Zapalenie przełyku – Patofizjologia i mechanizm

Zapalenie przełyku
Patofizjologia i mechanizm

Zapalenie przełyku to stan zapalny błony śluzowej przełyku o zróżnicowanej etiologii, w tym refluks żołądkowo-przełykowy (GERD), eozynofilowe zapalenie przełyku (EoE), zapalenie wywołane lekami, infekcje oraz uszkodzenia popromienne i żrące. W patogenezie refluksowego zapalenia przełyku kluczową rolę odgrywa proces zapalny indukowany przez cytokiny, a nie bezpośrednie uszkodzenie kwasem. Mechanizm ten obejmuje aktywację HIF-2α i NF-κB, prowadzącą do migracji limfocytów T i produkcji cytokin prozapalnych, a także udział reaktywnych form tlenu (ROS) i peroksydacji lipidów. W EoE dominują mechanizmy immunoalergiczne z odpowiedzią Th2, gdzie cytokiny IL-4, IL-5, IL-9 i IL-13 indukują chemotaksję eozynofilów, hiperplazję komórek kubkowych oraz włóknienie nabłonka, z udziałem TGF-β1 i CAPN14, co prowadzi do upośledzenia bariery nabłonkowej i przebudowy przełyku. Zapalenie wywołane lekami, np. doksycykliną, bisfosfonianami czy NLPZ, wynika z miejscowego działania drażniącego i zaburzenia cytoprotekcji, natomiast infekcyjne zapalenie przełyku dotyczy głównie pacjentów z immunosupresją i może mieć etiologię bakteryjną, wirusową, grzybiczą lub pasożytniczą.

Patogeneza zapalenia przełyku

Zapalenie przełyku (esophagitis) to stan zapalny, charakteryzujący się obecnością stanu zapalnego w błonie śluzowej przełyku. Patogeneza zapalenia przełyku jest złożona i zależy od podtypu schorzenia. Wśród najczęstszych przyczyn wymienia się refluks żołądkowo-przełykowy, infekcje, uszkodzenia przez leki, promieniowanie oraz eozynofilowe zapalenie przełyku (EoE).¹ Mechanizmy patofizjologiczne różnią się znacząco w zależności od czynnika etiologicznego.

Refluksowe zapalenie przełyku

Refluks żołądkowo-przełykowy jest najczęstszą przyczyną zapalenia przełyku. Tradycyjnie uważano, że kwas żołądkowy bezpośrednio uszkadza nabłonek przełyku, powodując „chemiczne oparzenie”. Nowsze badania sugerują jednak, że zapalenie refluksowe przełyku jest wynikiem procesów zapalnych mediowanych przez cytokiny, a nie bezpośredniego działania żrącego kwasu.¹²

W patogenezie refluksowego zapalenia przełyku kluczową rolę odgrywa zaburzenie równowagi między czynnikami szkodliwymi (epizody refluksu, kwasowość refluksatu, wrażliwość przełyku) a czynnikami obronnymi (oczyszczanie kwasu z przełyku, integralność błony śluzowej). Stopień uszkodzenia błony śluzowej jest proporcjonalny do częstości epizodów refluksu, czasu ekspozycji błony śluzowej przełyku na kwas oraz żrącego potencjału refluksatu.¹

Nieefektywna bariera antyrefluksowa na poziomie połączenia żołądkowo-przełykowego jest najważniejszym czynnikiem w patogenezie refluksu. Gdy dochodzi do refluksu, odpowiednie oczyszczanie refluksatu jest niezbędne, aby zminimalizować czas kontaktu czynnika drażniącego z błoną śluzową przełyku.¹

Mechanizm cytokinowy zapalenia refluksowego

Aktualny model patogenezy zapalenia refluksowego zakłada, że refluks treści żołądkowej nie niszczy bezpośrednio komórek nabłonkowych, ale raczej indukuje je do wydzielania cytokin prozapalnych.¹ Badania wykazały, że najwcześniejszym objawem zapalenia przełyku jest naciek limfocytów w błonie podśluzowej, który dopiero później postępuje z udziałem neutrofilów i obejmuje powierzchnię nabłonka.¹

Refluks indukuje aktywację czynnika indukowanego hipoksją (HIF)-2α, który wzmacnia aktywność transkrypcyjną czynnika jądrowego κB (NF-κB), powodując wzrost cytokin prozapalnych i migrację limfocytów T, co stanowi podstawowy mechanizm molekularny tego urazu mediowanego przez cytokiny.¹ Ostatecznie to komórki zapalne uszkadzają błonę śluzową poprzez „sizzle” cytokinowe, a nie bezpośrednie działanie żrące kwasu.²

Reaktywne formy tlenu (ROS) i peroksydacja lipidów pochodzące głównie z neutrofilów, które są stymulowane i mobilizowane przez TNF-α i CINC-1, są również zaangażowane w patogenezę zapalenia przełyku wywołanego refluksem treści żołądkowo-dwunastniczej.¹

Eozynofilowe zapalenie przełyku

Eozynofilowe zapalenie przełyku (EoE) jest przewlekłą chorobą zapalną o podłożu immunoalergicznym, charakteryzującą się naciekiem eozynofilowym w przełyku. Patofizjologia EoE nie jest w pełni poznana, ale znaczące dowody sugerują, że jest to zaburzenie alergiczne wywołane przez uczulenie na antygeny pokarmowe i/lub aeroalergeny.¹

W patogenezie EoE kluczową rolę odgrywa odpowiedź immunologiczna typu Th2. Model patogenezy EoE zakłada, że antygeny, zarówno alergeny pokarmowe, jak i aerozolowe, są prezentowane w przełyku i stymulują odpowiedź Th2.¹ Komórki Th2 wytwarzają cytokiny typu 2, takie jak IL-4, IL-5 i IL-13, które odgrywają kluczową rolę w patogenezie EoE.¹

Rola cytokin w EoE

IL-13 odgrywa decydującą rolę w chemotaksji eozynofilów, hiperplazji komórek kubkowych, kurczliwości mięśni gładkich i odkładaniu kolagenu.² IL-13 stymuluje komórki nabłonkowe przełyku do produkcji genu eotaksyny-3 (CCL26), który z kolei rekrutuje eozynofile z krwi obwodowej do tkanki.¹

IL-5 jest głównym czynnikiem różnicującym eozynofile w szpiku kostnym, podczas gdy IL-9 odgrywa ważną rolę w aktywacji komórek ILC2 i komórek tucznych.¹ TGF-β1, wytwarzany przez komórki tuczne, eozynofile i komórki nabłonkowe przełyku, jest kluczową cytokiną dla włóknienia nabłonka i transformacji komórek nabłonkowych.²

Eozynofile uwalniają peroksydazę eozynofilową (EPO), białko kationowe eozynofilów (ECP) i główne białko wiążące (MBP), które bezpośrednio powodują uszkodzenie tkanki i zaburzenia motoryki przełyku.¹ Eozynofile produkują również IL-1, IL-3, IL-4, IL-5, IL-13, TGF-β, eotaksynę-3, RANTES, białko zapalne makrofagów 1 (MIP-1), czynnik martwicy nowotworów (TNF)-α, czynnik stymulujący tworzenie kolonii granulocytów i makrofagów (GM-CSF), czynnik aktywujący płytki (PAF) i leukotrien C4 (LTC4).¹

Genetyka i mechanizmy molekularne w EoE

EoE ma podłoże genetyczne, co zostało szeroko udowodnione. Blanchard i wsp. zidentyfikowali fragment ludzkiego genomu, nazwany „transkryptomem EoE”, z zachowaną ekspresją wielu loci genowych w przełyku pacjentów z EoE. Wśród zachowawczo wyrażonych genów CCL26, kodujący eotaksynę 3 (chemoatraktant i aktywator eozynofilów), okazał się najbardziej skorelowany z innymi loci genów obejmującymi kompleks różnicowania naskórka (EDC), „gorący punkt” transkrypcyjny w genetycznym napędzie chorób atopowych.¹

Jedno z największych badań GWAS ujawniło, że gen kalpainy 14 (CAPN14), kodujący proteazę cysteinową indukowaną przez IL-13, okazał się genem najbardziej skorelowanym z aktywnym EoE.¹ CAPN14 to cytozoowa aktywowana wapniem proteaza cysteinowa, która została zidentyfikowana jako locus 2p23 w badaniach asocjacji genomowych (GWAS) EoE. Nadekspresja CAPN14 znacząco upośledza funkcję bariery nabłonkowej.¹

Charakterystyczne dla EoE jest upośledzenie funkcji bariery nabłonka przełyku. Morfologia zapalnego nabłonka przełyku w EoE ma kilka cech, w tym hiperplazję strefy podstawnej w nabłonku przełyku, która zastępuje większość bardziej zróżnicowanej górnej warstwy komórek nabłonkowych, oraz pojawienie się poszerzonych przestrzeni międzykomórkowych (DIS) w warstwach suprabazalnych.²

Transformacja epithelialno-mezenchymalna w EoE

Transformacja nabłonkowo-mezenchymalna (EMT), czyli seria zmian, w których komórki nabłonkowe tracą swoje charakterystyczne właściwości (polarność, markery powierzchniowe i połączenia ścisłe itp.) i przekształcają się w komórki mezenchymalne, została wskazana w patogenezie włóknienia obserwowanego w EoE. Proces EMT w EoE wydaje się być napędzany przez TGF-β, co sugeruje proces mediowany przez eozynofile.¹

TGF-β indukuje również produkcję periostyny przez fibroblasty. Periostyna może zatem utrwalać cykl zapalenia eozynofilowego w przełyku.¹ Aktywacja eozynofilów i degranulacja mogą pośredniczyć w patogenezie EoE. W szczególności eozynofile indukują przebudowę przełyku za pośrednictwem szlaku TGF-β, prowadząc do włóknienia podśródbłonkowego, przejścia nabłonkowo-mezenchymalnego i dysfunkcji mięśni gładkich, a także zwiększają tempo proliferacji nabłonka w przełyku.¹

Zapalenie przełyku polekowe

Patogeneza zapalenia przełyku wywołanego lekami obejmuje bezpośredni efekt drażniący i przerwanie barier cytoprotekcyjnych.¹ Częstość występowania zapalenia przełyku wywołanego lekami szacuje się na 3,9 na 100 000 populacji rocznie, przy czym średni wiek wynosi 41,5 lat, a kobiety są dotknięte częściej niż mężczyźni.¹

Mechanizmy uszkodzenia przełyku zależą od konkretnego leku:

Doksycyklina gromadzi się w warstwie podstawnej nabłonka płaskiego przełyku, co sugeruje możliwy mechanizm miejscowego podrażnienia.¹
Bisfosfoniany, zwłaszcza alendronian, są dobrze znanymi przyczynami zapalenia przełyku. Chociaż krwawienie jest rzadkie, zapalenie i owrzodzenie z pogrubieniem ściany przełyku są często widoczne w endoskopii.²
NLPZ zaburzają normalne działanie cytoprotekcyjne prostaglandyn na błonę śluzową żołądka i mogą mieć podobny wpływ na błonę śluzową przełyku.³
Bisfosfoniany są miejscowym drażniącym środkiem dla przewodu pokarmowego, powodując chemiczne zapalenie żołądka. Przypuszcza się, że bisfosfoniany osłabiają ochronną, hydrofobową barierę śluzówkową przewodu pokarmowego, umożliwiając kwasowi żołądkowemu podrażnienie nabłonka.¹

Zapalenie przełyku infekcyjne

Infekcyjne zapalenie przełyku jest najczęściej obserwowane u osób z obniżoną odpornością, ale było również zgłaszane u zdrowych dorosłych i dzieci. Szeroki zakres nieprawidłowości w obronie gospodarza może predysponować osobę do zakażeń oportunistycznych, takich jak neutropenia, zaburzenia chemotaksji i fagocytozy, zmiany w odporności humoralnej i upośledzona funkcja limfocytów T.¹

Infekcyjne zapalenie przełyku może być spowodowane przez bakterie, grzyby, pasożyty i wirusy. Bakteryjne przyczyny infekcyjnego zapalenia przełyku są trudne do wyizolowania, ponieważ często mają charakter polimikrobialny i pochodzą z normalnej flory jamy ustnej.¹

Pacjenci z chorobami układowymi (np. cukrzycą, dysfunkcją nadnerczy, alkoholizmem) oraz osoby w podeszłym wieku mogą być predysponowani do infekcyjnego zapalenia przełyku z powodu zmienionej funkcji immunologicznej.²

Żrące zapalenie przełyku

Żrące zapalenie przełyku rozwija się po spożyciu silnie kwaśnych lub zasadowych substancji chemicznych. Zasady (zwykle o pH 11,5-12,5), jak na przykład ług lub baterie, powodują martwicę upłynniającą. Kwasy (np. kwas solny) powodują martwicę koagulacyjną.¹

W przebiegu żrącego zapalenia przełyku może dojść do perforacji przełyku, szczególnie w ciągu 10 dni, kiedy tworzenie się tkanki ziarninowej powoduje osłabienie ściany przełyku. Po około 3 tygodniach, w miarę postępu fibrynogenezy, może dojść do powstania zwężenia przełyku.¹

Zapalenie przełyku popromienne

Patofizjologia zapalenia przełyku popromiennego obejmuje uszkodzenie DNA i śmierć komórek przez wysokoenergetyczne elektrony prowadzące do powstawania niestabilnych wolnych rodników tlenowych.¹ Zapalenie popromienne może prowadzić do znaczących uszkodzeń i zwłóknienia przełyku.

Zapalenie przełyku – złożoność mechanizmów patofizjologicznych

Zapalenie przełyku jest złożonym stanem patologicznym, obejmującym różne mechanizmy w zależności od czynnika wywołującego. W refluksowym zapaleniu przełyku główną rolę odgrywa zapalenie mediowane przez cytokiny, a nie bezpośrednie działanie żrące treści żołądkowej. W eozynofilowym zapaleniu przełyku kluczowa jest odpowiedź immunologiczna typu Th2 z udziałem eozynofilów, komórek tucznych oraz limfocytów B i T. Zapalenie przełyku wywołane lekami wiąże się z bezpośrednim działaniem drażniącym na błonę śluzową, podczas gdy zapalenie infekcyjne zależy od rodzaju patogenu i stanu układu immunologicznego gospodarza.¹²³

Zrozumienie złożonych mechanizmów patofizjologicznych zapalenia przełyku jest kluczowe dla opracowania skutecznych metod diagnostycznych i terapeutycznych, które będą ukierunkowane na podstawowe przyczyny choroby, a nie tylko na jej objawy.¹²³

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Materiały źródłowe

#1 Esophagitis – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK442012/
Esophagitis refers to inflammation or injury to the esophageal mucosa. One of the most common causes is gastroesophageal reflux, which can lead to erosive esophagitis. Other etiologies include radiation, infections, local injury caused by medications, pill esophagitis, and eosinophilic esophagitis (EoE). […] The pathophysiology also depends in large part on the subset of esophagitis to which one refers. […] Reflux esophagitis: Abnormal amount and frequent reflux of gastric content into the esophagus lead to mucosal injury. Several mechanisms take place in the pathophysiology of reflux. […] Medication-induced esophagitis: The pathogenesis of medication-induced esophagitis involves a direct irritant effect and disruption of cytoprotective barriers. […] Eosinophilic esophagitis: The pathogenesis of EoE is incompletely defined. Considerable evidence suggests that eosinophilic esophagitis is an allergic disorder induced by antigen sensitization either through foods and/or aeroallergens. […] Radiation esophagitis: The pathophysiology involves DNA damage and cell death from high-energy electrons leading to the formation of volatile oxygen-free radicals. […] Infectious esophagitis: Infection esophagitis can be caused by bacterial, fungal, parasitic and viral micro-organisms.
#1
https://link.springer.com/article/10.1007/s00535-017-1342-1
Reflux esophagitis damages the squamous epithelium that normally lines the esophagus, and promotes replacement of the damaged squamous lining by the intestinal metaplasia of Barretts esophagus, the precursor of esophageal adenocarcinoma. […] Therefore, to prevent the development of Barretts metaplasia and esophageal adenocarcinoma, the pathogenesis of reflux esophagitis must be understood. […] We have reported that reflux esophagitis, both in a rat model and in humans, develops as a cytokine-mediated inflammatory injury (i.e., cytokine sizzle), not as a caustic chemical injury (i.e., acid burn), as traditionally has been assumed. […] Moreover, reflux induces activation of hypoxia inducible factor (HIF)-2, which enhances the transcriptional activity of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-B) causing increases in pro-inflammatory cytokines and in migration of T lymphocytes, an underlying molecular mechanism for this cytokine-mediated injury.
#1 Pathophysiology of gastroesophageal reflux disease – UpToDate
https://www.uptodate.com/contents/pathophysiology-of-gastroesophageal-reflux-disease
Some degree of gastroesophageal reflux is physiologic. Physiologic reflux episodes typically occur postprandially, are short-lived, asymptomatic, and rarely occur during sleep. Pathologic reflux is associated with symptoms or mucosal injury (esophagitis) and often occurs nocturnally. In general, the term gastroesophageal reflux disease (GERD) is applied to patients with symptoms suggestive of reflux or complications thereof, but not necessarily with esophageal inflammation. Reflux esophagitis describes a subset of patients with GERD who have endoscopic evidence of esophageal erosions, described in the Los Angeles classification as mucosal breaks, usually confined to the area of the gastroesophageal junction. […] The development of GERD reflects an imbalance between injurious or symptom-eliciting factors (reflux events, acidity of refluxate, esophageal sensitivity) and defensive factors (esophageal acid clearance, mucosal integrity). The extent of mucosal injury is proportional to the frequency of reflux events, the duration of esophageal mucosal acidification, and the caustic potency of refluxed fluid. Although the same can be said of symptom severity, it is complicated by the added determinant of esophageal hypersensitivity.
#1 Pathophysiology of reflux esophagitis
https://lirias.kuleuven.be/833885
Prolonged (24 h) intra-esophageal pH measurements have shown that short-lasting reflux episodes regularly occur in normal subjects, especially in the postprandial period. […] When the reflux episodes become more frequent and last longer, symptoms and esophagitis ensue. […] The mechanism of symptom production (pyrosis and/or chest pain) is incompletely understood. […] The pathogenesis of pathological reflux is multifactorial: 1. An ineffective anti-reflux barrier at the level of the gastroesophageal junction is the most important factor in the pathogenesis of reflux. […] Once reflux has occurred, an appropriate clearing of the refluxed material is necessary to minimize the contact time of the noxious agent with the esophageal mucosa. […] In the refluxed material the concentration of H+ is the most irritant factor although pepsine increases its noxious character. […] Bile acid reflux decreases the epithelial resistance. […] The mucosal resistance to noxious agents is determined by the mucous layer, the cytoprotective properties of the epithelium, the regeneration capacity of the cells and by a number of post-epithelial factors.
#1
https://link.springer.com/article/10.1007/s00535-017-1342-1
In order to make advances in preventing Barretts esophagus and the other serious esophageal complications of reflux esophagitis, a better understanding of the pathogenesis of reflux esophagitis and its contribution to the development of Barretts esophagus is essential. […] In this model, the reflux of acid and bile does not destroy epithelial cells directly, but rather induces them to secrete pro-inflammatory cytokines. […] We postulate that, ultimately, it is inflammatory cells that mediate the epithelial injury through a cytokine sizzle, rather than the direct caustic effects of an acid burn. […] Our alternative concept on the pathogenesis of reflux esophagitis was based on rat and cell lines studies, and it was not clear if this model is applicable to humans. […] Data from a rat model and humans suggest that reflux esophagitis develops as a cytokine-mediated inflammatory injury (i.e., sizzle), not as a caustic chemical injury (i.e., acid burn), as has traditionally been assumed.
#1 The Pathogenesis of Gastroesophageal Reflux Disease â Gastroenterology & Hepatology
https://www.gastroenterologyandhepatology.net/archives/april-2012/the-pathogenesis-of-gastroesophageal-reflux-disease/
Our animal model findings suggest that the earliest sign of inflammation in the esophagus is infiltration of the submucosa by lymphocytes, which only later progresses to include neutrophils and involve the epithelial surface. We also found that the initial event appears to be reflux-induced stimulation of esophageal squamous cells resulting in secretion of inflammatory cytokines. […] A key feature of our alternative concept for the development of reflux esophagitis is that reflux stimulates esophageal squamous epithelial cells to secrete chemokines that attract inflammatory cells, and it is the inflammatory cells that ultimately damage the esophageal mucosa.
#1 Cytokine-induced neutrophil accumulation in the pathogenesis of acute reflux esophagitis in rats
https://www.spandidos-publications.com/10.3892/ijmm.16.1.71
Although recent reports indicate an increasing incidence of patients with reflux esophagitis, its pathomechanism remains unclear. […] This study investigated the roles of neutrophils, ROS, and cytokines in the pathogenesis of experimental reflux esophagitis. […] These results indicate that ROS and lipid peroxidation mainly derived from neutrophils, which are stimulated and mobilized by TNF- and CINC-1, are implicated in the pathogenesis of esophageal inflammation induced by the reflux of gastroduodenal contents.
#1
https://link.springer.com/article/10.1007/s10620-013-2679-9
The current model of EoE pathogenesis holds that antigens, either food allergens or aeroallergens, are presented to the esophagus and stimulate a Th2 response. […] Eotaxin-3 is associated strongly with the pathogenesis of EoE since it is the most upregulated gene and bears a disease-associated single nucleotide polymorphism (SNP). […] TGF- also induces periostin production by fibroblasts. […] Therefore, periostin can perpetuate the cycle of eosinophilic inflammation in the esophagus. […] Defects in barrier function can facilitate penetration of luminal antigens into the tissue, serving as the initial trigger for EoE. […] It is an immunologically active tissue involved in the multiple inflammatory pathways in EoE. […] There have been rapid developments in our understanding of the pathogenesis of EoE over the past decade, with an increasing recognition that cell types beyond the eosinophil are likely critical to disease development.
#1 Pathogenesis of Eosinophilic Esophagitis: A Comprehensive Review of the Genetic and Molecular Aspects
https://pmc.ncbi.nlm.nih.gov/articles/PMC7582808/
Eosinophils also serve as antigen-presenting cells (APCs) with MHC-II presentation as well as co-stimulatory molecules (CD40, CD28, CD86, and CD27). […] Eosinophils also produce IL-1, IL-3, IL-4, IL-5, IL-13, TGF-, eotaxin-3, RANTES, macrophage inflammatory protein 1 (MIP-1), tumor necrosis factor (TNF)-, granulocyte-macrophage colony-stimulating factor (GM-CSF), platelet-activating factor (PAF), and leukotriene C4 (LTC4). […] The importance of eosinophils in EoE has been studied in both mouse and human models. […] In EoE, the numbers of CD3+, CD4+, and CD8+ T cells, as well as the CD8+/CD4+ T cell ratio, increase in the esophageal mucosa. […] Th2 cells produce type 2 cytokines such as IL-4, IL-5, and IL-13, which play a key role in the pathogenesis of EoE. […] TGF-1, produced by mast cells, eosinophils, and esophageal epithelial cells, is a key cytokine for epithelial fibrosis and epithelial cell transformation. […] IL-13, a key cytokine and the most studied cytokine in EoE pathogenesis, is secreted by Th2 cells and activates eosinophils.
#1 Esophagitis pathophysiology – wikidoc
https://www.wikidoc.org/index.php/Esophagitis_pathophysiology
IL-13 stimulates the epithelial cells of the esophagus to induce a gene called eotaxin-3, which in turn recruits eosinophils from the peripheral blood into the tissue. […] Eosinophils cause inflammation in the EoE patients by the following mechanisms […] Eventually resulting in tissue remodeling and esophageal dysfunction.
#1 From Pathogenesis to Treatment: Targeting Type-2 Inflammation in Eosinophilic Esophagitis
https://www.mdpi.com/2218-273X/14/9/1080
IL-13 plays a determinant role in eosinophil chemotaxis, goblet cell hyperplasia, smooth muscle contractility, and collagen deposition. Together with IL-13, IL-5 is the main driver for eosinophil differentiation in the bone marrow, while IL-9 has an important role in ILC2 and mast cell (MC) activation. […] The type 2 response, with an increased production of Th2-related cytokines (IL-4, IL-5, and IL-13), fuels this vicious cycle, further hindering barrier permeability. Many hypotheses have tried to unravel the common pathway shared by type 2 inflammatory disorders. […] The genetic predisposition is nonetheless the most relevant topic in type 2 immune-mediated disorders. Marenholz and colleagues recently performed a Genome-Wide Association Study (GWAS) meta-analysis in asthma and AD patients, identifying two genome-wide significant single nucleotide polymorphisms (SNPs) in the epidermal differentiation complex (EDC), associated with FLG gene. […] EoE is believed to be a late protagonist in susceptible individuals.
#1 Pathogenesis of Eosinophilic Esophagitis: A Comprehensive Review of the Genetic and Molecular Aspects
https://pmc.ncbi.nlm.nih.gov/articles/PMC7582808/
Eosinophilic esophagitis (EoE) is a relatively new condition described as an allergic-mediated disease of the esophagus. […] The pathophysiology of EoE is described by separately presenting the known function of each cell and molecule, with the major contributors being eosinophils, Th2 cells, thymic stromal lymphopoietin (TSLP), transforming growth factor (TGF)-1, and interleukin (IL)-13. […] EoE is caused by an allergic inflammation reaction in patients that have genetic and environmental risks of EoE, and it relies on both the innate and adaptive immune pathways. […] Eosinophils are recruited from the blood with local chemotaxis and they seem to be integral to EoE disease pathogenesis. […] Eosinophils release eosinophilic peroxidase (EPO), eosinophil cationic protein (ECP), and major binding protein (MBP), which directly causes tissue damage and esophageal dysmotility.
#1 From Pathogenesis to Treatment: Targeting Type-2 Inflammation in Eosinophilic Esophagitis
https://www.mdpi.com/2218-273X/14/9/1080
Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder of the esophagus. EoE shares a common pathogenetic mechanism with other chronic disorders pertaining to the type 2 inflammatory spectrum, such as atopic dermatitis (AD), allergic rhinitis (AR), asthma, and chronic rhinosinusitis with nasal polyps (CRSwNP). The recent advancements in EoE pathogenesis understanding have unveiled new molecular targets implied within the âatopic marchâ picture as well as specific to EoE. These discoveries have led to the clinical evaluation of several novel drugs (monoclonal antibodies and immune modulators), specifically aimed at the modulation of Th2 inflammation. […] EoE pathogenesis has been intensively studied in recent years. EoE has an underlying genetic susceptibility, widely proven. Blanchard et al. identified a section of the human genome, termed the âEoE transcriptomeâ, with a conserved expression of multiple gene loci, in the esophagus of EoE patients. Among the conservatively expressed genes, CCL26, encoding for eotaxin 3 (an eosinophil chemoattractant and activator), resulted to be the most correlated among other gene loci comprising the EDC, a transcriptional âhot spotâ in the atopic diseasesâ genetic drive. One of the largest GWASs revealed how the Calpain 14 (CAPN14) gene, encoding for an IL-13-induced cysteine protease, resulted to be the highest correlated gene with active EoE.
#1 Molecular Mechanisms of Eosinophilic Esophagitis
https://www.mdpi.com/1422-0067/22/24/13183
The prominent pathophysiological feature of EoE is impairment of esophageal epithelium barrier function (BF). […] The morphology of the inflamed esophageal epithelium in EoE has several features, including basal zone hyperplasia in the esophageal epithelium, which replaces much of the more differentiated upper layer of epithelial cells, and the emergence of DIS in the suprabasal layers, which is believed to be associated with an increase in permeability of esophageal epithelium to food allergens, refluxed acid, microbes, and other alternating factors in EoE. […] CAPN14 is a cytosolic calcium-activated cysteine protease that was identified as an associated locus 2p23 in EoE genome-wide association studies (GWAS). […] CAPN14 overexpression significantly impairs epithelial BF. […] These findings revealed a profound loss of esophageal tissue differentiation in patients with EoE.
#1 Biomechanics of Esophageal Function in Eosinophilic Esophagitis
https://www.jnmjournal.org/journal/view.html?uid=263&vmd=Full
Recognition of these antigens by the immune system leads to a series of cytokine-mediated inflammatory responses resulting in eosinophilic infiltration of the esophagus and alterations to the structure of the esophagus with basal zone hypertrophy. […] The results of these changes to the structure of the esophagus lead to functional changes that manifest as the clinical symptoms of EoE. […] Epithelial mesenchymal transformation (EMT), or the series of changes in which epithelial cells lose their characteristic properties (polarity, surface markers and tight junctions etc) and transform into mesenchymal cells, has been implicated in the pathogenesis of fibrosis seen in EoE. […] The process of EMT in EoE appears to be driven by TGF-, suggestive of an eosinophil-mediated process. […] Studying mechanics should be a major focus of research into EoE as the predominant symptoms of EoE are directly related to changes that occur secondary to remodeling of the esophagus, including compliance and possibly motor function.
#1
https://link.springer.com/article/10.1007/s10620-013-2679-9
Over the past two decades, eosinophilic esophagitis (EoE) has undergone a remarkable transformation. […] In parallel with this has been a rapid increase in our understanding of the pathogenesis and genetic basis of EoE. […] While the consensus is that EoE is an allergic/immune-mediated condition in which the eosinophil plays a central role, recent data suggest that non-eosinophil cell types play important, and possibly crucial, roles as well. […] Recognizing and characterizing the role of the non-eosinophil cell types is likely to be central to future advances in the diagnosis and treatment of EoE. […] Eosinophil activation and degranulation may mediate the pathogenesis of EoE. […] In particular, eosinophils induce esophageal remodeling via a TGF- pathway resulting in subepithelial fibrosis, epithelial-mesenchymal transition, and smooth muscle dysfunction, and increase the rate of epithelial proliferation in the esophagus.
#1 Drug-Induced Esophagitis: What Pharmacists Need to Know
https://www.pharmacytimes.com/view/drug-induced-esophagitis-what-pharmacists-need-to-know
Pharmacists, as medication experts and the most accessible healthcare professionals, are in the perfect position to prevent such situations. It is, therefore, imperative that pharmacists recognize the medications that are most likely to cause drug-induced esophagitis and know how to counsel patients. […] The incidence of drug-induced esophagitis is estimated to be 3.9 per 100,000 population per year. The mean age is 41.5 years, with women being affected more often than men; this may be due to the fact that women consume more offending medications. Other risk factors include increasing age, decreased saliva production, and altered esophageal motility. Patients often present with retrosternal pain, odynophagia, and dysphagia, with abdominal pain and hematemesis being uncommon symptoms. Esophageal irregularities can be a result of systemic abnormalities, such as gastroesophageal reflux or compromise of the immune system, or direct esophageal irritation. Medications that cause direct esophageal mucosal injury will be reviewed here.
#1 Drug-Induced Esophagitis: What Pharmacists Need to Know
https://www.pharmacytimes.com/view/drug-induced-esophagitis-what-pharmacists-need-to-know
Doxycycline has also been shown to accumulate within the basal layer of esophageal squamous epithelium, suggesting another possible mechanism for local irritation. […] Potassium is known for causing small bowel ulceration, and as a hyperosmotic solution, it may cause esophageal damage. […] Bisphosphonates, especially alendronate, are well-known causes of esophagitis. While bleeding is rare, inflammation and ulceration with thickening of the esophageal wall are often seen on endoscopy. […] NSAIDs disrupt the normal cytoprotective action of prostaglandins on gastric mucosa and may have similar effects on the esophageal mucosa. Drugs implicated in case reports include ibuprofen, indomethacin, aspirin, phenylbutazone, and naproxen. […] Most cases of drug-induced esophagitis resolve with no complications. Reinjury with the offending drug should be avoided with proper measures to prevent recurrence.
#1 Bisphosphonates Mechanism of Esophageal and Gastrointestinal Irritation
https://www.ebmconsult.com/articles/what-is-the-mechanism-by-which-bisphosphonates-cause-esophageal-and-gastrointestinal-irritation
Bisphosphonates are a local irritant to the gastrointestinal tract resulting in chemical gastritis. […] It is hypothesized that bisphosphonates compromise the protective, hydrophobic mucosal barrier of the GI tract allowing gastric acid to agitate the epithelial lining. The chronic irritation and inflammation leads to erosions and/or ulcerations. […] Bisphosphonates act as topical irritants to the GI lining resulting in chemical esophagitis. […] The comparable molecular composition of bisphosphonates and zwitterionic phospholipids creates competitive binding on the mucosal layer. When bisphosphonates bind, this prevents PC or other protective phospholipids from binding and producing the hydrophobic barrier that protects the epithelial lining from gastric acid.
#1 Esophagitis: Practice Essentials, Background, Pathophysiology
https://emedicine.medscape.com/article/174223-overview
Reflux esophagitis develops when gastric contents are regurgitated into the esophagus. […] In other cases, where acid reflux from the stomach is persistent, the result is damage to the esophagus, causing symptoms and macroscopic changes. Gastric acid, pepsin, and bile irritate the squamous epithelium, leading to inflammation, erosion, and ulceration of the esophageal mucosa. […] Infectious esophagitis is most commonly observed in immunosuppressed hosts but has also been reported in healthy adults and children. A wide range of abnormalities in the host defense may predispose an individual to opportunistic infections, such as neutropenia, impaired chemotaxis and phagocytosis, alteration in humoral immunity, and impaired T-cell lymphocyte function. […] Patients with systemic diseases (eg, diabetes mellitus, adrenal dysfunction, alcoholism) and those of advanced age can be predisposed to infectious esophagitis because of an altered immune function.
#1 infectious-esophagitis-pathogenesis-and-clinical-findings | Calgary Guide
https://calgaryguide.ucalgary.ca/infectious-esophagitis-pathogenesis-and-clinical-findings/infectious-esophagitis-final/
Infectious Esophagitis: Pathogenesis and clinical findings […] Bacterial causes of infectious esophagitis are difficult to isolate as they are often polymicrobial in nature and derived from normal oral flora. […] Cytomegalovirus Infection of endothelial cells and fibroblasts […] Herpes Simplex Infection of squamous cells and macrophages […] Colonization facilitated by use of antacid therapy […] Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications.
#1
https://step2.medbullets.com/gastrointestinal/122036/esophagitis
Etiology […] Pathogenesis […] eosinophilic […] corrosive […] infectious […] Candida […] herpes virus […] cytomegalovirus (CMV) […] gastroesophageal reflux disease (GERD) […] medication-induced […] Corrosive esophagitis […] pathogenesis […] ingestion of strongly acidic or basic chemical […] alkali (usually pH 11.5-12.5) […] i.e., lye or batteries […] causes liquefaction necrosis […] acids (usually pH […] i.e., hydrochloric acid […] causes coagulation necrosis […] esophageal perforation […] pathogenesis […] especially within 10 days during which granulation tissue formation causes weakening of the esophageal wall […] esophageal stricture formation […] pathogenesis […] usually around 3 weeks as fibrogenesis occurs […] Candida esophagitis […] pathogenesis […] most secondary to C. albicans […] Medication-induced esophagitis […] pathogenesis […] direct irritant effect […] disruption of cytoprotective barrier
#2 The Pathogenesis of Gastroesophageal Reflux Disease â Gastroenterology & Hepatology
https://www.gastroenterologyandhepatology.net/archives/april-2012/the-pathogenesis-of-gastroesophageal-reflux-disease/
RFS The traditional pathogenesis of gastroesophageal reflux diseaseâthe explanation that is taught in medical schools and that has probably been around for 100 yearsâis that reflux esophagitis develops when gastric juice refluxes from the stomach into the esophagus, and gastric acid inflicts a chemical burn on the esophageal mucosa. A number of studies have shown that reflux hydrogen ions directly damage esophageal epithelial cells. […] If caustic injury is not the primary mechanism underlying reflux esophagitis, then one alternative hypothesis is that gastroesophageal reflux triggers a cytokine-mediated immune response, and it is that immune response that causes the esophageal injury. […] Thus, our studies support a new understanding of the development of reflux esophagitis, in which the reflux of gastric juice stimulates esophageal squamous epithelial cells to secrete chemokines that attract inflammatory cells, and it is the inflammatory cells, not the acid, that ultimately damage the esophageal mucosa.
#2
https://link.springer.com/article/10.1007/s00535-017-1342-1
In order to make advances in preventing Barretts esophagus and the other serious esophageal complications of reflux esophagitis, a better understanding of the pathogenesis of reflux esophagitis and its contribution to the development of Barretts esophagus is essential. […] In this model, the reflux of acid and bile does not destroy epithelial cells directly, but rather induces them to secrete pro-inflammatory cytokines. […] We postulate that, ultimately, it is inflammatory cells that mediate the epithelial injury through a cytokine sizzle, rather than the direct caustic effects of an acid burn. […] Our alternative concept on the pathogenesis of reflux esophagitis was based on rat and cell lines studies, and it was not clear if this model is applicable to humans. […] Data from a rat model and humans suggest that reflux esophagitis develops as a cytokine-mediated inflammatory injury (i.e., sizzle), not as a caustic chemical injury (i.e., acid burn), as has traditionally been assumed.
#2
https://link.springer.com/article/10.1007/s10620-013-2679-9
The current model of EoE pathogenesis holds that antigens, either food allergens or aeroallergens, are presented to the esophagus and stimulate a Th2 response. […] Eotaxin-3 is associated strongly with the pathogenesis of EoE since it is the most upregulated gene and bears a disease-associated single nucleotide polymorphism (SNP). […] TGF- also induces periostin production by fibroblasts. […] Therefore, periostin can perpetuate the cycle of eosinophilic inflammation in the esophagus. […] Defects in barrier function can facilitate penetration of luminal antigens into the tissue, serving as the initial trigger for EoE. […] It is an immunologically active tissue involved in the multiple inflammatory pathways in EoE. […] There have been rapid developments in our understanding of the pathogenesis of EoE over the past decade, with an increasing recognition that cell types beyond the eosinophil are likely critical to disease development.
#2 Pathogenesis of Eosinophilic Esophagitis: A Comprehensive Review of the Genetic and Molecular Aspects
https://pmc.ncbi.nlm.nih.gov/articles/PMC7582808/
Eosinophils also serve as antigen-presenting cells (APCs) with MHC-II presentation as well as co-stimulatory molecules (CD40, CD28, CD86, and CD27). […] Eosinophils also produce IL-1, IL-3, IL-4, IL-5, IL-13, TGF-, eotaxin-3, RANTES, macrophage inflammatory protein 1 (MIP-1), tumor necrosis factor (TNF)-, granulocyte-macrophage colony-stimulating factor (GM-CSF), platelet-activating factor (PAF), and leukotriene C4 (LTC4). […] The importance of eosinophils in EoE has been studied in both mouse and human models. […] In EoE, the numbers of CD3+, CD4+, and CD8+ T cells, as well as the CD8+/CD4+ T cell ratio, increase in the esophageal mucosa. […] Th2 cells produce type 2 cytokines such as IL-4, IL-5, and IL-13, which play a key role in the pathogenesis of EoE. […] TGF-1, produced by mast cells, eosinophils, and esophageal epithelial cells, is a key cytokine for epithelial fibrosis and epithelial cell transformation. […] IL-13, a key cytokine and the most studied cytokine in EoE pathogenesis, is secreted by Th2 cells and activates eosinophils.
#2 Molecular Mechanisms of Eosinophilic Esophagitis
https://www.mdpi.com/1422-0067/22/24/13183
The prominent pathophysiological feature of EoE is impairment of esophageal epithelium barrier function (BF). […] The morphology of the inflamed esophageal epithelium in EoE has several features, including basal zone hyperplasia in the esophageal epithelium, which replaces much of the more differentiated upper layer of epithelial cells, and the emergence of DIS in the suprabasal layers, which is believed to be associated with an increase in permeability of esophageal epithelium to food allergens, refluxed acid, microbes, and other alternating factors in EoE. […] CAPN14 is a cytosolic calcium-activated cysteine protease that was identified as an associated locus 2p23 in EoE genome-wide association studies (GWAS). […] CAPN14 overexpression significantly impairs epithelial BF. […] These findings revealed a profound loss of esophageal tissue differentiation in patients with EoE.
#2 Drug-Induced Esophagitis: What Pharmacists Need to Know
https://www.pharmacytimes.com/view/drug-induced-esophagitis-what-pharmacists-need-to-know
Doxycycline has also been shown to accumulate within the basal layer of esophageal squamous epithelium, suggesting another possible mechanism for local irritation. […] Potassium is known for causing small bowel ulceration, and as a hyperosmotic solution, it may cause esophageal damage. […] Bisphosphonates, especially alendronate, are well-known causes of esophagitis. While bleeding is rare, inflammation and ulceration with thickening of the esophageal wall are often seen on endoscopy. […] NSAIDs disrupt the normal cytoprotective action of prostaglandins on gastric mucosa and may have similar effects on the esophageal mucosa. Drugs implicated in case reports include ibuprofen, indomethacin, aspirin, phenylbutazone, and naproxen. […] Most cases of drug-induced esophagitis resolve with no complications. Reinjury with the offending drug should be avoided with proper measures to prevent recurrence.
#2 Esophagitis: Practice Essentials, Background, Pathophysiology
https://emedicine.medscape.com/article/174223-overview
Reflux esophagitis develops when gastric contents are regurgitated into the esophagus. […] In other cases, where acid reflux from the stomach is persistent, the result is damage to the esophagus, causing symptoms and macroscopic changes. Gastric acid, pepsin, and bile irritate the squamous epithelium, leading to inflammation, erosion, and ulceration of the esophageal mucosa. […] Infectious esophagitis is most commonly observed in immunosuppressed hosts but has also been reported in healthy adults and children. A wide range of abnormalities in the host defense may predispose an individual to opportunistic infections, such as neutropenia, impaired chemotaxis and phagocytosis, alteration in humoral immunity, and impaired T-cell lymphocyte function. […] Patients with systemic diseases (eg, diabetes mellitus, adrenal dysfunction, alcoholism) and those of advanced age can be predisposed to infectious esophagitis because of an altered immune function.
#2
https://link.springer.com/article/10.1007/s00535-017-1342-1
Reflux esophagitis damages the squamous epithelium that normally lines the esophagus, and promotes replacement of the damaged squamous lining by the intestinal metaplasia of Barretts esophagus, the precursor of esophageal adenocarcinoma. […] Therefore, to prevent the development of Barretts metaplasia and esophageal adenocarcinoma, the pathogenesis of reflux esophagitis must be understood. […] We have reported that reflux esophagitis, both in a rat model and in humans, develops as a cytokine-mediated inflammatory injury (i.e., cytokine sizzle), not as a caustic chemical injury (i.e., acid burn), as traditionally has been assumed. […] Moreover, reflux induces activation of hypoxia inducible factor (HIF)-2, which enhances the transcriptional activity of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-B) causing increases in pro-inflammatory cytokines and in migration of T lymphocytes, an underlying molecular mechanism for this cytokine-mediated injury.
#2 Pathophysiology of gastroesophageal reflux disease – UpToDate
https://www.uptodate.com/contents/pathophysiology-of-gastroesophageal-reflux-disease
Esophagitis results from cytokine-triggered inflammation rather than a direct chemical effect of prolonged exposure to acid, pepsin, and bile on the esophageal epithelium, the „burn” hypothesis. This is substantiated by the observation that histopathologic events during the development of esophagitis (lymphocytic inflammation, dilated intercellular spaces) occur deep in the epithelium, not at the luminal surface, and that regenerative changes (basal cell hyperplasia, papillary elongation) are initiated prior to the development of surface necrosis that was formerly hypothesized as the stimulus for those changes. Cytokine-triggered inflammation may also cause alterations in mucosal permeability and esophageal sensitivity in the absence of esophagitis. […] The antireflux barrierâGERD exists as a spectrum that includes reflux esophagitis, nonerosive reflux disease, extraesophageal GERD, reflux hypersensitivity, and Barrett’s esophagus. Within this wide spectrum, the dominance of a defective antireflux barrier as the primary pathophysiologic determinant differs widely, being greater for entities with esophagitis or sequalae of esophagitis and nonerosive reflux disease with quantitatively abnormal esophageal acid exposure on pH-metry. Within the realm of esophagitis, high-grade esophagitis (Los Angeles grade C or D) implies greater antireflux barrier dysfunction than low-grade esophagitis (Los Angeles grade A or B).
#3 Drug-Induced Esophagitis: What Pharmacists Need to Know
https://www.pharmacytimes.com/view/drug-induced-esophagitis-what-pharmacists-need-to-know
Doxycycline has also been shown to accumulate within the basal layer of esophageal squamous epithelium, suggesting another possible mechanism for local irritation. […] Potassium is known for causing small bowel ulceration, and as a hyperosmotic solution, it may cause esophageal damage. […] Bisphosphonates, especially alendronate, are well-known causes of esophagitis. While bleeding is rare, inflammation and ulceration with thickening of the esophageal wall are often seen on endoscopy. […] NSAIDs disrupt the normal cytoprotective action of prostaglandins on gastric mucosa and may have similar effects on the esophageal mucosa. Drugs implicated in case reports include ibuprofen, indomethacin, aspirin, phenylbutazone, and naproxen. […] Most cases of drug-induced esophagitis resolve with no complications. Reinjury with the offending drug should be avoided with proper measures to prevent recurrence.
#3 Pathogenesis of Eosinophilic Esophagitis: A Comprehensive Review of the Genetic and Molecular Aspects
https://pmc.ncbi.nlm.nih.gov/articles/PMC7582808/
Eosinophilic esophagitis (EoE) is a relatively new condition described as an allergic-mediated disease of the esophagus. […] The pathophysiology of EoE is described by separately presenting the known function of each cell and molecule, with the major contributors being eosinophils, Th2 cells, thymic stromal lymphopoietin (TSLP), transforming growth factor (TGF)-1, and interleukin (IL)-13. […] EoE is caused by an allergic inflammation reaction in patients that have genetic and environmental risks of EoE, and it relies on both the innate and adaptive immune pathways. […] Eosinophils are recruited from the blood with local chemotaxis and they seem to be integral to EoE disease pathogenesis. […] Eosinophils release eosinophilic peroxidase (EPO), eosinophil cationic protein (ECP), and major binding protein (MBP), which directly causes tissue damage and esophageal dysmotility.
#3
https://link.springer.com/article/10.1007/s10620-013-2679-9
The current model holds that food or environmental allergens contact a possibly leaky esophageal epithelium, triggering a Th2-mediated cytokine response where IL-5 and IL-13 stimulate the esophageal epithelium to produce eotaxin-3. […] Eosinophils and mast cells produce TGF-, which induces the epithelial-mesenchymal transition and esophageal remodeling. […] Yet, the recognition of the importance of non-eosinophil cell types in EoE is an important step forward.