Bliznowiec – Patofizjologia i mechanizm

Bliznowiec
Patofizjologia i mechanizm

Bliznowiec (keloid) jest wynikiem patologicznego procesu gojenia ran, charakteryzującym się nadmierną proliferacją fibroblastów i nadprodukcją kolagenu, zwłaszcza typu I i III, co prowadzi do powstania nieprawidłowej, przerosłej tkanki bliznowatej wykraczającej poza granice pierwotnej rany. Synteza kolagenu w bliznowcach jest około 20-krotnie wyższa niż w zdrowej skórze i 3-krotnie wyższa niż w bliznach przerostowych. Patogeneza obejmuje dysregulację kluczowych szlaków sygnałowych, takich jak TGF-β/Smad, JAK/STAT, MAPK, PI3K/AKT oraz mechanotransdukcję przez integryny i kinazę ogniska adhezyjnego (FAK). W bliznowcach obserwuje się także zwiększoną aktywność metaboliczną, hipoksję lokalną oraz przewlekły stan zapalny z udziałem makrofagów M2, komórek T i mastocytów, co sprzyja utrzymaniu nadmiernej produkcji macierzy pozakomórkowej (ECM) i zaburzeniu równowagi między syntezą a degradacją kolagenu.

Patogeneza bliznowca (keloid)

Bliznowiec (keloid) powstaje w wyniku nieprawidłowego procesu gojenia się ran w odpowiedzi na uraz skóry lub stan zapalny. Rozwój bliznowca zależy od czynników genetycznych i środowiskowych. Wyższa częstość występowania jest obserwowana u osób o ciemniejszym kolorze skóry pochodzenia afrykańskiego, azjatyckiego i latynoamerykańskiego. W patogenezie bliznowców zaangażowane są nadaktywne fibroblasty produkujące duże ilości kolagenu i czynników wzrostu. W rezultacie, klasyczne badanie histologiczne wykazuje duże, nieprawidłowe, zhialinizowane wiązki kolagenu określane jako kolagen keloidalny oraz liczne fibroblasty.¹

Nieprawidłowy proces gojenia ran

Bliznowce są wynikiem zaburzonego procesu gojenia ran. Standardowe gojenie ran składa się z trzech faz: (1) zapalnej, (2) fibroblastycznej i (3) dojrzewania. W przypadku bliznowców, faza fibroblastyczna trwa nieprzerwanie, prowadząc do charakterystycznych zmian klinicznych i histopatologicznych.¹ Fibroblasty keloidalne wykazują zwiększoną aktywność proliferacyjną, utrzymują się dłużej i mają niższy wskaźnik apoptozy w porównaniu do typowego procesu gojenia ran. Prowadzi to do nadmiernej produkcji kolagenu i cytokin. Synteza kolagenu w bliznowcach jest 20 razy większa niż w zdrowej skórze i 3 razy większa niż w bliźnie przerostowej.²

Proces powstawania bliznowców jest wciąż słabo poznany. Wiadomo, że jest on wywoływany urazem skóry u predysponowanych osób. Urazy skóry mogą być wtórne do trądziku, zapalenia mieszków włosowych, piercingu, oparzeń, ran ciętych i ran chirurgicznych.¹ Tkanka bliznowca wykazuje większą aktywność metaboliczną i zużywa więcej tlenu niż normalna tkanka blizny. Prowadzi to do względnego stanu hipoksji w fibroblastach keloidalnych.¹

Czynniki wzrostu i cytokiny

Transformujący czynnik wzrostu beta (TGF-β) i płytkopochodny czynnik wzrostu (PDGF) są uważane za główne czynniki napędzające ten proces. TGF-β, integralny element gojenia ran, promuje chemotaksję fibroblastów do miejsca zapalenia i produkuje kolagen. Dysregulacja tego szlaku prowadzi do włóknienia i nieprawidłowej odpowiedzi bliznowatej.² TGF-β1 jest wielofunkcyjną cytokiną zaangażowaną w patogenezę bliznowców ze względu na swoją rolę jako kluczowy regulator fibrogenezy. TGF-β1 ma działanie pro-fibrotyczne poprzez zwiększanie proliferacji ludzkich komórek fibroblastów, zwiększanie syntezy kolagenu i zmniejszanie degradacji kolagenu.¹

Fibroblasty keloidalne, w porównaniu z fibroblastami wyizolowanymi z normalnej rany, nadproduktywnie wytwarzają prokolagen typu I i wykazują wyższe poziomy niektórych czynników wzrostu, w tym: czynnika wzrostu śródbłonka naczyniowego (VEGF), transformującego czynnika wzrostu 1 i 2 (TGF-1 i TGF-2), oraz płytkopochodnego czynnika wzrostu (PDGF).¹

Szlaki sygnałowe w patogenezie bliznowca

Zaburzenia regulacji szlaków molekularnych, szczególnie szlaku sygnałowego TGF-β/Smad, odgrywają centralną rolę w patogenezie bliznowca. Inne szlaki, w tym JAK/STAT, MAPK, PI3K/AKT, oraz szlaki transdukcji mechanicznej (integryny, YAP/TAZ), również przyczyniają się do nieprawidłowego zachowania fibroblastów keloidalnych.¹

Szlak JAK-STAT wpływa na kilka czynników wzrostu zaangażowanych w patogenezę bliznowca. Inhibicja JAK2 zmniejsza ekspresję czynnika wzrostu tkanki łącznej (CTGF), nawet w obecności stymulacji TGF-β, podkreślając rolę tego szlaku we włóknieniu.² Szlak MAPK oddziałuje ze szlakiem TGF-β/Smad, wpływając na proliferację fibroblastów i akumulację kolagenu. Szlak PI3K/AKT reguluje proliferację fibroblastów i ich różnicowanie w miofibroblasty, przyczyniając się do fenotypu włóknienia bliznowców.¹

Szlak NF-κB ma ścisły związek z nieprawidłową proliferacją i nadmierną produkcją macierzy pozakomórkowej w fibroblastach keloidalnych. Szlak sygnałowy STAT3 służy jako kluczowy regulator różnicowania komórek, apoptozy, zapalenia i włóknienia.¹

Rola mechanotransdukcji

Podwyższone lokalne siły mechaniczne są powiązane z pojawianiem się nietypowego włóknienia skóry, przy czym bliznowce powszechnie występują w regionach poddawanych ciągłemu napięciu.² Szlak kinazy ogniska adhezyjnego (FAK), znany ze swojej roli w mechanotransdukcji, został uznany za nieprawidłowo aktywowany w tkankach bliznowca, przyczyniając się do przyspieszenia włóknienia skóry.²

Napięcie w obszarze rany znacząco wpływa na ilość i właściwości tkanki bliznowatej bardziej niż jakiekolwiek inne czynniki. Bliznowce są często widoczne na przedniej części klatki piersiowej i w okolicach łopatek, ale rzadko na skórze głowy i przedniej części dolnych kończyn; ten wzorzec ściśle koreluje z częstotliwością, z jaką te obszary ciała są poddawane lokalnym naprężeniom fizycznym lub ruchom.¹

Zmiany mikrostruktury tkanki bliznowca

Histologicznie, bliznowce wykazują zwiększoną zawartość kolagenu i glikozaminoglikanów z wrzecienowatymi pęczkami zgrubiałych zhialinizowanych wiązek kolagenu.¹ Włókna kolagenowe w bliznowcach są bardziej nieregularne, nieprawidłowo grube i mają jednokierunkowe włókna ułożone w orientacji o wysokim napięciu. Aktywność kolagenazy, tj. prolilowej hydroksylazy, w bliznowcach jest 14 razy większa niż zarówno w bliznach przerostowych, jak i normalnych bliznach.¹

Kolagen typu III, siarczan chondroityny 4 i zawartość glikozaminoglikanów są wyższe w bliznowcach niż zarówno w bliznach przerostowych, jak i normalnych. Sieciowanie kolagenu jest większe w normalnych bliznach, podczas gdy bliznowce mają niedojrzałe połączenia krzyżowe, które nie tworzą normalnej stabilności blizny.¹

Zmiany komórkowe w tkance bliznowca

Zwiększona liczba fibroblastów, rekrutowanych do miejsca uszkodzenia tkanki, syntetyzuje nadmiar fibronektyny, a ekspresja receptorów jest zwiększona w bliznowcach. Populacja komórek tucznych w obrębie blizn keloidowych również jest zwiększona, a co za tym idzie, zwiększona jest produkcja histaminy.¹ Obecność komórek tucznych i histaminy w tkance bliznowca, zwłaszcza we wczesnym etapie przebiegu klinicznego, wyjaśnia świąd związany z tymi zmianami.²

Badanie przeprowadzone przez Touchi i wsp. wykazało, że centralna część bliznowców jest poważnie niedokrwiona. Badacze stwierdzili większą ekspresję czynnika indukowanego hipoksją-1, a także mniejszą gęstość naczyń w centrum niż na obwodzie tych zmian.² Badania immunohistochemiczne bliznowców wykazują zwiększoną produkcję czynnika martwicy nowotworów alfa (TNF-alfa), interferonu beta (IFN-beta) i interleukiny-6. Produkcja IFN-alfa, IFN-gamma i TNF-beta jest zmniejszona. IFN-alfa, IFN-beta i IFN-gamma zmniejszają syntezę kolagenu typów I, III i prawdopodobnie VI przez fibroblasty.³

Porównanie z bliznami przerostowymi

Tkanka bliznowca, w przeciwieństwie do blizn przerostowych, składa się głównie z niezorganizowanego kolagenu typu I i III, zawierającego słabo barwiące się hipokomórkowe pęczki kolagenu bez guzków ani nadmiaru miofibroblastów.¹ Obie zmiany stanowią aberracje w podstawowych procesach gojenia ran, w których istnieje wyraźny brak równowagi między fazami anabolicznymi i katabolicznymi; jednak bliznowce wydają się być bardziej trwałym i agresywnym zaburzeniem włóknienia niż blizny przerostowe.¹

Blizny keloidalne różnią się od blizn przerostowych wyższą ekspresją jądrowego antygenu komórek proliferujących, co wskazuje na większą proliferację fibroblastów w bliznowcach. Opóźniona apoptoza fibroblastów może być odpowiedzialna za charakterystyczny niedobór fibroblastów w centrum bliznowców: możliwe, że to opóźnienie pozwala komórkom na wytworzenie ogromnych ilości macierzy pozakomórkowej (ECM) zanim ostatecznie znikną, pozostawiając tylko bezkomórkową masę kolagenową.¹

Mechanizmy zapalenia i aktywacji komórkowej

Dowody wskazują na dłuższy okres zapalny, z naciekiem komórek odpornościowych obecnym w tkance blizny bliznowców, czego konsekwencją może być zwiększona aktywność fibroblastów z większym i bardziej trwałym osadzaniem ECM.² Przekształcenie skrzepu rany w tkankę ziarninową wymaga więc delikatnej równowagi między osadzaniem białek ECM a lizą, a gdy proces ten zostanie zakłócony, pojawiają się nieprawidłowości w bliznowaceniu, co prowadzi do powstawania bliznowców lub blizn przerostowych.³

Rola komórek układu odpornościowego

Najnowsze dowody sugerują, że to nie tylko nasilenie stanu zapalnego predysponuje osoby do bliznowców i blizn przerostowych, ale także rodzaj odpowiedzi immunologicznej.¹ Komórki odpornościowe obecne w mikrośrodowisku bliznowca, w tym makrofagi, komórki T i komórki tuczne, odgrywają kluczową rolę w inicjacji i utrzymywaniu bliznowców.¹

Infiltracja makrofagów M2 jest znacznie wyższa niż makrofagów M1 w tkance bliznowca. Komórki Th1 mogą osłabiać włóknienie tkanki poprzez uwalnianie IFN-γ.¹ Zwiększona liczba komórek tucznych była raportowana podczas aktywnego okresu powstawania blizn przerostowych i bliznowców.¹

Rola keratynocytów i miofibroblastów

Keratynocyty mogą pośredniczyć w zachowaniu fibroblastów podczas gojenia się ran poprzez ich wydzielanie, aktywację lub inhibicję czynników wzrostu, takich jak TGF-β.¹ Miofibroblasty są kluczowymi komórkami efektorowymi powodującymi rozwój i wzrost bliznowca.²

Centralnym elementem powstawania blizny przerostowej i tkanki bliznowca jest zmiana fenotypu fibroblastów.¹ W porównaniu do normalnych fibroblastów skóry, fibroblasty pochodzące z bliznowców wykazują zwiększoną produkcję kolagenu i metaloproteinaz macierzy.¹

Rola czynników genetycznych w patogenezie bliznowca

Do tej pory nie zidentyfikowano konkretnego genu powiązanego z rozwojem bliznowców.¹ Jednak w niektórych przypadkach tendencja do tworzenia bliznowców wydaje się występować rodzinnie. Mutacja w genie znanym jako gen NEDD4 może wskazywać, że dana osoba ma predyspozycję do tworzenia bliznowców.¹

Bliznowce uważane są za chorobę genetyczną ze względu na silną genetyczną podatność na tworzenie bliznowców, ponieważ występują głównie u ludzi pochodzenia afrykańskiego i azjatyckiego, pojawiają się rodzinnie i zostały stwierdzone u bliźniąt.¹ Złożoność i różnice w trybach dziedziczenia i rodzinnego bliznowacenia odzwierciedlają zmienność i heterogeniczność w podatności genetycznej, historii rodzinnej, składzie genetycznym bliźniąt, wzorcach dziedziczenia, powiązaniu, asocjacjach genetycznych, zmianie ekspresji genów i odpowiednich szlaków genów, polimorfizmie HLA (ludzki antygen leukocytarny), epigenetyce i populacjach etnicznych.²

Modyfikacje epigenetyczne

Nagromadzone dowody wykazały, że wiele różnorodnych i odwracalnych modyfikacji epigenetycznych, reprezentowanych przez metylację DNA, modyfikację histonów i niekodujące RNA (ncRNA), odgrywa kluczową rolę w regulacji genów i funkcji fibroblastów w bliznowcu.¹ Ważne jest to, że nieprawidłowa modyfikacja epigenetyczna manipuluje wieloma zachowaniami fibroblastów pochodzących z bliznowca, które służą jako główne składniki komórkowe w tkance skóry bliznowca, w tym proliferacją, migracją, apoptozą i różnicowaniem.¹

Uważa się, że dysregulacja epigenetyczna prowadzi do braku równowagi w procesie naprawy i regeneracji tkanki bliznowatej.¹ Powyższe badania dostarczają dowodów na metylację DNA w regulacji stabilnego wzorca różnicowej ekspresji genów w powstawaniu bliznowca.¹

Fizjopatologia mechanizmów naprawy tkanki

Niedawno wykazano, że apoptoza odgrywa kluczową rolę w przejściu od tkanki ziarninowej do tworzenia blizny po urazie tkanki.² W tkance blizny przerostowej u pacjentów z ciężkimi oparzeniami autorzy stwierdzili jednak, że maksymalna apoptoza wystąpiła znacznie później.¹

W badaniu blizn pooperacyjnych u pacjentów bez jakiejkolwiek historii nadmiernego bliznowacenia, Bond i współpracownicy stwierdzili postępujące zmiany w odniesieniu do struktury skóry właściwej, ale utrzymującą się gęstość fibroblastyczną w 4 miesiącu, wskazując na istnienie ciągłego stanu o wysokim obrocie podobnego do fazy proliferacyjnej.²

Zaburzenia metabolizmu macierzy pozakomórkowej

Poziomy ekspresji MMP (metaloproteinaz macierzy) w normalnych komórkach są niskie i umożliwiają zdrową przebudowę tkanki łącznej.² Brak równowagi w ekspresji MMP został powiązany z wieloma stanami patologicznymi, takimi jak włóknienie skóry właściwej oraz inwazja i przerzuty nowotworów.³

Decorin reguluje organizację włókien, włókienek i pęczków włókien kolagenu i wykazano, że jest zmniejszony o około 75% w bliznach przerostowych.⁴ Nadmierna synteza kolagenu i innych komponentów włóknistych spowodowana zaburzeniami i brakiem równowagi w metabolizmie macierzy pozakomórkowej (ECM) może prowadzić do tworzenia blizn, a nie do ich destrukcji.¹

W tym złożonym procesie gojenia ran, TGF-β odgrywa kluczową rolę. Jednak w przeciwieństwie do normalnego procesu gojenia ran, w bliznach obserwuje się nieprawidłową ekspresję fibroblastów, która jest związana z mediatorami zapalnymi, które mogą stymulować fibroblasty, takimi jak VEGF i inhibitor aktywatora plazminogenu (PAI)-1.²

Czynniki ryzyka i wyzwalające bliznowce

Bliznowce i blizny przerostowe (HTS) powstają w wyniku przerostu tkanki włóknistej po wygojeniu urazu skóry i powodują chorobowość.¹ Bliznowce wykraczają poza granice pierwotnej rany, zwykle nie ustępują samoistnie i mają tendencję do nawracania po wycięciu, podczas gdy HTS nie rozszerzają się poza granice pierwotnego urazu i mogą ulec częściowej samoistnej regresji.¹

Czynniki osobnicze i środowiskowe

Na powstanie blizn wpływają zarówno czynniki wewnętrzne (takie jak rozmiar, głębokość, lokalizacja i czas gojenia) związane z samą raną, jak i czynniki zewnętrzne (takie jak genetyka, wiek i hormony) związane z cechami osobniczymi.¹ Najważniejszymi czynnikami przyczyniającymi się do powstawania blizn są rozmiar i głębokość rany.²

Szybkość gojenia ran jest uzależniona od czynników genetycznych. Występowanie blizn jest ściśle związane z genetyką. Ogólnie rzecz biorąc, blizny są bardziej powszechne u młodszych osób, zazwyczaj w wieku od 11 do 30 lat, niż u starszych dorosłych.³

Stres psychologiczny może potencjalnie być czynnikiem ryzyka powstawania blizn. W rzeczywistości wiadomo, że bliznowce mogą być wyzwalane lub zaostrzane przez czynniki psychologiczne.¹

Rodzaje urazów wyzwalających bliznowce

Najważniejszym czynnikiem ryzyka rozwoju nieprawidłowych blizn, takich jak bliznowce, jest gojenie rany przez ziarninowanie, szczególnie jeśli czas gojenia jest dłuższy niż 3 tygodnie. Rany poddane przedłużonemu stanowi zapalnemu, czy to z powodu ciała obcego, infekcji, oparzenia czy niewłaściwego zamknięcia rany, są narażone na nieprawidłowe tworzenie blizn. Obszary przewlekłego zapalenia, takie jak miejsce kolczyka lub miejsce powtarzających się urazów, są również bardziej podatne na rozwój bliznowców. Czasami bliznowce powstają samoistnie bez historii urazu.³

Bliznowce powstają w wyniku urazu skóry i podrażnienia, w tym urazów, ugryzień owadów, oparzeń, zabiegów chirurgicznych, kriochirurgii, terapii miejscowych (np. imikwimod), trądziku, zakażeń (np. półpasiec) i szczepień.¹

Co charakterystyczne, powierzchowne urazy, które nie sięgają skóry właściwej, nigdy nie powodują bliznowacenia i powstawania blizn przerostowych. Sugeruje to, że te patologiczne blizny są spowodowane urazem tej warstwy skóry i następującym po nim nieprawidłowym gojeniem się ran, które charakteryzuje się ciągłym i histologicznie zlokalizowanym stanem zapalnym.¹

Podsumowanie mechanizmów patogenetycznych

Patogeneza bliznowca jest złożonym procesem, obejmującym dynamiczne współdziałanie różnych komórek, cytokin i szlaków sygnałowych. Głębsze zrozumienie tych mechanizmów otwiera drogi do ukierunkowanych interwencji terapeutycznych mających na celu przerwanie kaskady zdarzeń prowadzących do tworzenia bliznowca.¹

Rozłożenie zawiłości patologii bliznowca przybliża nas do bardziej skutecznych i spersonalizowanych podejść do leczenia tego trudnego schorzenia dermatologicznego.¹ Patogeneza bliznowca jest wieloczynnikowa i obejmuje predyspozycje genetyczne, dysregulację odpowiedzi immunologicznej i nieprawidłowe procesy gojenia ran. Mimo intensywnych badań, dokładne mechanizmy pozostają słabo poznane, podkreślając potrzebę dalszych badań i opracowania bardziej skutecznych strategii leczenia.¹

Równowaga między anaboliczną i kataboliczną fazą procesu gojenia jest zaburzona – produkowane jest więcej kolagenu niż jest degradowane, a blizna rozrasta się we wszystkich kierunkach. Blizna jest uniesiona ponad skórę i pozostaje przekrwiona.¹

Bliznowiec jest wynikiem zaburzenia fizjologii gojenia się ran z nadmiernym osadzaniem tkanki łącznej. Występuje nadmierna produkcja kolagenu, zmniejszona degradacja lub oba procesy występują równocześnie.¹

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Materiały źródłowe

#1 Keloid – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK507899/
Keloids result from abnormal wound healing in response to skin trauma or inflammation. Keloid development rests on genetic and environmental factors. Higher incidences are seen in darker skinned individuals of African, Asian, and Hispanic descent. Overactive fibroblasts producing high amounts of collagen and growth factors are implicated in the pathogenesis of keloids. As a result, classic histologic findings demonstrate large, abnormal, hyalinized bundles of collagen referred to as keloidal collagen and numerous fibroblasts. […] Keloids are a result of aberrant wound healing. Standard wound healing consists of three phases: (1) inflammatory, (2) fibroblastic, and (3) maturation. In keloids, the fibroblastic phase continues, unchecked, resulting in the clinical and histopathological findings.
#1 Keloids: Pathogenesis, Clinical Features, and Management
https://pmc.ncbi.nlm.nih.gov/articles/PMC2884925/
The process by which keloids develop is poorly understood. […] The process is known to be induced by skin trauma in predisposed individuals. Skin trauma can be secondary to acne, folliculitis, body piercings, burns, lacerations, and surgical wounds. […] There are several theories of keloid etiology, most of which are related to fibroblast dysfunction. Keloid fibroblasts, when compared with fibroblasts isolated from a normal wound, overproduce type I procollagen and express higher levels of certain growth factors including vascular endothelial growth factor, transforming growth factor 1 and 2, and platelet-derived growth factor. […] Abnormalities in connexins, which are specialized proteins that are important for gap junction formation, have been implicated in keloid formation. […] Histologically, keloids demonstrate increased collagen and glycosaminoglycan content with whorls of thickened hyalinized collagen bundles.
#1 Keloids: Pathogenesis, Clinical Features, and Management
https://pmc.ncbi.nlm.nih.gov/articles/PMC2884925/
Keloid tissue has been shown to be more metabolically active and to use more oxygen than normal scar tissue. This leads to a relative state of hypoxia in keloid fibroblasts. […] Several investigators have reported the presence of mast cells and histamine in keloid tissue, especially early in the clinical course, which explains the pruritus associated with these lesions. […] The etiology of keloid-related pain is unclear, but evidence suggests a small nerve fiber neuropathy affecting the perikeloidal skin as a possible explanation.
#1 Comprehensive Insights into Keloid Pathogenesis and Advanced Therapeutic Strategies
https://www.mdpi.com/1422-0067/25/16/8776
Dysregulated molecular pathways, particularly the TGF-Î²/Smad signaling pathway, play a central role in keloid pathogenesis. Other pathways, including JAK/STAT, MAPK, PI3K/AKT, and mechanical transduction pathways (integrin, YAP/TAZ), also contribute to the abnormal behavior of keloid fibroblasts. […] TGF-Î²1 is a multifunctional cytokine implicated in keloid pathogenesis due to its role as a key regulator of fibrogenesis. TGF-Î²1 has a pro-fibrotic effect by enhancing human fibroblast cell proliferation, increasing collagen synthesis, and reducing collagen degradation. […] The JAK-STAT pathway influences several growth factors involved in keloid pathogenesis. JAK2 inhibition reduces the expression of connective tissue growth factor (CTGF), even in the presence of TGF-Î² stimulation, highlighting the pathwayâs role in fibrosis.
#1 Comprehensive Insights into Keloid Pathogenesis and Advanced Therapeutic Strategies
https://www.mdpi.com/1422-0067/25/16/8776
The MAPK pathway interacts with the TGF-Î²/Smad pathway, influencing fibroblast proliferation and collagen accumulation. The PI3K/AKT pathway regulates fibroblast proliferation and differentiation into myofibroblasts, contributing to the fibrotic phenotype of keloids. […] Current treatments for keloids, including silicone dressings, topical corticosteroids, cryotherapy, surgical excision, radiation therapy, laser therapies, and intralesional injections, aim to reduce scar size and symptoms but often result in high recurrence rates and potential side effects. […] Emerging therapies focus on targeting specific molecular pathways to disrupt the signaling processes driving keloid formation. Biologics and small molecule inhibitors target pathways such as TGF-Î²/Smad and STAT3 to reduce fibroblast proliferation and ECM production.
#1 Keloid scars: pathogenesis, therapies, and future directions | CCID
https://www.dovepress.com/future-directions-about-keloid-scars-based-on-pathogenesis-and-therapi-peer-reviewed-fulltext-article-CCID
Th1 cells could attenuate the tissue fibrosis by releasing IFN-. […] Myofibroblasts are the key effector cells causing keloid development and growth. […] TGF-1 stands out as the predominant known factor driving fibrosis, and the TGF-/Smad signaling pathway serves as the quintessential route regulating collagen formation in fibroblasts and myofibroblasts. […] The NF-B pathway have a close association with abnormal proliferation and excessive ECM production in keloid fibroblasts. […] The STAT3 signaling pathway serves as a crucial regulator of cell differentiation, apoptosis, inflammation, and fibrosis. […] Elevated local mechanical forces are linked to the emergence of atypical skin fibrosis, with keloids commonly manifesting in regions subjected to continual tension. […] Focal adhesion kinase (FAK) pathway, recognized for its role in mechanotransduction, has been found to be aberrantly activated in keloid tissues, contributing to the acceleration of skin fibrosis.
#1
https://journals.lww.com/prsgo/fulltext/2013/07000/keloids_and_hypertrophic_scars__update_and_future.5.aspx
Keloids are frequently seen on the anterior chest and scapular regions but rarely on the scalp and anterior lower legs; this pattern correlates closely with the frequencies with which these body regions are subjected to local physical tension or movement. […] In summary, HSs and keloids are the result of aberrant wound healing. The pathogenesis of these pathological scars involves cellular and ECM components in both the epidermal and dermal layers that are regulated by a wide array of interfering factors in the inflammation, proliferation, and remodeling phases.
#1 Keloids: Practice Essentials, Epidemiology, Race
https://emedicine.medscape.com/article/1298013-overview
After the initial insult to the skin and the formation of a wound clot, the balance between granulation tissue degradation and biosynthesis becomes essential to adequate healing. Extensive studies of the biochemical and cellular composition of keloids compared to mature scar tissue demonstrate significant differences. Keloids have an increased blood vessel density, higher mesenchymal cell density, a thickened epidermal layer, and increased mucinous ground substance. The alphasmooth muscle actin fibroblasts, myofibroblasts important for contractile situations, are few, if present at all. […] The collagen fibrils in keloids are more irregular, abnormally thick, and have unidirectional fibers arranged in a highly stressed orientation. Biochemical differences in collagen content in normal hypertrophic scars and keloids have been examined in numerous studies. Collagenase activity, ie, prolyl hydroxylase, has been found to be 14 times greater in keloids than in both hypertrophic scars and normal scars. Collagen synthesis in keloids is 3 times greater than in hypertrophic scars and 20 times greater than in normal scars. Type III collagen, chondroitin 4-sulfate, and glycosaminoglycan content are higher in keloids than in both hypertrophic and normal scars. Collagen cross-linking is greater in normal scars, while keloids have immature cross-links that do not form normal scar stability.
#1 Keloids: Practice Essentials, Epidemiology, Race
https://emedicine.medscape.com/article/1298013-overview
The increased numbers of fibroblasts, recruited to the site of tissue damage, synthesize an overabundance of fibronectin, and receptor expression is increased in keloids. Mast cell population within keloid scars is also increased, and, subsequently, histamine production increases. […] A study by Touchi et al indicated that the central portion of keloids is severely ischemic. The investigators found greater expression of hypoxia-induced factor-1, as well as less vascular density, in the center than on the periphery of these lesions. Growth factors and cytokines are intimately involved in the cycle of wound healing. Immunohistochemical studies of keloids demonstrate an amplified production of tumor necrosis factor (TNF)alpha, interferon (INF)beta, and interleukin-6. Production of INF-alpha, INF-gamma, and TNF-beta is diminished. INF-alpha, INF-beta, and INF-gamma reduce fibroblast synthesis of collagen types I, III, and, possibly, VI. A relationship appears to exist between immunoglobulins and keloid formation; while levels of immunoglobulin G and immunoglobulin M are normal in the serum of patients with keloids, the concentration of immunoglobulin G in the scar tissue is elevated when compared to hypertrophic and normal scar tissue.
#1 Hypertrophic Scarring and Keloids: Pathomechanisms and Current and Emerging Treatment Strategies | Molecular Medicine | Full Text
https://molmed.biomedcentral.com/articles/10.2119/molmed.2009.00153
Keloid tissue, in contrast, is mostly composed of disorganized type I and III collagen, containing pale-staining hypocellular collagen bundles with no nodules or excess myofibroblasts. […] Both lesions represent aberrations in the fundamental processes of wound healing, in which there is an obvious imbalance between the anabolic and catabolic phases; however, keloids seem to be a more sustained and aggressive fibrotic disorder than hypertrophic scars. […] Evidence to date strongly suggests a more prolonged inflammatory period, with immune cell infiltrate present in the scar tissue of keloids, the consequence of which may contribute to increased fibroblast activity with greater and more sustained ECM deposition. […] The transformation of a wound clot into granulation tissue thus requires a delicate balance between ECM protein deposition and degradation, and when this process is disrupted, abnormalities in scarring appear, resulting in either keloid or hypertrophic scar formation.
#1
https://journals.lww.com/prsgo/fulltext/2013/07000/keloids_and_hypertrophic_scars__update_and_future.5.aspx
The excessive ECM in HSs and keloids is caused by the accumulation of dermal fibroblasts. […] Keloids differ from HSs in having a higher proliferating cell nuclear antigen expression, which indicates that the fibroblasts in keloids are more proliferative. […] Delayed fibroblast apoptosis may be responsible for the characteristic paucity of fibroblasts in the center of keloids: it is possible that this delay allows the cells to produce vast amounts of ECM before they eventually disappear, leaving only an acellular collagenous mass. […] Many studies have sought to describe and explain the pathogenesis of pathological scars, mainly from the perspectives of genetics, mechanics, endocrinology, immunology, and nutrition. […] The skin injury-wound tension theory is a milestone in our understanding of keloid formation.
#1 Hypertrophic Scarring and Keloids: Pathomechanisms and Current and Emerging Treatment Strategies | Molecular Medicine | Full Text
https://molmed.biomedcentral.com/articles/10.2119/molmed.2009.00153
Recent evidence suggests that it is not simply the severity of inflammation that predisposes individuals to hypertrophic and keloid scarring, but also the type of immune response. […] Central to the formation of hypertrophic scar and keloid scar tissue is an alteration of the fibroblast phenotype. […] Many of the biologic actions of TGF- contribute to the normal wound-healing process and have been implicated in a wide variety of fibrotic disorders. […] TGF- has been linked to hypertrophic scar and keloid formation in a number of ways. […] Thus, specifically, beyond 1 week, differential expression of TGF- isoforms, receptors and activity modulators, rather than the mere presence or absence of TGF-, may have a major role in the development of both keloids and hypertrophic scarring. […] The potential importance of SMAD3 and its relationship with TGF- in keloid etiology has been demonstrated by Wang et al., who showed that downregulation of SMAD3 expression can significantly decrease procollagen gene expression and reduce ECM deposition by keloid fibroblasts.
#1 Advances and future directions in keloid research: Pathogenesis, diagnosis and personalized treatment strategies
https://www.wjgnet.com/2307-8960/full/v11/i34/8094.htm
Keloids, which are abnormal manifestations of wound healing, can result in significant functional impairment and aesthetic deformities. The pathogenesis of keloids is multifaceted and complex and influenced by various factors, such as genetics, the environment, and immune responses. […] Immune cells present within the keloid microenvironment, including macrophages, T cells, and mast cells, play a crucial role in the initiation and persistence of keloids. […] One critical signaling pathway implicated in the development of keloids is the TGF- pathway. TGF- cytokines participate in and promote various cellular processes, including growth, differentiation, and the generation of the ECM. In keloids, there is an abnormal increase in TGF- expression, leading to increased collagen production and reduced degradation.
#1 Hypertrophic Scarring and Keloids: Pathomechanisms and Current and Emerging Treatment Strategies | Molecular Medicine | Full Text
https://molmed.biomedcentral.com/articles/10.2119/molmed.2009.00153
Keratinocytes have been shown to mediate the behavior of fibroblasts during wound healing through their secretion, activation or inhibition of growth factors such as TGF-. […] Increased numbers of mast cells have been reported during the active period of hypertrophic and keloid scar formation. […] The levels of MMP expression in normal cells are low and allow healthy connective tissue remodeling. […] An imbalance in expression of MMPs has been implicated in a number of pathological conditions such as dermal fibrosis and tumor invasion and metastasis. […] Decorin regulates collagen fibril, fiber and fiber-bundle organization and has been shown to be decreased by about 75% in hypertrophic scars. […] Recently, apoptosis has been shown to play a critical role in the transition from granulation tissue into scar formation after tissue injury.
#1 Keloids: Pathophysiology and management
https://escholarship.org/uc/item/2m43548r
Keloid formation occurs as a result of abnormal wound healing. […] The pathogenesis of keloids is complex and involves both genetic and environmental factors. It is widely accepted that keloids develop subsequent to injury or inflammation of the skin, but the exact pathogenesis is still unknown. […] Aberrant expression of various growth factors and their receptors has been described for keloid-derived fibroblasts. For example, keloidal fibroblasts have been shown to over express the growth factors: VEGF, TGF-1, TGF-2, CTGF, as well as the PDGF- receptor. […] TGF-1 is a well-studied player in the pathogenesis of abnormal scarring and much research is focused on this pathway. […] Compared to normal dermal fibroblasts, fibroblasts derived from keloids exhibit increased production of collagen and matrix metalloproteinases.
#1 Keloids: Pathophysiology and management
https://escholarship.org/uc/item/2m43548r
This suggests the negative feedback mechanism is somehow defective in keloidal fibroblasts ultimately resulting in exuberant scar formation with the propensity to recur. […] To date, no specific gene has been linked to the development of keloids. […] Recent advances in genetic technology allowing for the simultaneous analysis of multiple genes have significantly contributed to our knowledge of keloid pathogenesis. […] It is clear that analysis of multiple genes through microarray technology to compare gene expression among keloids and normal scars, holds promise for understanding the genetic control of keloids.
#1 Keloid Scar Pictures, Causes, Symptoms, Cream & Removal
https://www.medicinenet.com/keloid/article.htm
Special techniques must be used soon after the surgical procedure has concluded to prevent the formation of a new, larger keloid. […] The best way to deal with a keloid is not to get one. A person who has had a keloid should not undergo elective or cosmetic skin surgeries or procedures such as piercing. When it comes to keloids, prevention is crucial, because current treatments leave a lot to be desired.
#1 Genetics of Keloid Scarring | SpringerLink
https://link.springer.com/chapter/10.1007/978-3-030-44766-3_8
Keloid disease is a benign fibro-proliferative reticular dermal tumor that develops in response to dysregulated cutaneous wound-healing process. The key alterations result in keloid formation have not been fully understood yet. […] Keloid disease is considered a genetic disease due to a strong genetic susceptibility to keloid formation as it occurs predominantly in people of African and Asian descent, runs in families, and has been found in twins. […] Complexity and differences in the inheritance modes and familial keloid scarring reflect the variability and heterogeneity in genetic susceptibility, family history, twin genetic makeup, inheritance patterns, linkage, genetic associations, variation in gene expression and respective gene pathways, HLA (human leukocyte antigen) polymorphism, epigenetics, and ethnic populations.
#1 Epigenetic modification mechanisms involved in keloid: current status and prospect | Clinical Epigenetics | Full Text
https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-020-00981-8
Keloid, a common dermal fibroproliferative disorder, is benign skin tumors characterized by the aggressive fibroblasts proliferation and excessive accumulation of extracellular matrix. […] Accumulating evidence has demonstrated that multiple diverse and reversible epigenetic modifications, represented by DNA methylation, histone modification, and non-coding RNAs (ncRNAs), play a critical role in gene regulation and downstream fibroblastic function in keloid. […] Importantly, abnormal epigenetic modification manipulates multiple behaviors of keloid-derived fibroblasts, which served as the main cellular components in keloid skin tissue, including proliferation, migration, apoptosis, and differentiation. […] Epigenetic modification including DNA methylations, histone modifications, and ncRNAs regulations, are emerging intriguing research fields of illuminating the molecular pathogenesis of keloid investigation.
#1 Epigenetic modification mechanisms involved in keloid: current status and prospect | Clinical Epigenetics | Full Text
https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-020-00981-8
It is believed that the epigenetic dysregulation will lead to an imbalance in the process of scar tissue repair and regeneration. […] The epigenetic mechanism in other diseases is relatively thorough, but the pathogenesis of scars is still not very clear. […] More recently, the role of epigenetic modification especially DNA methylation, histone modification, and ncRNAs, in the etiology and fibrosis progression of keloid has recently attracted widespread attention. […] KFs with aberrant expression and activation is regulated by several epigenetic mechanisms, forming the complex dynamic regulatory networks in the epigenetic pathogenesis. […] The imbalance between the inflammation, proliferation, and remodeling stages is believed to be responsible for the differences in histological characteristics related to keloid and other skin fibrosis.
#1 Epigenetic modification mechanisms involved in keloid: current status and prospect | Clinical Epigenetics | Full Text
https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-020-00981-8
The above studies provide evidence of DNA methylation for the regulation of the stable pattern of differential gene expression in keloid formation. […] As a pervasive alternative mechanism for gene regulation in keloid pathogenesis, DNA methylation possesses the capacity of becoming novel potential therapies to reverse destructive epigenetic modification. […] The profibrotic transcriptional patterns in fibroblasts are regulated by histone modifications via diverse mechanisms. […] These findings revealed that through the miR-124-3p/TGFR1 axis, HOXA11-AS inhibited cell apoptosis and promoted fibroblast-induced angiogenesis, contributing to the progression of keloid formation. […] The expression profiles of mRNAs, lncRNAs, and circRNAs are altered with certainty in keloid tissue, which may partly contribute to the etiology of keloid by impacting several signaling pathways relevant to scaring healing. […] Overall, it is of great value to excavate and build epigenetics-associated diagnostic strategies.
#1 Hypertrophic Scarring and Keloids: Pathomechanisms and Current and Emerging Treatment Strategies | Molecular Medicine | Full Text
https://molmed.biomedcentral.com/articles/10.2119/molmed.2009.00153
In hypertrophic scar tissue of severely burned patients, however, the authors found that maximal apoptosis occurred much later. […] In a study of incisional scars in patients without any history of excessive scarring, Bond and colleagues found progressive changes in relation to the dermal structure but persistent fibroblastic density at 4 months, indicating the existence of a continuing high-turnover state similar to the proliferative phase. […] Existing prophylactic and therapeutic strategies include pressure therapy, silicone gel sheeting, intralesional TAC, cryosurgery, radiation, laser therapy, INF, 5-FU and surgical excision as well as a multitude of extracts and topical agents. […] Emerging therapies for patients prone to excessive scars support earlier interventions aimed at modulating single cell types, inflammatory metabolites, cytokines or signaling receptors.
#1 A narrative review of scar formation
https://www.jkslms.or.kr/view.html?uid=318&vmd=Full
Excessive synthesis of collagen and other fibrous components caused by disturbances and imbalance in the metabolism of extracellular matrix (ECM) can lead to scar formation rather than their destruction. […] In this complex process of wound healing, TGF- plays a crucial role. […] However, in contrast to the normal wound healing process, abnormal fibroblast expression is observed in scars, which is associated with inflammatory mediators that can stimulate fibroblasts such as VEGF and plasminogen activator inhibitor (PAI)-1. […] An abnormal increase in TGF- signaling involved in inflammatory response of the skin contributes to normal tissue healing. It is considered a major cause of scar formation. […] Compared to normal skin tissue, scar tissue has relatively high levels of TGF-1 and TGF-2 (TGF- isoforms that promote collagen proliferation).
#1 Standard guidelines of care: Keloids and hypertrophic scars – Indian Journal of Dermatology, Venereology and Leprology
https://ijdvl.com/standard-guidelines-of-care-keloids-and-hypertrophic-scars/
Keloids and hypertrophic scars (HTS) are the result of overgrowth of fibrous tissue, following healing of a cutaneous injury, and cause morbidity. […] Keloids extend beyond the margins of the original wound, do not usually regress spontaneously, and tend to recur after excision, while HTS do not expand beyond the boundaries of the initial injury and may undergo partial spontaneous resolution. […] It is important to note that it is difficult to eradicate keloids and most of the modalities are associated with some adverse effects. […] The primary goals while planning a treatment protocol should be a low recurrence rate, significant cosmetic and symptomatic improvement and minimal adverse effects. […] Intralesional corticosteroids: This is the most frequently used modality, the steroid most commonly used, being depot preparation of triamcinolone acetonide.
#1 A narrative review of scar formation
https://www.jkslms.or.kr/view.html?uid=318&vmd=Full
The formation of scars is influenced by both internal factors (such as size, depth, location, and healing duration) related to wound itself and external factors (such as genetics, age, and hormones) associated with individual characteristics. […] The most significant factors contributing to scar formation are the size and depth of the wound. […] The tension in the wound area significantly affects the amount and characteristics of scar tissue more than any other factors. […] The speed of wound healing is influenced by genetic factors. […] The occurrence of scars is closely related to genetics. […] Generally, scars are more common in younger individuals, typically between ages of 11 and 30 years, than in older adults. […] One specific type of scar, known as striae distensae or stretch marks, commonly occurs during sudden growth spurts, weight gain, pregnancy, and prolonged use of corticosteroid medications.
#1 A narrative review of scar formation
https://www.jkslms.or.kr/view.html?uid=318&vmd=Full
A person’s psychological stress can potentially be a risk factor for scarring. In fact, it has been known that keloids can be triggered or exacerbated by psychological factors. […] As mentioned above scar formation is influenced by various internal and external factors. Therefore, it is important to have a clear understanding about these factors because each of these factors can be targets in the development of various scar prevention or treatment options.
#1 Hypertrophic Scars and Keloids: A Complete Overview â DermNet
https://dermnetnz.org/topics/keloid-and-hypertrophic-scar
A keloid scar is a firm, smooth, hard growth that occurs as a result of excessive scar formation. […] The exact pathogenesis of keloids and hypertrophic scar formation is unknown. Keloids may develop after minor injuries such as trauma, burns, insect bites, surgery, cryotherapy, topical therapies (eg, imiquimod), acne, infections (eg, shingles), and immunisation. […] The pathogenesis is hypothesised to involve dysregulation of the normal healing process resulting in excessive production of collagen, elastin, proteoglycans, and extracellular matrix proteins. There is an increase in the number of fibroblasts and mast cells. Growth factors and cytokines are altered in keloid scars, with increased amounts of TNF alpha, interferon-beta and interleukin 6.
#1 Keloid and Hypertrophic Scars Are the Result of Chronic Inflammation in the Reticular Dermis
https://www.mdpi.com/1422-0067/18/3/606
Keloids and hypertrophic scars are caused by cutaneous injury and irritation, including trauma, insect bite, burn, surgery, vaccination, skin piercing, acne, folliculitis, chicken pox, and herpes zoster infection. […] Notably, superficial injuries that do not reach the reticular dermis never cause keloidal and hypertrophic scarring. This suggests that these pathological scars are due to injury to this skin layer and the subsequent aberrant wound healing therein, which is characterized by continuous and histologically localized inflammation. As a result, the reticular layer of keloids and hypertrophic scars contains inflammatory cells, increased numbers of fibroblasts, newly formed blood vessels, and collagen deposits. […] Moreover, proinflammatory factors, such as interleukin (IL)-1Î±, IL-1Î², IL-6, and tumor necrosis factor-Î± are upregulated in keloid tissues, which suggests that, in patients with keloids, proinflammatory genes in the skin are sensitive to trauma. This may promote chronic inflammation, which in turn may cause the invasive growth of keloids.
#1 Keloid scars: pathogenesis, therapies, and future directions | CCID
https://www.dovepress.com/future-directions-about-keloid-scars-based-on-pathogenesis-and-therapi-peer-reviewed-fulltext-article-CCID
Keloids are pathologic scars that pose a significant functional and cosmetic burden. […] The pathogenesis of keloid scars is not fully elucidated. This review delves into the intricate pathogenesis of keloids, exploring the molecular and cellular mechanisms underlying their formation. […] Keloid pathogenesis is a multifaceted process involving a dynamic interplay of various cells, cytokines, and signaling pathways. A deeper understanding of these mechanisms opens avenues for targeted therapeutic interventions aimed at disrupting the cascade of events leading to keloid formation. […] By dissecting the intricacies of keloid pathology, we move closer to more effective and personalized approaches for the management of this challenging dermatological condition. […] The infiltration of M2 macrophages is significantly higher than that of M1 macrophages in keloid tissue.
#1 Comprehensive Insights into Keloid Pathogenesis and Advanced Therapeutic Strategies
https://www.mdpi.com/1422-0067/25/16/8776
Keloid scars, characterized by abnormal fibroproliferation and excessive extracellular matrix (ECM) production that extends beyond the original wound, often cause pruritus, pain, and hyperpigmentation, significantly impacting the quality of life. Keloid pathogenesis is multifactorial, involving genetic predisposition, immune response dysregulation, and aberrant wound-healing processes. Central molecular pathways such as TGF-Î²/Smad and JAK/STAT are important in keloid formation by sustaining fibroblast activation and ECM deposition. […] The pathogenesis of keloid formation involves a multifaceted interplay of genetic, immunological, and mechanical factors that disrupt normal wound healing, leading to persistent fibroblast activation and excessive extracellular matrix production. […] The pathogenesis of keloids is complex and multifactorial, involving genetic susceptibility, immune response dysregulation, and aberrant wound-healing processes. Despite extensive research, the exact mechanisms remain poorly understood, highlighting the need for further investigation and the development of more effective treatment strategies.
#1 Keloid and Hypertrophic Scar: Background, Pathophysiology, Etiology
https://emedicine.medscape.com/article/1057599-overview
Keloids are the result of an overgrowth of dense fibrous tissue that usually develops after healing of a skin injury. […] When an imbalance occurs between the anabolic and catabolic phases of the healing process, more collagen is produced than is degraded, and the scar grows in all directions. The scar is elevated above the skin and remains hyperemic. Excessive fibrous tissue is classified as either a keloid or a hypertrophic scar. […] Trauma to the skin, both physical (eg, earlobe piercing, surgery) and pathological (eg, acne, chickenpox), is the primary cause identified for the development of keloids. The presence of foreign material, infection, hematoma, or increased skin tension can also lead to keloid or hypertrophic scar formation in susceptible individuals. Transforming growth factor-beta and adiponectin are implicated in the pathogenesis.
#1 Pathogenesis â GPnotebook
https://gpnotebook.com/en-IE/pages/dermatology/aetiology/pathogenesis
Keloid scars are a result of an imbalance in wound healing physiology with an excessive deposition of collagenous connective tissue. There is excessive production of collagen, reduced degradation or both processes occurring concurrently. […] A variety of theories have been put forward to explain this: excessive inflammation: fibroproliferative scars have many features of ongoing inflammation. […] The balance of these molecules is suggested to attract an excessive number of fibroblasts which secrete increased amounts of collagen. […] Cultured fibroblasts from keloids demonstrate increased procollagen production with elevated levels of type I to type III collagen. […] Keloid, as opposed to normal, fibroblasts secrete other extracellular matrix elements at increased concentration including fibronectin, elastin and proteoglycans.
#2 Keloid – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK507899/
Keloidal fibroblasts have increased proliferative activity, persist for longer, and have lower rates of apoptosis compared to typical wound healing. This results in an overproduction of collagen and cytokines. Collagen synthesis in keloids is 20 times greater than that of healthy skin and three times greater than a hypertrophic scar. […] Transforming growth factor-beta and platelet-derived growth factor are thought to be the primary drivers of this process. Transforming growth factor-beta, an integral part of wound healing, promotes chemotaxis of fibroblasts to the site of inflammation and produces collagen. Dysregulation of this pathway leads to fibrosis and abnormal scar response.
#2 Comprehensive Insights into Keloid Pathogenesis and Advanced Therapeutic Strategies
https://www.mdpi.com/1422-0067/25/16/8776
Dysregulated molecular pathways, particularly the TGF-Î²/Smad signaling pathway, play a central role in keloid pathogenesis. Other pathways, including JAK/STAT, MAPK, PI3K/AKT, and mechanical transduction pathways (integrin, YAP/TAZ), also contribute to the abnormal behavior of keloid fibroblasts. […] TGF-Î²1 is a multifunctional cytokine implicated in keloid pathogenesis due to its role as a key regulator of fibrogenesis. TGF-Î²1 has a pro-fibrotic effect by enhancing human fibroblast cell proliferation, increasing collagen synthesis, and reducing collagen degradation. […] The JAK-STAT pathway influences several growth factors involved in keloid pathogenesis. JAK2 inhibition reduces the expression of connective tissue growth factor (CTGF), even in the presence of TGF-Î² stimulation, highlighting the pathwayâs role in fibrosis.
#2 Keloid scars: pathogenesis, therapies, and future directions | CCID
https://www.dovepress.com/future-directions-about-keloid-scars-based-on-pathogenesis-and-therapi-peer-reviewed-fulltext-article-CCID
Th1 cells could attenuate the tissue fibrosis by releasing IFN-. […] Myofibroblasts are the key effector cells causing keloid development and growth. […] TGF-1 stands out as the predominant known factor driving fibrosis, and the TGF-/Smad signaling pathway serves as the quintessential route regulating collagen formation in fibroblasts and myofibroblasts. […] The NF-B pathway have a close association with abnormal proliferation and excessive ECM production in keloid fibroblasts. […] The STAT3 signaling pathway serves as a crucial regulator of cell differentiation, apoptosis, inflammation, and fibrosis. […] Elevated local mechanical forces are linked to the emergence of atypical skin fibrosis, with keloids commonly manifesting in regions subjected to continual tension. […] Focal adhesion kinase (FAK) pathway, recognized for its role in mechanotransduction, has been found to be aberrantly activated in keloid tissues, contributing to the acceleration of skin fibrosis.
#2 Keloids: Pathogenesis, Clinical Features, and Management
https://pmc.ncbi.nlm.nih.gov/articles/PMC2884925/
Keloid tissue has been shown to be more metabolically active and to use more oxygen than normal scar tissue. This leads to a relative state of hypoxia in keloid fibroblasts. […] Several investigators have reported the presence of mast cells and histamine in keloid tissue, especially early in the clinical course, which explains the pruritus associated with these lesions. […] The etiology of keloid-related pain is unclear, but evidence suggests a small nerve fiber neuropathy affecting the perikeloidal skin as a possible explanation.
#2 Keloids: Practice Essentials, Epidemiology, Race
https://emedicine.medscape.com/article/1298013-overview
The increased numbers of fibroblasts, recruited to the site of tissue damage, synthesize an overabundance of fibronectin, and receptor expression is increased in keloids. Mast cell population within keloid scars is also increased, and, subsequently, histamine production increases. […] A study by Touchi et al indicated that the central portion of keloids is severely ischemic. The investigators found greater expression of hypoxia-induced factor-1, as well as less vascular density, in the center than on the periphery of these lesions. Growth factors and cytokines are intimately involved in the cycle of wound healing. Immunohistochemical studies of keloids demonstrate an amplified production of tumor necrosis factor (TNF)alpha, interferon (INF)beta, and interleukin-6. Production of INF-alpha, INF-gamma, and TNF-beta is diminished. INF-alpha, INF-beta, and INF-gamma reduce fibroblast synthesis of collagen types I, III, and, possibly, VI. A relationship appears to exist between immunoglobulins and keloid formation; while levels of immunoglobulin G and immunoglobulin M are normal in the serum of patients with keloids, the concentration of immunoglobulin G in the scar tissue is elevated when compared to hypertrophic and normal scar tissue.
#2 Hypertrophic Scarring and Keloids: Pathomechanisms and Current and Emerging Treatment Strategies | Molecular Medicine | Full Text
https://molmed.biomedcentral.com/articles/10.2119/molmed.2009.00153
Keloid tissue, in contrast, is mostly composed of disorganized type I and III collagen, containing pale-staining hypocellular collagen bundles with no nodules or excess myofibroblasts. […] Both lesions represent aberrations in the fundamental processes of wound healing, in which there is an obvious imbalance between the anabolic and catabolic phases; however, keloids seem to be a more sustained and aggressive fibrotic disorder than hypertrophic scars. […] Evidence to date strongly suggests a more prolonged inflammatory period, with immune cell infiltrate present in the scar tissue of keloids, the consequence of which may contribute to increased fibroblast activity with greater and more sustained ECM deposition. […] The transformation of a wound clot into granulation tissue thus requires a delicate balance between ECM protein deposition and degradation, and when this process is disrupted, abnormalities in scarring appear, resulting in either keloid or hypertrophic scar formation.
#2 Genetics of Keloid Scarring | SpringerLink
https://link.springer.com/chapter/10.1007/978-3-030-44766-3_8
Keloid disease is a benign fibro-proliferative reticular dermal tumor that develops in response to dysregulated cutaneous wound-healing process. The key alterations result in keloid formation have not been fully understood yet. […] Keloid disease is considered a genetic disease due to a strong genetic susceptibility to keloid formation as it occurs predominantly in people of African and Asian descent, runs in families, and has been found in twins. […] Complexity and differences in the inheritance modes and familial keloid scarring reflect the variability and heterogeneity in genetic susceptibility, family history, twin genetic makeup, inheritance patterns, linkage, genetic associations, variation in gene expression and respective gene pathways, HLA (human leukocyte antigen) polymorphism, epigenetics, and ethnic populations.
#2 Hypertrophic Scarring and Keloids: Pathomechanisms and Current and Emerging Treatment Strategies | Molecular Medicine | Full Text
https://molmed.biomedcentral.com/articles/10.2119/molmed.2009.00153
Keratinocytes have been shown to mediate the behavior of fibroblasts during wound healing through their secretion, activation or inhibition of growth factors such as TGF-. […] Increased numbers of mast cells have been reported during the active period of hypertrophic and keloid scar formation. […] The levels of MMP expression in normal cells are low and allow healthy connective tissue remodeling. […] An imbalance in expression of MMPs has been implicated in a number of pathological conditions such as dermal fibrosis and tumor invasion and metastasis. […] Decorin regulates collagen fibril, fiber and fiber-bundle organization and has been shown to be decreased by about 75% in hypertrophic scars. […] Recently, apoptosis has been shown to play a critical role in the transition from granulation tissue into scar formation after tissue injury.
#2 Hypertrophic Scarring and Keloids: Pathomechanisms and Current and Emerging Treatment Strategies | Molecular Medicine | Full Text
https://molmed.biomedcentral.com/articles/10.2119/molmed.2009.00153
In hypertrophic scar tissue of severely burned patients, however, the authors found that maximal apoptosis occurred much later. […] In a study of incisional scars in patients without any history of excessive scarring, Bond and colleagues found progressive changes in relation to the dermal structure but persistent fibroblastic density at 4 months, indicating the existence of a continuing high-turnover state similar to the proliferative phase. […] Existing prophylactic and therapeutic strategies include pressure therapy, silicone gel sheeting, intralesional TAC, cryosurgery, radiation, laser therapy, INF, 5-FU and surgical excision as well as a multitude of extracts and topical agents. […] Emerging therapies for patients prone to excessive scars support earlier interventions aimed at modulating single cell types, inflammatory metabolites, cytokines or signaling receptors.
#2 A narrative review of scar formation
https://www.jkslms.or.kr/view.html?uid=318&vmd=Full
Excessive synthesis of collagen and other fibrous components caused by disturbances and imbalance in the metabolism of extracellular matrix (ECM) can lead to scar formation rather than their destruction. […] In this complex process of wound healing, TGF- plays a crucial role. […] However, in contrast to the normal wound healing process, abnormal fibroblast expression is observed in scars, which is associated with inflammatory mediators that can stimulate fibroblasts such as VEGF and plasminogen activator inhibitor (PAI)-1. […] An abnormal increase in TGF- signaling involved in inflammatory response of the skin contributes to normal tissue healing. It is considered a major cause of scar formation. […] Compared to normal skin tissue, scar tissue has relatively high levels of TGF-1 and TGF-2 (TGF- isoforms that promote collagen proliferation).
#2 A narrative review of scar formation
https://www.jkslms.or.kr/view.html?uid=318&vmd=Full
The formation of scars is influenced by both internal factors (such as size, depth, location, and healing duration) related to wound itself and external factors (such as genetics, age, and hormones) associated with individual characteristics. […] The most significant factors contributing to scar formation are the size and depth of the wound. […] The tension in the wound area significantly affects the amount and characteristics of scar tissue more than any other factors. […] The speed of wound healing is influenced by genetic factors. […] The occurrence of scars is closely related to genetics. […] Generally, scars are more common in younger individuals, typically between ages of 11 and 30 years, than in older adults. […] One specific type of scar, known as striae distensae or stretch marks, commonly occurs during sudden growth spurts, weight gain, pregnancy, and prolonged use of corticosteroid medications.
#3 Keloids: Practice Essentials, Epidemiology, Race
https://emedicine.medscape.com/article/1298013-overview
The increased numbers of fibroblasts, recruited to the site of tissue damage, synthesize an overabundance of fibronectin, and receptor expression is increased in keloids. Mast cell population within keloid scars is also increased, and, subsequently, histamine production increases. […] A study by Touchi et al indicated that the central portion of keloids is severely ischemic. The investigators found greater expression of hypoxia-induced factor-1, as well as less vascular density, in the center than on the periphery of these lesions. Growth factors and cytokines are intimately involved in the cycle of wound healing. Immunohistochemical studies of keloids demonstrate an amplified production of tumor necrosis factor (TNF)alpha, interferon (INF)beta, and interleukin-6. Production of INF-alpha, INF-gamma, and TNF-beta is diminished. INF-alpha, INF-beta, and INF-gamma reduce fibroblast synthesis of collagen types I, III, and, possibly, VI. A relationship appears to exist between immunoglobulins and keloid formation; while levels of immunoglobulin G and immunoglobulin M are normal in the serum of patients with keloids, the concentration of immunoglobulin G in the scar tissue is elevated when compared to hypertrophic and normal scar tissue.
#3 Hypertrophic Scarring and Keloids: Pathomechanisms and Current and Emerging Treatment Strategies | Molecular Medicine | Full Text
https://molmed.biomedcentral.com/articles/10.2119/molmed.2009.00153
Keloid tissue, in contrast, is mostly composed of disorganized type I and III collagen, containing pale-staining hypocellular collagen bundles with no nodules or excess myofibroblasts. […] Both lesions represent aberrations in the fundamental processes of wound healing, in which there is an obvious imbalance between the anabolic and catabolic phases; however, keloids seem to be a more sustained and aggressive fibrotic disorder than hypertrophic scars. […] Evidence to date strongly suggests a more prolonged inflammatory period, with immune cell infiltrate present in the scar tissue of keloids, the consequence of which may contribute to increased fibroblast activity with greater and more sustained ECM deposition. […] The transformation of a wound clot into granulation tissue thus requires a delicate balance between ECM protein deposition and degradation, and when this process is disrupted, abnormalities in scarring appear, resulting in either keloid or hypertrophic scar formation.
#3 Hypertrophic Scarring and Keloids: Pathomechanisms and Current and Emerging Treatment Strategies | Molecular Medicine | Full Text
https://molmed.biomedcentral.com/articles/10.2119/molmed.2009.00153
Keratinocytes have been shown to mediate the behavior of fibroblasts during wound healing through their secretion, activation or inhibition of growth factors such as TGF-. […] Increased numbers of mast cells have been reported during the active period of hypertrophic and keloid scar formation. […] The levels of MMP expression in normal cells are low and allow healthy connective tissue remodeling. […] An imbalance in expression of MMPs has been implicated in a number of pathological conditions such as dermal fibrosis and tumor invasion and metastasis. […] Decorin regulates collagen fibril, fiber and fiber-bundle organization and has been shown to be decreased by about 75% in hypertrophic scars. […] Recently, apoptosis has been shown to play a critical role in the transition from granulation tissue into scar formation after tissue injury.
#3 A narrative review of scar formation
https://www.jkslms.or.kr/view.html?uid=318&vmd=Full
The formation of scars is influenced by both internal factors (such as size, depth, location, and healing duration) related to wound itself and external factors (such as genetics, age, and hormones) associated with individual characteristics. […] The most significant factors contributing to scar formation are the size and depth of the wound. […] The tension in the wound area significantly affects the amount and characteristics of scar tissue more than any other factors. […] The speed of wound healing is influenced by genetic factors. […] The occurrence of scars is closely related to genetics. […] Generally, scars are more common in younger individuals, typically between ages of 11 and 30 years, than in older adults. […] One specific type of scar, known as striae distensae or stretch marks, commonly occurs during sudden growth spurts, weight gain, pregnancy, and prolonged use of corticosteroid medications.
#3 Keloids: Practice Essentials, Epidemiology, Race
https://emedicine.medscape.com/article/1298013-overview
Keloid formation can occur within a year after injury, and keloids enlarge well beyond the original scar margin. The most frequently involved sites of keloids are areas of the body that are constantly subjected to high skin tension. Wounds on the anterior chest, shoulders, flexor surfaces of the extremities (eg, deltoid region), and anterior neck and wounds that cross skin tension lines are more susceptible to abnormal scar formation. […] The most important risk factor for the development of abnormal scars such as keloids is a wound healing by secondary intention, especially if healing time is greater than 3 weeks. Wounds subjected to a prolonged inflammation, whether due to a foreign body, infection, burn, or inadequate wound closure, are at risk of abnormal scar formation. Areas of chronic inflammation, such as an earring site or a site of repeated trauma, are also more likely to develop keloids. Occasionally, spontaneous keloids occur without a history of trauma.
#4 Hypertrophic Scarring and Keloids: Pathomechanisms and Current and Emerging Treatment Strategies | Molecular Medicine | Full Text
https://molmed.biomedcentral.com/articles/10.2119/molmed.2009.00153
Keratinocytes have been shown to mediate the behavior of fibroblasts during wound healing through their secretion, activation or inhibition of growth factors such as TGF-. […] Increased numbers of mast cells have been reported during the active period of hypertrophic and keloid scar formation. […] The levels of MMP expression in normal cells are low and allow healthy connective tissue remodeling. […] An imbalance in expression of MMPs has been implicated in a number of pathological conditions such as dermal fibrosis and tumor invasion and metastasis. […] Decorin regulates collagen fibril, fiber and fiber-bundle organization and has been shown to be decreased by about 75% in hypertrophic scars. […] Recently, apoptosis has been shown to play a critical role in the transition from granulation tissue into scar formation after tissue injury.