosal integrity is compromised, patients complain of pain and may need caregivers management. […] The presence of breaks in the submucosa, allows several microorganisms, symbiotic inhabitant of the healthy mucosa, to invade this tissue district leading to mononucler-infiltrating cells-mediated inflammation response, thus promoting new pro-inflammatory cytokines release that amplify expression of pro-apoptotic mediators and increase tissue damage. […] Mucositis is an acute event that mostly self-resolves as the anticancer treatment ends.
#5 Mechanism-based management for mucositis: option for treating side eff | OTT
https://www.dovepress.com/mechanism-based-management-for-mucositis-option-for-treating-side-effe-peer-reviewed-fulltext-article-OTT
The cellular ROS level is controlled by a balance between ROS generation and their elimination by antioxidant systems consisting of antioxidant enzymes and endogenous antioxidants. […] Many studies demonstrated that the enhancement of antioxidative activity protects against radiation-induced mucositis. […] Therefore, studies using antioxidant enzymes or small-molecule ROS scavengers have reinforced the idea that ROS are an important early trigger leading to mucositis. […] Inflammatory cytokines have been considered to play a critical role in the development of mucositis induced by chemotherapy and radiotherapy. […] Studies have also reported the application of commonly utilized pharmacological agents to treat mucositis, due to their inhibitory effects on cytokine production and/or secretion.
#5 The Role of the Innate Immune Response in Oral Mucositis Pathogenesis
https://www.mdpi.com/1422-0067/24/22/16314
The innate immune system comprises barriers, cells, and humoral factors, which are responsible for control of homeostatic tolerance to commensal microbes as well as indiscriminate host responses to potential physiological threats. […] The constant threat of microbial breaches across the epithelium ensures that innate immunity is highly developed at the oral microbeâhost interface. […] A sophisticated network of interactions between the innate immune system and the oral microbiota creates a bidirectional relationship to maintain optimal physiology for both systems. […] Where there is a loss of spatial separation between surface microbial factors and the lamina propria, the result is activation of oral mucosal innate immune cells proper, including macrophages, dendritic cells, neutrophils, and innate lymphoid cells. […] In particular, type I macrophages have been associated with OM progression due to submucosal release of a range of proinflammatory cytokines and chemokines, including TNFÎ±, IL-1Î², IL-6, CXCL8, and MIP.
#5 The Role of the Innate Immune Response in Oral Mucositis Pathogenesis
https://www.mdpi.com/1422-0067/24/22/16314
TLRs have been increasingly recognized as being important in mucositis pathogenesis, established through a range of studies focusing predominantly on lower gastrointestinal tract injury. […] All TLRs are expressed in the oral mucosa and appear to be upregulated during periods of inflammation, establishing their potential role in OM pathology. […] The oral microbiome is known to be altered by chemotherapy and radiotherapy, contributes to the severity of oral injury, and may be a predictive factor for risk of OM development. […] The mechanisms by which the microbiome exerts this influence have yet to be fully uncovered; however, evidence supports a bidirectional relationship between these oral microbial communities and the innate immune system. […] The introduction of germ-free mice in experimental research has elegantly confirmed the critical role of microbes in both OM development and shaping the innate immune system. […] The results of this study cannot confirm the microbial community responsible, with both the oral and gut microbiome hypothesized to play a role in OM development in isolation to one another and collectively.
#5 Mechanisms of PhotoBioModulation (PBM) focused on oral mucositis prevention and treatment: a scoping review | BMC Oral Health | Full Text
https://bmcoralhealth.biomedcentral.com/articles/10.1186/s12903-021-01574-4
Thirdly, it was hypothesized that PBM could have antagonist effects on ROS formation. […] The downstream intracellular responses are driven by photosignal transduction and amplification in response mostly to ATP, ROS and NO concentration change. […] AP-1 is the main signalling pathway generated after ATP increase. […] The activation of these signalling pathway results in transcription factors upregulating genes. NF-B is the main signalling pathway due to oxidative stress. […] At the tissue level, PBM for OM is used in order to accelerate and ensure each phase of the wound healing process. […] In short, PBM in near infra-red can lead to a reduction in inflammation through inflammatory markers and vascularisation. […] The effect of PBM on cancer cells is a controversial issue in the literature. Many studies found that PBM could enhance malignant cell proliferation; and biostimulation, suggesting that PBM had no protection effects.
#5 Mechanism-based management for mucositis: option for treating side eff | OTT
https://www.dovepress.com/mechanism-based-management-for-mucositis-option-for-treating-side-effe-peer-reviewed-fulltext-article-OTT
NF-B is a central regulator of genes induced by 5-FU, and the expression of NF-B-regulated genes correlates with a mucositis-related phenomenon. […] Therefore, targeting NF-B could be a good strategy to treat cancer cells and protect normal cells from cancer treatment. […] It has been demonstrated that apoptosis is critical for the development of mucositis. […] Therefore, agents developed for the prevention of mucositis should protect normal cells from cancer therapy-induced apoptotic cell death without impeding cancer therapy-induced apoptosis in cancer cells. […] Mucositis can be inhibited by the modulation of radiotherapy- or chemotherapy-induced pathways independently of cancer treatment, which provides an opportunity for the development of more targeted therapies and interventions.
#6 The Role of the Innate Immune Response in Oral Mucositis Pathogenesis
https://www.mdpi.com/1422-0067/24/22/16314
TLRs have been increasingly recognized as being important in mucositis pathogenesis, established through a range of studies focusing predominantly on lower gastrointestinal tract injury. […] All TLRs are expressed in the oral mucosa and appear to be upregulated during periods of inflammation, establishing their potential role in OM pathology. […] The oral microbiome is known to be altered by chemotherapy and radiotherapy, contributes to the severity of oral injury, and may be a predictive factor for risk of OM development. […] The mechanisms by which the microbiome exerts this influence have yet to be fully uncovered; however, evidence supports a bidirectional relationship between these oral microbial communities and the innate immune system. […] The introduction of germ-free mice in experimental research has elegantly confirmed the critical role of microbes in both OM development and shaping the innate immune system. […] The results of this study cannot confirm the microbial community responsible, with both the oral and gut microbiome hypothesized to play a role in OM development in isolation to one another and collectively.
#6 Mechanisms of PhotoBioModulation (PBM) focused on oral mucositis prevention and treatment: a scoping review | BMC Oral Health | Full Text
https://bmcoralhealth.biomedcentral.com/articles/10.1186/s12903-021-01574-4
Thirdly, it was hypothesized that PBM could have antagonist effects on ROS formation. […] The downstream intracellular responses are driven by photosignal transduction and amplification in response mostly to ATP, ROS and NO concentration change. […] AP-1 is the main signalling pathway generated after ATP increase. […] The activation of these signalling pathway results in transcription factors upregulating genes. NF-B is the main signalling pathway due to oxidative stress. […] At the tissue level, PBM for OM is used in order to accelerate and ensure each phase of the wound healing process. […] In short, PBM in near infra-red can lead to a reduction in inflammation through inflammatory markers and vascularisation. […] The effect of PBM on cancer cells is a controversial issue in the literature. Many studies found that PBM could enhance malignant cell proliferation; and biostimulation, suggesting that PBM had no protection effects.