Next Article in Journal
Transcriptomic Evidence of a Link between Cell Wall Biogenesis, Pathogenesis, and Vigor in Walnut Root and Trunk Diseases
Next Article in Special Issue
The New Therapeutic Frontiers in the Treatment of Eosinophilic Esophagitis: Biological Drugs
Previous Article in Journal
Genome-Wide Identification of DUF668 Gene Family and Expression Analysis under F. solani, Chilling, and Waterlogging Stresses in Zingiber officinale
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 25
Issue 2
10.3390/ijms25020927
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Fibrous Remodeling in Eosinophilic Esophagitis: Clinical Facts and Pathophysiological Uncertainties

by
Laura Arias-González
1,2,3,4,
Leticia Rodríguez-Alcolado
1,3,
Emilio J. Laserna-Mendieta
1,2,3,4,
Pilar Navarro
1,2,3,
Alfredo J. Lucendo
1,2,3,4,* and
Elena Grueso-Navarro
1,3
1
Department of Gastroenterology, Hospital General de Tomelloso, Vereda de Socuéllamos s/n, 13700 Tomelloso, Spain
2
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 28029 Madrid, Spain
3
Instituto de Investigación Sanitaria de Castilla-La Mancha (IDISCAM), 45071 Toledo, Spain
4
Instituto de Investigación Sanitaria Princesa, 28006 Madrid, Spain
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2024, 25(2), 927; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25020927
Submission received: 17 December 2023 / Revised: 8 January 2024 / Accepted: 9 January 2024 / Published: 11 January 2024
(This article belongs to the Special Issue Eosinophilic Esophagitis: Molecular Mechanisms, Diagnosis, and Therapeutic Strategies)
Browse Figure
Versions Notes

Abstract

:
Eosinophilic esophagitis (EoE) is a chronic, progressive, type 2 inflammatory disease with increasing global prevalence. An eosinophil-predominant inflammation that permeates the epithelium and deeper esophageal layers characterizes the disease. Several cytokines, mainly derived from inflammatory T-helper 2 (Th2) cells and epithelial cells, are involved in perpetuating inflammatory responses by increasing surface permeability and promoting tissue remodeling characterized by epithelial–mesenchymal transition (EMT) and collagen deposition. This leads to esophageal strictures and narrow caliber esophagi, which are proportional a patient’s age and untreated disease length. Pathophysiological mechanisms leading to EoE have been described in recent years, and transforming growth factor beta (TGF)-beta have been involved in fibrotic phenomena in EoE. However, evidence on the dependence of these phenomena on TGF-beta is scarce and contradictory. This review provides state-of-the art knowledge on intimate mechanisms of esophageal fibrosis in EoE and its clinical consequences.

1. Introduction

Eosinophilic esophagitis (EoE) is a syndrome characterized clinically by symptoms related to esophageal dysfunction and histologically by an eosinophil-predominant inflammatory infiltration limited to the esophagus, for which additional secondary causes of esophageal eosinophilia are excluded [1]. First defined in the 1990s [2,3], EoE was initially described as a particular form of food allergy [4], in which immunoglobulin E (IgE) plays quite a limited role [5]. At first considered a rare condition, the epidemiology of EoE in recent years has risen sharply [6], and currently affects up to 1 in 850 people in developed countries [7,8]. EoE is also emerging in developing countries, with cases being reported on all continents. In the absence of treatment, esophageal inflammation and symptoms tend to persist or even worsen over time [9]. The chronicity of EoE symptoms deteriorates patients’ quality of life [10], while the persistence of eosinophilic inflammation has been linked to structural changes in the esophagus [11], thus indicating a need to treat patients with active disease.
The cumulative literature over the last 3 decades has described the clinical picture of EoE [12] and investigated several therapeutic approaches. These are either based on dietary modifications aimed at identifying and avoiding food triggers, or on drugs with anti-inflammatory effects and consisting of topical corticosteroids and proton pump inhibitors [13]. An increasing number of studies focused on characterizing the disease at the molecular level [14] have also allowed for the development of new therapies, mainly based on monoclonal antibodies that target cytokines involved in the pathophysiology of EoE [15]. However, the pathophysiological processes involving cells and cytokines that contribute to EoE, its regulatory mechanisms and the complex interplay between genes and the environment that triggers it [16] still need to be fully understood [17].
This review aims to provide an overview of the inflammatory phenomena in EoE, its chronicity, progression to esophageal fibrosis, and its clinical consequences and to reveal some pathophysiological issues which have not been fully analyzed until now.

2. Immunological Aspects of EoE

EoE is characterized by a specific cytokine secretion pattern that determines it as a type 2 inflammatory disease [18,19]. In healthy conditions, T helper 2 (Th2) cells are primarily important in defense against helminth infections and exposure to venoms [20], but in atopic individuals, they are also involved in different types of allergic diseases including asthma, atopic dermatitis, allergic rhinitis, and food allergies [21]. Thus, a Th2 response is induced in EoE as a particular form of non-IgE-mediated food allergy, and typically associated with increased expression of interleukin (IL)-4, IL-5, IL-13, and eotaxins [22].
IL-5 promotes the differentiation, maturation, and release of eosinophils from the bone marrow [23], enhances eosinophil trafficking to the esophagus [24] and, in murine models of EoE, drives esophageal fibrous remodeling [25]. Among other functions, IL-4 promotes the differentiation of Th2 lymphocytes, the proliferation and differentiation of B lymphocytes, and is a potent inhibitor of apoptosis, thus playing an important role in the development of atopic diseases [26]. Treatment with dupilumab, which blocks IL-4 receptors I and II, has been shown to be effective in several atopies, including asthma and atopic dermatitis, and also improves histological, endoscopic, and EoE symptoms [27,28]. For its part, IL-13, mainly released by esophageal epithelial cells, induces pleiotropic effects in the pathophysiology of EoE. This is due to its ability to selectively reproduce in vitro the esophageal transcriptome characteristic of EoE in epithelial cell cultures [29], and induce the expression and secretion of the eosinophil-activating chemoattractants eotaxin-1/CCL11 and eotaxin-3/CCL26 [30], which then move eosinophils from blood to the esophageal tissues. In fact, eotaxin-3/CCL23 is the most intensively upregulated gene in the esophageal mucosa of EoE patients, compared to controls [31].
In addition, by presiding over the CAPN14 gene, which codifies for Calpain-14 (CAPN14) esophageal specific protease [32,33], IL-13 downregulates the gene expression of proteins that keep the intercellular spaces sealed. These include filaggrin (FLG) and involucrin (IVL) [34], the adhesion molecule desmoglein-1 (DSG) [35], and tight junction-associated proteins [36]. The alteration of all these proteins leads to epithelial dysfunction, whereby dilated intercellular spaces [37] facilitate luminal antigen penetration into the epithelial layers [38,39] and thus perpetuate inflammatory responses.
The central position of IL-13 in the pathophysiology of EoE at multiple levels is clear, therefore, and is exemplified by its independent ability to produce experimental EoE in mice when intratracheally instilled [40].
IL-13, together with IL-4 are synergistically involved in activating fibroblasts to secrete enhanced amounts of extracellular matrix (ECM) [41,42]—a complex three-dimensional network of interlaced fibrillar proteins, multiple matrix protein macromolecules, proteoglycans, anchored growth factors, and other bioactive components [43]. As a consequence of sustained inflammatory phenomena in the esophageal mucosa, fibrous remodeling is triggered in EoE in a similar way to other type 2 inflammatory conditions [44,45].
Infiltration by eosinophils, as the most significant cell in the inflammatory infiltrate of EoE, is usually found in endoscopic biopsies taken from the epithelial surface. Here, eosinophils frequently tend to aggregate forming microabsceses [46]. However, evidence from surgical specimens also demonstrated eosinophilic infiltration and fibrous remodeling in deep esophageal layers. Eosinophils permeating the submucosal and muscle layers and the neuronal plexus promote fibrous remodeling, intense collagen deposition, and smooth muscle hypertrophy [47,48], all of which contributed to altering the mechanical properties of the esophageal wall and to reducing esophageal distensibility in EoE patients [49]. Murine models also demonstrated transmural inflammatory and fibrotic involvement in experimental EoE [25], the same as in the pathophysiology of bronchial asthma [50].

3. Inflammation to Fibrosis in EoE: A Dynamic Process

Inflammation and fibrosis are two inter-related conditions with many overlapping mechanisms [51]. Sustained inflammation may result in fibrosis when it exceeds the normal wound-healing response to injury [52] in a highly orchestrated process, with common pathways that occur in many different tissues. Fibrogenesis results from defined sequences of molecular signals and cellular response mechanisms that provoke tissue inflammation, macrophage activation, and immune cell infiltration. The release of soluble mediators by the tissue (including alarmins, cytokines and chemokines) leads to the local activation of collagen-producing mesenchymal cells, (the composition of ECM varies according to specific tissues [53]) and provides a distinctive cell microenvironment for the various tissue compartments [54]. As a result, local activation of fibroblasts, recruitment of fibroblast precursors, and the transition of various cell types into myofibroblasts lead to an excessive deposition of ECM, which replaces healthy parenchymal tissue with collagen-rich ECM components, thus resulting in a loss of the normal function of affected organs [55].
EoE is characterized by an abnormal exacerbated response to harmless antigens (mainly derived from dietary components). Early-life factors have been involved in the origin of the immune imbalance that converts the innate esophageal surveillance system into a reactive one in susceptible individuals [56]. These are common in other allergic diseases [57], and usually involve changes in the abundance or composition of the esophageal microbiome [58] in adaptive responses, with epithelial cells releasing alarmins such as IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) [59]. TSLP is a relevant player in EoE [59] and other type 2 inflammatory and allergic diseases. It activates antigen-presenting cells, including food antigen-presenting dendritic cells in the esophageal mucosa, and promotes T cells maturation and polarization to Th2 cells [60]. These Th2 cells are also involved in the repair of tissues that are damaged by parasitic infections, and in allergic reactions, and activate macrophages and epithelial cells to enhance the production of ECM, which is crucial for tissue repair. Th2 cells produce the so-called Th2 cytokines IL-4, IL-5, and IL-13.
Tissue remodeling is a dynamic process that combines different mechanisms such as hyperplasia of the epithelium, subepithelial fibrosis, epithelial to mesenchymal transdifferentiation (EMT), angiogenesis, and hypertrophy of esophageal smooth muscle [61]. An EMT is a biological process that allows an epithelial cell, which normally interacts with the basement membrane via its basal surface, to interact with myofibroblasts, undifferentiated mesenchymal cell phenotypes, which achieve migratory capacity, invasiveness, elevated resistance to apoptosis, and greatly increased production of ECM components [62]. EMT contributes to fibrosis in EoE (as it is present in the esophageal tissue of patients with EoE), correlates with inflammatory activity measured as eosinophil density and reverses with treatments that decrease inflammation [41,63].
During the initial inflammatory phase, cytokines produced by Th2 cells target a wide variety of immune and non-immune cells, including fibroblasts, epithelial cells, macrophages, and endothelial cells, which act directly or indirectly to repair injured tissues [45]. In the process of tissue formation, the pro-inflammatory signals weaken, and cell proliferation is initiated by growth factors, such as transforming growth factor-β (TGF-β) and basic fibroblast growth factor (FGF-2). Both promote the induction of fibroblasts proliferation simultaneously, activating macrophages to remove apoptotic cell debris [64]. In particular, macrophages that receive type 2 cytokines (also referred as to alternatively activated or M2 macrophages) are involved in tissue repair in some organs, including the liver, central nervous system, heart, skeletal muscle, and lungs [65]. Interestingly, M2 macrophages activated by IL-4 also contribute to slow the progression of fibrosis [66] in schistosomiasis-induced liver fibrosis. Therefore, macrophages play an essential role in regulating tissue regeneration. They can produce reactive oxygen species that worsen tissue damage, and produce a variety of growth factors, such as insulin-like growth factor 1 (IGF-1), vascular endothelial growth factor (VEGF-α), and TGF-β, which regulate epithelial and endothelial cell proliferation, myofibroblast activation, stem and tissue progenitor cell differentiation and angiogenesis [67].
Myofibroblasts develop from EMT or by TGF-β1-dependent differentiation from fibroblast cells [68], and they are typically found in granulation tissue and scar tissue. Upon activation, these cells secrete ECM components (such as collagen), proliferate, migrate, and become contractile. In the particular case of EoE, in vitro studies demonstrated that esophageal epithelial cells stimulated with the profibrotic cytokines tumor necrosis factor-alpha (TNFα), TGFβ, and IL1β acquired a mesenchymal phenotype to become active myofibroblasts [69]. TGFβ stimulation has a robust effect upon epithelial collagen production [42], and under prolonged activation, myofibroblast activity promotes tissue stiffness, collagen deposition, tissue retraction, and the formation of esophageal strictures, which aggravate dysphagia and cause food impaction.

4. Clinical Consequences of Fibrous Remodeling in EoE

The natural history of EoE has been defined as a progressive condition that, in the absence of treatment, tends to evolve from an inflamed to a rigid esophagus [70]. If left untreated, symptoms and esophageal inflammation tend to persist over time, and patients can develop esophageal rings, focal strictures, or a long narrowing in the esophageal caliber [9]. Although not every EoE patient will experience this process [71], the cumulative literature demonstrates a significant prevalence of esophageal strictures and narrow-caliber esophagi in the untreated disease, and this is directly proportional to diagnostic delay. The prevalence of fibrotic features of EoE, based on endoscopic evaluation, increases from 46.5% when the diagnostic delay from symptoms onset is less than 2 years to 87.5% in patients diagnosed after >20 years of experiencing symptoms [72,73]. The chances of finding esophageal strictures in EoE doubles with every 10 years of diagnostic delay [70]. As a consequence, fibrotic phenomena develops proportionally to the duration of the untreated disease and patient’s age [58].
The origin of symptoms in EoE is complex and not fully understood. Displayed symptoms vary according a patient’s age [12], and include abdominal pain, nausea, vomiting, and slow eating as early symptoms in children, and typically dysphagia, food impaction, and heartburn in adults. Differences in disease presentation have been related to progressive fibrous remodeling of the esophagus [74], and also abnormal esophageal motility. This has been documented by manometry records: a variety of ineffective peristalsis patterns have been described in patients with EoE (which reverse after short-term anti-inflammatory treatment), together with dysphagia improvement [75,76,77,78]. Most patients usually develop coping strategies by adapting eating behaviors, or the use of dietary restrictions to manage symptoms and avoid food impactions in particular [79]. Esophageal narrowing and stricture formation under a certain lumen caliber will be a major determinant for food impaction.
The Endoflip™ impedance planimetry system is a novel method with the potential to assess esophageal function overall, which has provided evidence of the fibrotic changes that may appear as a consequence of fibrous remodeling resulting from long-term inflammation in EoE [80]. It allows for the determination of esophageal distensibility and esophageal diameter at the distensibility plateau, thus providing a measure of fibrostenotic severity that can be used to clinically phenotype EoE patients. Esophageal compliance is found to be reduced in EoE patients with a stricturing disease, and Endoflip™ measurements are able to predict the risk of food impaction. However, the potential use of Endoflip™ to assess EoE severity and therapeutic monitoring, as well as its possible superiority to esophageal biopsies to guide EoE treatment, still remains unclear.

5. TGF-β1: A Major Mediator of Fibrosis

Chronic inflammatory diseases, including diabetes, cardiovascular diseases, interstitial lung disease, viral and non-viral hepatitis, non-alcoholic steatohepatitis, and immune-related disorders such as scleroderma and inflammatory bowel disease, are all associated with fibrotic tissue responses that determine disease prognosis [81,82,83,84,85,86]. In all these diseases, the fibrosis process is triggered in response to an injury that jeopardizes tissue integrity. It is mediated by pro-fibrotic cytokines, with TGF-β as a key driver [87]. They directly induce differentiation of fibroblasts into collagen-secreting fibroblasts, and their production correlates with dysfunction in affected organs [88].
The TGF-β superfamily consists of more than 40 members of secreted polypeptide growth factors that were identified in 1981 as “transforming”, due to their ability to trigger proliferation in cultured fibroblasts [89]. In particular, TGF-β presents three isoforms characterized by different expression patterns, including TGF-β1 (which is expressed in endothelial, hematopoietic, and connective tissue cells); TGF-β2 (expressed in epithelial and neuronal cells); and TGF-β3 (which is expressed primarily in mesenchymal cells) [90,91]. The three members of the TGF-β family are active as secreted peptides and share similar biological activities in vitro, while eliciting more specific biological responses in vivo [92]. During inflammation and fibrosis, TGF-β1 is the most important member in physiological repair and collagen accumulation, as it regulates accumulation of ECM; it is involved in the modulation of inflammation by suppressing its excess [93]; and regulates essential cellular processes, including proliferation, differentiation, apoptosis, adhesion, and migration in several cell types [94].
Binding of TGF-β1 to its specific receptor activates different signaling pathways, the TGF-β/Smad one being involved in fibrogenesis. Multiple non-canonical (Smad-independent) TGF-β signaling pathways have also been described [95]. The tissue environment greatly determines the effect of TGF-β1 on the same cell and regulates several cellular functions such as actin cytoskeleton changes, tight-junction resolution, and transcriptional regulation [96]. Cellular responses to signaling pathways culminate in the expression of genes involved in tissue repair, with ECM accumulation by proliferation and migration of epithelial and mesenchymal elements being an early effect.

6. Contribution of TGF-β1 to Fibrosis in EoE: Distinct Methods and Variable Result

The TGFβ1 signaling pathway has been involved in fibrous remodeling phenomena in several type 2 inflammatory diseases, including bronchial asthma [97,98], atopic dermatitis [99], allergic rhinitis [100], nasal polyposis [101], and idiopathic eosinophilic pneumonia [102], all of them sharing common pathophysiological mechanisms with EoE. The inflammatory and fibrotic phenomena described in these organs are similar to those observed in EoE, and despite the differences in intimate molecular mechanisms, it was assumed that the patterns that occur in asthma [50] could be largely extrapolated to EoE [103].
Several studies, using different experimental approaches, tried to describe the potential involvement of TGF-β1 in the fibrous remodeling that happens in EoE [1] (Table 1). Used strategies ranged from esophageal epithelial cell cultures [104] to murine experimental models of EoE [105,106], while most evaluated biopsies were obtained from EoE patients [103,107,108,109,110,111,112,113,114,115,116]. Tissue results from human EoE were also applied to a murine model [25], and blood samples were exceptionally used [117]. The approach to determine TGF-β1 also varied from one study to another. Some of them attempted to demonstrate the protein mainly by staining TGF-β1-positive cells with immunohistochemistry (IHC) [103,105,108,111,112,114] or immunofluorescence (IF) staining [107,109], while others used ELISA [104,117] or measured the changes in TGF-β1 gene expression in EoE biopsies compared to controls [108,109,110,112,113,114,115,116,117] and the changes after therapy [103,110,111]. As demonstrated, the results of these different approaches have not always been comparable (Table 1).
Immunochemical techniques (IHC [103,105,108,111,112,113,114] and IF [107,109]) on esophageal biopsies were the first ones applied to study the role of TGF-β1 in EoE. Using this semi-quantitative assessment, greater numbers of TGF-β1 positive cells were found in esophageal samples taken from patients with active disease, compared to biopsies obtained after effective anti-inflammatory treatment based on topical budesonide.
In contrast, studies based on quantifying TGF-β1 mRNA expression on esophageal biopsies by reverse transcription polymerase chain reaction (RT-PCR) failed in reproducing the results obtained with IHC or IF [105,110,115,116]: It was immaterial whether the treatment tested was an elimination diet [115] or a topical corticosteroid [110,112], whether it was measured after only 6 weeks [115,116], or after years from the initiation of therapy [112]. Unfortunately, no studies have evaluated whether changes at the gene expression level were reproduced in terms of protein expression, thus preventing definitive conclusions. It also remains unclear whether TGF-β1 gene expression is increased in patients with EoE compared to healthy controls or those with GERD, as studies are very scarce and show contradictory results [110,116,117,118].
To provide a deeper insight into the research about TGF-β1 in fibrosis, the study design, the patient or sample groups that were compared, the techniques used to detect TGF-β1 (Figure 1A), and whether the analysis was carried out at the pre-transcriptional or post-translational level were then analyzed. The experimental designs consisted of determining TGF-β1 mRNA and protein by quantitative methods in human esophageal samples, comparing patients and controls, as well as patients with active EoE versus inactive disease (Figure 1B). Overall, five publications included a more complete study design to determine whether TGF-β1 was involved in EoE fibrosis (Figure 1C), since they were carried out on human samples using quantitative methods.
It seems that the available literature is either inconclusive or inadequate in regard to being able to claim a definitive pro-fibrotic role of TGF-β1 in EoE. This is due to the fact that most studies were performed using cell line cultures [112], or animal models [107,114,119,120], a method which does not necessarily reproduce the pathophysiology of the disease in humans. Where studies were performed on human samples, such as Sarbinowska et al. [117] and Pronio et al. [118], they used an inadequate (serum samples) or limited number of patients, respectively, which increased the risk of biased conclusions. Excluding these research works, only two papers claimed to have found differences in TGF-β1 [25,105], with another two having found no differences [110,115]. However, none of these studies parallelly analyzed TGF-β1 at the protein level (Figure 1C).

7. TGFβ Receptor Signaling: The Key of TGF-β1 Effects in EoE?

Recent research has focused attention on the role of TGF-β1 in EoE over its receptor TGFβR1 [121]. There are three receptors specific for the different TGFβ family ligands, which can be distinguished by their structural and functional properties and peptide mapping [122]. Research on murine models has shown that TGFβR participates in the increase in bronchial secretion secondary to rhinovirus infection [123] and in airway smooth muscle cell proliferation [124]. A role of TGFβR 1 variant has been more recently involved in EoE; based on the demonstration, this receptor was essential in maintaining epithelial cell homeostasis to control allergic inflammation in a mouse model of EoE [121]. Knockout mice bearing TGFβR1 loss-of-function variants developed symptoms, pathological, immunological, and transcriptional changes in the esophagus consistent with human EoE. In particular, the primary defect in epithelial development in knockout mice led to initiate a Th2 inflammatory cascade independent of lymphocytes or allergen exposure. Eosinophilic inflammation in this murine model was restricted to esophageal and gastric mucosa, whilst absent in other organs and tissues. Despite the undoubted value of this observation to advance the knowledge of the potential phenomena leading to fibrosis in EoE, some differences with the disease in humans should be noted, mainly including that mice with experimental EoE developed the disease independently of the exposure to allergens or the presence of lymphocyte infiltrate in the esophageal tissue, which is completely different in the human disease. Exclusive feeding with an elemental diet (completely lacking food antigens) almost universally reverses inflammatory infiltration in EoE patients [4,125], while lymphocytes are part of the cellular infiltrate of the esophagus, and their density varies with eosinophil density [126]. Finally, eosinophilic infiltration of the gastric mucosa is absent in the human form of the disease, but not in this experimental EoE model. The authors justified this finding in that the proximal forestomach in mice is lined by stratified squamous epithelium that is contiguous with the esophagus up to the limiting ridge.

8. Profibrotic Mechanisms Aside of TGF-β

TGF-β signaling, with its downstream activation of Smad-mediated (also referred to as the canonical profibrotic pathway), [127] is the most widely involved mechanism in disease-associated fibrosis in many organs. However, non-canonical pathways have also been identified as primary drivers of this process in some organs and under specific circumstances. Non-TGF-β-mediated pathways involve different inflammatory agents and metabolic shifts in intercellular communication within the tissue microenvironment and can also trigger EMT; some of these pathways are presented below:
(a)
Bone Morphogenetic Protein (BMP) is part of the TGF-β superfamily. BMP signaling regulates the maintenance of adult tissue homeostasis within multiple tissues [128], being mostly studied in bone. Its role in the morphogenesis of the digestive tract is increasingly recognized [129], however, including its role in the development of the Barrett esophagus [130]; but as of yet, no role in EoE has been described.
(b)
Macrophages are highly heterogeneous cells of the innate immune system, involved in innate immunity, inflammatory responses, homeostasis, and tissue regeneration [131]. Th2 cytokines, such as IL-4 and IL-13, are able to: polarize macrophages to M2 cells, which produce chemokines that recruit Th2 lymphocytes and T regulatory; promote dysfunction, which can impair the proper regenerative process; and promote the development of fibrosis, deposition of type I and III collagen, and myofibroblasts activation [132]. The M2-derived specific chemokine CCL18 has been involved in pulmonary/alveolar, peritoneal, and hepatic fibrosis [133]. High plasma levels of CCL18 have been associated with progressive fibrosing disorders of the lungs and liver; and their elevated concentration in the peritoneal dialysis effluent predicts fibrosis and dysfunction of the peritoneal membrane [120]. Preliminary evidence points towards a role for M2 signaling in fibrosis associated with EoE [110]; and this should be further investigated.
(c)
An IL-13-dependent fibrotic mechanism, independent of the downstream actions of TGF-β1 and MMP-9, was described in Schistosoma mansoni infection-related liver fibrosis [134]. These mechanisms might be particularly relevant for diseases where a vigorous type-2 cytokine response is also present, as in EoE, but no study has addressed them in this context to date.

9. Reversibility of Fibrosis in EoE

Fibrosis is a common outcome in many inflammatory diseases that may disintegrate the regular structure of organs and cause persistent damage. However, clinical observations and experimental models provide evidence that fibrosis is not irreversible, and once the chronic tissue injury is resolved, fibrosis may regress through the deactivation of myofibroblasts, degradation of ECM, and fibrolysis of excess matrix scaffold [52]. The ability of fibrosis to reverse and the degree of recovery may vary depending on the tissue type, its capacity to regenerate, its originating mechanism, and to a certain extent, on its degree of evolution. Termination of the underlying cause of tissue damage avoids further activation of myofibroblasts and deactivates the inflammatory pathways, while regenerative pathways in parenchymal cells are provided by the development of an anti-inflammatory microenvironment. Thus, myofibroblasts undergo apoptosis or revert to an inactive phenotype. The ECM is then degraded by matrix metalloproteinases (MMPs) that digest collagen and other components. Macrophages contribute to phagocytizing ECM fragments and to reducing MMP-inhibitory proteins [135].
Evidence of fibrosis reversion in EoE after effective anti-inflammatory therapy has been provided at both tissue and clinical levels [103,110,136,137]. The degree of lamina propria remodeling, demonstrated with Mason trichrome staining in esophageal biopsies obtained from children with EoE, before and after at least 3 months of therapy with budesonide, reduced fibrosis among responders, where TGF-β1- and pSmad2/3-positive cells were diminished [113]. Similar findings were reported in adults treated with fluticasone propionate for one year [110]. In this study, reduced fibrosis was visible in deep esophageal biopsies (including the whole lamina propria) accompanied by vanishing eosinophils in both epithelial and lamina propria layers and reduced mRNA levels for IL-5, FGF-9, and CCL18. Notably, mRNA expression levels of TGF-β1 still remained. In another trial, treatment with viscous budesonide reduced the TGF-β epithelial cells by 75% in areas of intense eosinophil infiltration [109].
Rings and strictures are the endoscopic features characteristic of fibrosis in EoE, along with narrow caliber esophagi. Some evidence in the literature showed that endoscopic fibrotic changes in EoE may improve with anti-inflammatory therapy when assessed with endoFLIP. Improvements in esophageal dysmotility have been demonstrated with topical corticosteroids [138], diets [137,139], and even proton pump inhibitors [136]. Improvements in endoscopic features of fibrosis after anti-inflammatory treatment have also been described; recently, the benefit of Dupilumab (a monoclonal antibody that blocks the heterodimeric receptor common for IL-4 and IL-13) on severe, refractory, and fibrostenotic EoE was assessed. After a median of 6 months, most patients achieved histological, endoscopic, and symptom improvement, along with improved esophageal stricture diameter [140].
There are, however, few therapeutics that have shown to be effective once dense fibrotic tissue has been formed and patients present with strictures that cannot be passed with an endoscope. Endoscopic dilation has been used as a mechanical procedure to enlarge a narrowed esophageal lumen when patients are unable to swallow solid food properly or present repeated episodes of esophageal choking, which typically occurs with an esophageal diameter lower than 13 mm [141].

10. Conclusions and Perspectives

The recognition of EoE as a prevalent cause of esophageal symptoms, capable of deteriorating the quality of life of those who suffer from it, has been accompanied by rapid progress in the description of the cellular and molecular bases of the disease. The development of therapies for EoE now includes drugs specifically directed against cytokines, with a key role in the initiation and maintenance of the inflammatory response. Fibrous remodeling of the esophagus represents the main sequel of untreated or insufficiently treated disease, and the major consequence of delayed diagnosis. Collagen deposition in the esophagus, in its most advanced forms, seriously alters the structure and functionality of the esophagus and severely impairs quality of life. Limited evidence suggests that available anti-inflammatory treatments are effective in reversing fibrotic phenomena in EoE, at least in its initial stages, and preliminary experiences with new biological drugs seem promising for the most severe fibrotic forms of EoE. However, research on the molecular basis that leads to it has been scarce, and has often tried to reproduce in the esophagus mechanisms well known in other type 2 inflammatory diseases, such as bronchial asthma. Still, there is no solid evidence that fibrosis in EoE appears to be mainly mediated by TGF-β, thus opening the door to investigating alternative mechanisms largely independent of TGF-β. This approach might identify potential therapeutic targets directed to one of the most severe consequences of EoE.

Author Contributions

Conceptualization, L.A.-G. and A.J.L.; writing—original draft preparation, L.A.-G. and A.J.L.; writing—review and editing, A.J.L., L.A.-G., E.G.-N., E.J.L.-M., P.N. and L.R.-A. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by Asociación de Investigación Biomédica La-Mancha Centro, which had no role in study design, data collection, interpretation, or writing of the report.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

We are grateful to Melanie Radcliff for English language revision.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Lucendo, A.J.; Molina-Infante, J.; Arias, A.; Von Arnim, U.; Bredenoord, A.J.; Bussmann, C.; Dias, J.A.; Bove, M.; González-Cervera, J.; Larsson, H.; et al. Guidelines on eosinophilic esophagitis: Evidence-based statements and recommendations for diagnosis and management in children and adults. United Eur. Gastroenterol. J. 2017, 5, 335–358. [Google Scholar] [CrossRef]
  2. Attwood, S.E.A.; Smyrk, T.C.; Demeester, T.R.; Jones, J.B. Esophageal eosinophilia with dysphagia. A distinct clinicopathologic syndrome. Dig. Dis. Sci. 1993, 38, 109–116. [Google Scholar] [CrossRef] [PubMed]
  3. Straumann, A.; Spichtin, H.P.; Bernoulli, R.; Loosli, J.; Vögtlin, J. Idiopathic eosinophilic esophagitis: A frequently overlooked disease with typical clinical aspects and discrete endoscopic findings. Schweiz. Med. Wochenschr. 1994, 124, 1419–1429. [Google Scholar]
  4. Kelly, K.J.; Lazenby, A.J.; Rowe, P.C.; Yardley, J.H.; Perman, J.A.; Sampson, H.A. Eosinophilic esophagitis attributed to gastroesophageal reflux: Improvement with an amino acid-based formula. Gastroenterology 1995, 109, 1503–1512. [Google Scholar] [CrossRef] [PubMed]
  5. Simon, D.; Cianferoni, A.; Spergel, J.M.; Aceves, S.; Holbreich, M.; Venter, C.; Rothenberg, M.E.; Terreehorst, I.; Muraro, A.; Lucendo, A.J.; et al. Eosinophilic esophagitis is characterized by a non-IgE-mediated food hypersensitivity. Allergy 2016, 71, 611–620. [Google Scholar] [CrossRef]
  6. Hahn, J.W.; Lee, K.; Shin, J.I.; Cho, S.H.; Turner, S.; Shin, J.U.; Yeniova, A.; Koyanagi, A.; Jacob, L.; Smith, L.; et al. Global Incidence and Prevalence of Eosinophilic Esophagitis, 1976–2022: A Systematic Review and Meta-analysis. Clin. Gastroenterol. Hepatol. 2023, 21, 3270–3284.e77. [Google Scholar] [CrossRef]
  7. Arias, Á.; Lucendo, A.J. Incidence and prevalence of eosinophilic oesophagitis increase continiously in adults and children in Central Spain: A 12-year population-based study. Dig. Liver Dis. 2019, 51, 55–62. [Google Scholar] [CrossRef] [PubMed]
  8. Robson, J.; O’gorman, M.; McClain, A.; Mutyala, K.; Davis, C.; Barbagelata, C.; Wheeler, J.; Firszt, R.; Smith, K.; Patel, R.; et al. Incidence and Prevalence of Pediatric Eosinophilic Esophagitis in Utah Based on a 5-Year Population-Based Study. Clin. Gastroenterol. Hepatol. 2019, 17, 107–114. [Google Scholar] [CrossRef]
  9. Straumann, A.; Spichtin, H.-P.; Grize, L.; Bucher, K.A.; Beglinger, C.; Simon, H.-U. Natural history of primary eosinophilic esophagitis: A follow-up of 30 adult patients for up to 11.5 years. Gastroenterology 2003, 125, 1660–1669. [Google Scholar] [CrossRef]
  10. Lucendo, A.J.; Arias-González, L.; Molina-Infante, J.; Arias, Á. Systematic review: Health-related quality of life in children and adults with eosinophilic oesophagitis-instruments for measurement and determinant factors. Aliment. Pharmacol. Ther. 2017, 46, 401–409. [Google Scholar] [CrossRef]
  11. Alexander, J.; Katzka, D. Editorial: Expanding a narrow perspective on narrow calibre oesophagus in eosinophilic oesophagitis—Authors’ reply. Aliment. Pharmacol. Ther. 2015, 41, 148–149. [Google Scholar] [CrossRef] [PubMed]
  12. Laserna-Mendieta, E.J.; Navarro, P.; Casabona-Francés, S.; Savarino, E.V.; Pérez-Martínez, I.; Guagnozzi, D.; Barrio, J.; Perello, A.; Guardiola-Arévalo, A.; Betoré-Glaria, M.E.; et al. Differences between childhood- and adulthood-onset eosinophilic esophagitis: An analysis from the EoE connect registry. Dig. Liver Dis. 2023, 55, 350–359. [Google Scholar] [CrossRef]
  13. Lucendo, A.; Molina-Infante, J. Current treatment options and long-term outcomes in patients with eosinophilic esophagitis. Expert. Rev. Clin. Immunol. 2022, 18, 859–872. [Google Scholar] [CrossRef]
  14. Grueso-Navarro, E.; Navarro, P.; Laserna-Mendieta, E.J.; Lucendo, A.J.; Arias-González, L. Blood-Based Biomarkers for Eosinophilic Esophagitis and Concomitant Atopic Diseases: A Look into the Potential of Extracellular Vesicles. Int. J. Mol. Sci. 2023, 24, 3669. [Google Scholar] [CrossRef] [PubMed]
  15. Tamarit-Sebastian, S.; Ferrer-Soler, F.M.; Lucendo, A.J. Current options and investigational drugs for the treatment of eosinophilic esophagitis. Expert. Opin. Investig. Drugs 2022, 31, 193–210. [Google Scholar] [CrossRef] [PubMed]
  16. Molina-Jiménez, F.; Ugalde-Triviño, L.; Arias-González, L.; Relaño-Rupérez, C.; Casabona, S.; Pérez-Fernández, M.T.; Martín-Domínguez, V.; Fernández-Pacheco, J.; Laserna-Mendieta, E.J.; Muñoz-Hernández, P.; et al. Proteomic analysis of the esophageal epithelium reveals key features of eosinophilic esophagitis pathophysiology. Allergy 2023, 78, 2732–2744. [Google Scholar] [CrossRef]
  17. Underwood, B.; Troutman, T.D.; Schwartz, J.T. Breaking down the complex pathophysiology of eosinophilic esophagitis. Ann. Allergy Asthma Immunol. 2023, 130, 28–39. [Google Scholar] [CrossRef]
  18. Straumann, A.; Bauer, M.; Fischer, B.; Blaser, K.; Simon, H.-U. Idiopathic eosinophilic esophagitis is associated with a T(H)2-type allergic inflammatory response. J. Allergy Clin. Immunol. 2001, 108, 954–961. [Google Scholar] [CrossRef]
  19. Racca, F.; Pellegatta, G.; Cataldo, G.; Vespa, E.; Carlani, E.; Pelaia, C.; Paoletti, G.; Messina, M.R.; Nappi, E.; Canonica, G.W.; et al. Type 2 Inflammation in Eosinophilic Esophagitis: From Pathophysiology to Therapeutic Targets. Front. Physiol. 2021, 12, 815842. [Google Scholar] [CrossRef]
  20. McDaniel, M.M.; Lara, H.I.; von Moltke, J. Initiation of type 2 immunity at barrier surfaces. Mucosal Immunol. 2023, 16, 86–97. [Google Scholar] [CrossRef]
  21. Goretzki, A.; Zimmermann, J.; Rainer, H.; Lin, Y.-J.; Schülke, S. Immune Metabolism in TH2 Responses: New Opportunities to Improve Allergy Treatment—Disease-Specific Findings (Part 1). Curr. Allergy Asthma Rep. 2023, 23, 29–40. [Google Scholar] [CrossRef] [PubMed]
  22. Rothenberg, M.E. Biology and treatment of eosinophilic esophagitis. Gastroenterology 2009, 137, 1238–1249. [Google Scholar] [CrossRef] [PubMed]
  23. Fulkerson, P.C.; Rothenberg, M.E. Eosinophil Development, Disease Involvement, and Therapeutic Suppression. Adv. Immunol. 2018, 138, 1–34. [Google Scholar]
  24. Mishra, A.; Hogan, S.P.; Brandt, E.B.; Rothenberg, M.E. IL-5 promotes eosinophil trafficking to the esophagus. J. Immunol. 2002, 168, 2464–2469. [Google Scholar] [CrossRef] [PubMed]
  25. Mishra, A.; Wang, M.; Pemmaraju, V.R.; Collins, M.H.; Fulkerson, P.C.; Abonia, J.P.; Blanchard, C.; Putnam, P.E.; Rothenberg, M.E. Esophageal remodeling develops as a consequence of tissue specific IL-5-induced eosinophilia. Gastroenterology 2008, 134, 204–214. [Google Scholar] [CrossRef] [PubMed]
  26. Massironi, S.; Mulinacci, G.; Gallo, C.; Elvevi, A.; Danese, S.; Invernizzi, P.; Vespa, E. Mechanistic Insights into Eosinophilic Esophagitis: Therapies Targeting Pathophysiological Mechanisms. Cells 2023, 12, 2473. [Google Scholar] [CrossRef] [PubMed]
  27. Dellon, E.S.; Rothenberg, M.E.; Collins, M.H.; Hirano, I.; Chehade, M.; Bredenoord, A.J.; Lucendo, A.J.; Spergel, J.M.; Aceves, S.; Sun, X.; et al. Dupilumab in Adults and Adolescents with Eosinophilic Esophagitis. N. Engl. J. Med. 2022, 387, 2317–2330. [Google Scholar] [CrossRef]
  28. Rothenberg, M.E.; Dellon, E.S.; Collins, M.H.; Hirano, I.; Chehade, M.; Bredenoord, A.J.; Lucendo, A.J.; Spergel, J.M.; Sun, X.; Hamilton, J.D.; et al. Efficacy and safety of dupilumab up to 52 weeks in adults and adolescents with eosinophilic oesophagitis (LIBERTY EoE TREET study): A multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Gastroenterol. Hepatol. 2023, 8, 990–1004. [Google Scholar] [CrossRef]
  29. Blanchard, C.; Mingler, M.K.; Vicario, M.; Abonia, J.P.; Wu, Y.Y.; Lu, T.X.; Collins, M.H.; Putnam, P.E.; Wells, S.I.; Rothenberg, M.E. IL-13 involvement in eosinophilic esophagitis: Transcriptome analysis and reversibility with glucocorticoids. J. Allergy Clin. Immunol. 2007, 120, 1292–1300. [Google Scholar] [CrossRef]
  30. Neilsen, C.V.; Bryce, P.J. Interleukin-13 directly promotes oesophagus production of CCL11 and CCL24 and the migration of eosinophils. Clin. Exp. Allergy 2010, 40, 427–434. [Google Scholar] [CrossRef]
  31. Blanchard, C.; Wang, N.; Stringer, K.F.; Mishra, A.; Fulkerson, P.C.; Abonia, J.P.; Jameson, S.C.; Kirby, C.; Konikoff, M.R.; Collins, M.H.; et al. Eotaxin-3 and a uniquely conserved gene-expression profile in eosinophilic esophagitis. J. Clin. Investig. 2006, 116, 536–547. [Google Scholar] [CrossRef]
  32. Litosh, V.A.; Rochman, M.; Rymer, J.K.; Porollo, A.; Kottyan, L.C.; Rothenberg, M.E. Calpain-14 and its association with eosinophilic esophagitis. J. Allergy Clin. Immunol. 2017, 139, 1762–1771.e7. [Google Scholar] [CrossRef] [PubMed]
  33. Davis, B.P.; Stucke, E.M.; Khorki, M.E.; Litosh, V.A.; Rymer, J.K.; Rochman, M.; Travers, J.; Kottyan, L.C.; Rothenberg, M.E. Eosinophilic esophagitis-linked calpain 14 is an IL-13-induced protease that mediates esophageal epithelial barrier impairment. JCI Insight 2016, 1, e86355. [Google Scholar] [CrossRef]
  34. Blanchard, C.; Stucke, E.M.; Burwinkel, K.; Caldwell, J.M.; Collins, M.H.; Ahrens, A.; Buckmeier, B.K.; Jameson, S.C.; Greenberg, A.; Kaul, A.; et al. Coordinate interaction between IL-13 and epithelial differentiation cluster genes in eosinophilic esophagitis. J. Immunol. 2010, 184, 4033–4041. [Google Scholar] [CrossRef] [PubMed]
  35. Sherrill, J.D.; Kc, K.; Wu, D.; Djukic, Z.; Caldwell, J.M.; Stucke, E.M.; A Kemme, K.; Costello, M.S.; Mingler, M.K.; Blanchard, C.; et al. Desmoglein-1 regulates esophageal epithelial barrier function and immune responses in eosinophilic esophagitis. Mucosal Immunol. 2014, 7, 718–729. [Google Scholar] [CrossRef]
  36. Wu, L.; Oshima, T.; Li, M.; Tomita, T.; Fukui, H.; Watari, J.; Miwa, H. Filaggrin and tight junction proteins are crucial for IL-13-mediated esophageal barrier dysfunction. Am. J. Physiol. Gastrointest. Liver Physiol. 2018, 315, G341–G350. [Google Scholar] [CrossRef] [PubMed]
  37. Ravelli, A.; Villanacci, V.; Cadei, M.; Fuoti, M.; Gennati, G.; Salemme, M. Dilated intercellular spaces in eosinophilic esophagitis. J. Pediatr. Gastroenterol. Nutr. 2014, 59, 589–593. [Google Scholar] [CrossRef]
  38. Marietta, E.V.; Geno, D.M.; Smyrk, T.C.; Becker, A.; Alexander, J.A.; Camilleri, M.; Murray, J.A.; Katzka, D.A. Presence of intraepithelial food antigen in patients with active eosinophilic oesophagitis. Aliment. Pharmacol. Ther. 2017, 45, 427–433. [Google Scholar] [CrossRef]
  39. Ravi, A.; Marietta, E.V.; Alexander, J.A.; Peterson, K.; Lavey, C.; Geno, D.M.; Murray, J.A.; Katzka, D.A. Mucosal penetration and clearance of gluten and milk antigens in eosinophilic oesophagitis. Aliment. Pharmacol. Ther. 2021, 53, 410–417. [Google Scholar] [CrossRef]
  40. Akei, H.S.; Mishra, A.; Blanchard, C.; Rothenberg, M.E. Epicutaneous antigen exposure primes for experimental eosinophilic esophagitis in mice. Gastroenterology 2005, 129, 985–994. [Google Scholar] [CrossRef]
  41. Cheng, E.; Souza, R.F.; Spechler, S.J.; Judd, L.M.; Heine, R.G.; Menheniott, T.R.; Buzzelli, J.; O’Brien-Simpson, N.; Pavlic, D.; O’Connor, L.; et al. Tissue remodeling in eosinophilic esophagitis. Am. J. Physiol. Gastrointest. Liver Physiol. 2012, 303, G1175–G1187. [Google Scholar] [CrossRef] [PubMed]
  42. Muir, A.B.; Wang, J.X.; Nakagawa, H. Epithelial-stromal crosstalk and fibrosis in eosinophilic esophagitis. J. Gastroenterol. 2019, 54, 10–18. [Google Scholar] [CrossRef] [PubMed]
  43. Theocharis, A.D.; Skandalis, S.S.; Gialeli, C.; Karamanos, N.K. Extracellular matrix structure. Adv. Drug Deliv. Rev. 2016, 97, 4–27. [Google Scholar] [CrossRef] [PubMed]
  44. Sumida, A.; Hasegawa, Y.; Okamoto, M.; Hashimoto, N.; Imaizumi, K.; Yatsuya, H.; Yokoi, T.; Takagi, K.; Shimokata, K.; Kawabe, T. TH1/TH2 immune response in lung fibroblasts in interstitial lung disease. Arch. Med. Res. 2008, 39, 503–510. [Google Scholar] [CrossRef] [PubMed]
  45. Kokubo, K.; Onodera, A.; Kiuchi, M.; Tsuji, K.; Hirahara, K.; Nakayama, T. Conventional and pathogenic Th2 cells in inflammation, tissue repair, and fibrosis. Front. Immunol. 2022, 13, 945063. [Google Scholar] [CrossRef] [PubMed]
  46. Straumann, A.; Spichtin, H.-P.; Bucher, K.A.; Heer, P.; Simon, H.-U. Eosinophilic esophagitis: Red on microscopy, white on endoscopy. Digestion. 2004, 70, 109–116. [Google Scholar] [CrossRef] [PubMed]
  47. Fontillon, M.; Lucendo, A.J. Transmural eosinophilic infiltration and fibrosis in a patient with non-traumatic Boerhaave’s syndrome due to eosinophilic esophagitis. Am. J. Gastroenterol. 2012, 107, 1762. [Google Scholar] [CrossRef] [PubMed]
  48. Clayton, F.; Fang, J.C.; Gleich, G.J.; Lucendo, A.J.; Olalla, J.M.; Vinson, L.A.; Lowichik, A.; Chen, X.; Emerson, L.; Cox, K.; et al. Eosinophilic esophagitis in adults is associated with IgG4 and not mediated by IgE. Gastroenterology 2014, 147, 602–609. [Google Scholar] [CrossRef]
  49. Visaggi, P.; Ghisa, M.; Marabotto, E.; Venturini, A.; Donati, D.S.; Bellini, M.; Savarino, V.; de Bortoli, N.; Savarino, E. Esophageal dysmotility in patients with eosinophilic esophagitis: Pathogenesis, assessment tools, manometric characteristics, and clinical implications. Esophagus 2023, 20, 29–38. [Google Scholar] [CrossRef]
  50. Aceves, S.; Broide, D. Airway Fibrosis and Angiogenesis due to Eosinophil Trafficking in Chronic Asthma. Curr. Mol. Med. 2008, 8, 350–358. [Google Scholar] [CrossRef]
  51. Lupher, M.L.; Gallatin, W.M. Regulation of fibrosis by the immune system. Adv. Immunol. 2006, 89, 245–288. [Google Scholar] [PubMed]
  52. Weiskirchen, R.; Weiskirchen, S.; Tacke, F. Organ and tissue fibrosis: Molecular signals, cellular mechanisms and translational implications. Mol. Aspects Med. 2019, 65, 2–15. [Google Scholar] [CrossRef] [PubMed]
  53. Bonnans, C.; Chou, J.; Werb, Z. Remodelling the extracellular matrix in development and disease. Nat. Rev. Mol. Cell Biol. 2014, 15, 786–801. [Google Scholar] [CrossRef] [PubMed]
  54. Gattazzo, F.; Urciuolo, A.; Bonaldo, P. Extracellular matrix: A dynamic microenvironment for stem cell niche. Biochim. Biophys. Acta 2014, 1840, 2506–2519. [Google Scholar] [CrossRef] [PubMed]
  55. LLong, H.; Lichtnekert, J.; Andrassy, J.; Schraml, B.U.; Romagnani, P.; Anders, H.-J. Macrophages and fibrosis: How resident and infiltrating mononuclear phagocytes account for organ injury, regeneration or atrophy. Front. Immunol. 2023, 14, 1194988. [Google Scholar] [CrossRef] [PubMed]
  56. Jensen, E.T.; Kuhl, J.T.; Martin, L.J.; Langefeld, C.D.; Dellon, E.S.; Rothenberg, M.E. Early-life environmental exposures interact with genetic susceptibility variants in pediatric patients with eosinophilic esophagitis. J. Allergy Clin. Immunol. 2018, 141, 632–637.e5. [Google Scholar] [CrossRef] [PubMed]
  57. Castro-Rodriguez, J.A.; Forno, E.; Rodriguez-Martinez, C.E.; Celedón, J.C. Risk and Protective Factors for Childhood Asthma: What Is the Evidence? J. Allergy Clin. Immunol. Pract. 2016, 4, 1111–1122. [Google Scholar] [CrossRef]
  58. Laserna-Mendieta, E.J.; FitzGerald, J.A.; Arias-Gonzalez, L.; Ollala, J.M.; Bernardo, D.; Claesson, M.J.; Lucendo, A.J. Esophageal microbiome in active eosinophilic esophagitis and changes induced by different therapies. Sci. Rep. 2021, 11, 7113. [Google Scholar] [CrossRef]
  59. Arias, Á.; Lucendo, A.J. Molecular basis and cellular mechanisms of eosinophilic esophagitis for the clinical practice. Expert. Rev. Gastroenterol. Hepatol. 2019, 13, 99–117. [Google Scholar] [CrossRef]
  60. Noti, M.; Wojno, E.D.T.; Kim, B.S.; Siracusa, M.C.; Giacomin, P.R.; Nair, M.G.; Benitez, A.J.; Ruymann, K.R.; Muir, A.B.; Hill, D.A.; et al. Thymic stromal lymphopoietin-elicited basophil responses promote eosinophilic esophagitis. Nat. Med. 2013, 19, 1005–1013. [Google Scholar] [CrossRef]
  61. Kalluri, R.; Neilson, E.G. Epithelial-mesenchymal transition and its implications for fibrosis. J. Clin. Investig. 2003, 112, 1776–1784. [Google Scholar] [CrossRef] [PubMed]
  62. Kalluri, R.; Weinberg, R.A. The basics of epithelial-mesenchymal transition. J. Clin. Investig. 2009, 119, 1420–1428. [Google Scholar] [CrossRef] [PubMed]
  63. Aceves, S.S. Remodeling and fibrosis in chronic eosinophil inflammation. Dig. Dis. 2014, 32, 15–21. [Google Scholar] [CrossRef]
  64. Lech, M.; Anders, H.-J. Macrophages and fibrosis: How resident and infiltrating mononuclear phagocytes orchestrate all phases of tissue injury and repair. Biochim. Biophys. Acta 2013, 1832, 989–997. [Google Scholar] [CrossRef] [PubMed]
  65. Xia, T.; Fu, S.; Yang, R.; Yang, K.; Lei, W.; Yang, Y.; Zhang, Q.; Zhao, Y.; Yu, J.; Yu, L.; et al. Advances in the study of macrophage polarization in inflammatory immune skin diseases. J. Inflamm. 2023, 20, 33. [Google Scholar] [CrossRef]
  66. Vannella, K.M.; Wynn, T.A. Mechanisms of Organ Injury and Repair by Macrophages. Annu. Rev. Physiol. 2017, 79, 593–617. [Google Scholar] [CrossRef]
  67. Rappolee, D.A.; Mark, D.; Banda, M.J.; Werb, Z. Wound macrophages express TGF-alpha and other growth factors in vivo: Analysis by mRNA phenotyping. Science 1988, 241, 708–712. [Google Scholar] [CrossRef]
  68. Tai, Y.; Woods, E.L.; Dally, J.; Kong, D.; Steadman, R.; Moseley, R.; Midgley, A.C. Myofibroblasts: Function, Formation, and Scope of Molecular Therapies for Skin Fibrosis. Biomolecules 2021, 11, 1095. [Google Scholar] [CrossRef]
  69. Muir, A.B.; Dods, K.; Noah, Y.; Toltzis, S.; Chandramouleeswaran, P.M.; Lee, A.; Benitez, A.; Bedenbaugh, A.; Falk, G.W.; Wells, R.G.; et al. EEsophageal epithelial cells acquire functional characteristics of activated myofibroblasts after undergoing an epithelial to mesenchymal transition. Exp. Cell Res. 2015, 330, 102–110. [Google Scholar] [CrossRef]
  70. Dellon, E.S.; Kim, H.P.; Sperry, S.L.W.; Rybnicek, D.A.; Woosley, J.T.; Shaheen, N.J. A phenotypic analysis shows that eosinophilic esophagitis is a progressive fibrostenotic disease. Gastrointest. Endosc. 2014, 79, 577–585. [Google Scholar] [CrossRef]
  71. Shoda, T.; Wen, T.; Aceves, S.S.; Abonia, J.P.; Atkins, D.; A Bonis, P.; Caldwell, J.M.; E Capocelli, K.; Carpenter, C.L.; Collins, M.H.; et al. Eosinophilic oesophagitis endotype classification by molecular, clinical, and histopathological analyses: A cross-sectional study. Lancet Gastroenterol. Hepatol. 2018, 3, 477–488. [Google Scholar] [CrossRef]
  72. Schoepfer, A.M.; Safroneeva, E.; Bussmann, C.; Kuchen, T.; Portmann, S.; Simon, H.; Straumann, A. Delay in diagnosis of eosinophilic esophagitis increases risk for stricture formation in a time-dependent manner. Gastroenterology 2013, 145, 1230–1236. [Google Scholar] [CrossRef]
  73. Lipka, S.; Kumar, A.; Richter, J.E. Impact of Diagnostic Delay and Other Risk Factors on Eosinophilic Esophagitis Phenotype and Esophageal Diameter. J. Clin. Gastroenterol. 2016, 50, 134–140. [Google Scholar] [CrossRef] [PubMed]
  74. Chehade, M.; Jones, S.M.; Pesek, R.D.; Burks, A.W.; Vickery, B.P.; Wood, R.A.; Leung, D.Y.; Furuta, G.T.; Fleischer, D.M.; Henning, A.K.; et al. Phenotypic Characterization of Eosinophilic Esophagitis in a Large Multicenter Patient Population from the Consortium for Food Allergy Research. J. Allergy Clin. Immunol. Pract. 2018, 6, 1534–1544.e5. [Google Scholar] [CrossRef] [PubMed]
  75. Martín Martín, L.; Santander, C.; Lopez Martín, M.C.; Espinoza-Ríos, J.; Chavarría-Herbozo, C.; Gisbert, J.P.; Moreno-Otero, R. Esophageal motor abnormalities in eosinophilic esophagitis identified by high-resolution manometry. J. Gastroenterol. Hepatol. 2011, 26, 1447–1450. [Google Scholar] [CrossRef] [PubMed]
  76. Lucendo, A.J.; Pascual-Turrión, J.M.; Navarro, M.; Comas, C.; Castillo, P.; Letrán, A.; Caballero, M.T.; Larrauri, J. Endoscopic, bioptic, and manometric findings in eosinophilic esophagitis before and after steroid therapy: A case series. Endoscopy 2007, 39, 765–771. [Google Scholar] [CrossRef]
  77. Nurko, S.; Rosen, R.; Furuta, G.T. Esophageal dysmotility in children with eosinophilic esophagitis: A study using prolonged esophageal manometry. Am. J. Gastroenterol. 2009, 104, 3050–3057. [Google Scholar] [CrossRef] [PubMed]
  78. van Rhijn, B.D.; Oors, J.M.; Smout, A.J.P.M.; Bredenoord, A.J. Prevalence of esophageal motility abnormalities increases with longer disease duration in adult patients with eosinophilic esophagitis. Neurogastroenterol. Motil. 2014, 26, 1349–1355. [Google Scholar] [CrossRef]
  79. de Rooij, W.E.; Evertsz, F.B.; Lei, A.; Bredenoord, A.J. General Well-being and Coping Strategies in Adult Eosinophilic Esophagitis Patients. J. Neurogastroenterol. Motil. 2022, 28, 390–400. [Google Scholar] [CrossRef]
  80. Lin, Z.; Kahrilas, P.J.; Xiao, Y.; Nicodème, F.; Gonsalves, N.; Hirano, I.; Pandolfino, J.E. Functional luminal imaging probe topography: An improved method for characterizing esophageal distensibility in eosinophilic esophagitis. Ther. Adv. Gastroenterol. 2013, 6, 97–107. [Google Scholar] [CrossRef]
  81. Kong, P.; Christia, P.; Frangogiannis, N.G. The pathogenesis of cardiac fibrosis. Cell. Mol. Life Sci. 2014, 71, 549–574. [Google Scholar] [CrossRef] [PubMed]
  82. Noble, P.W.; Barkauskas, C.E.; Jiang, D. Pulmonary fibrosis: Patterns and perpetrators. J. Clin. Investig. 2012, 122, 2756–2762. [Google Scholar] [CrossRef]
  83. Humphreys, B.D. Mechanisms of Renal Fibrosis. Annu. Rev. Physiol. 2018, 80, 309–326. [Google Scholar] [CrossRef] [PubMed]
  84. Ho, Y.Y.; Lagares, D.; Tager, A.M.; Kapoor, M. Fibrosis—A lethal component of systemic sclerosis. Nat. Rev. Rheumatol. 2014, 10, 390–402. [Google Scholar] [CrossRef] [PubMed]
  85. Latella, G.; Di Gregorio, J.; Flati, V.; Rieder, F.; Lawrance, I.C. Mechanisms of initiation and progression of intestinal fibrosis in IBD. Scand. J. Gastroenterol. 2015, 50, 53–65. [Google Scholar] [CrossRef] [PubMed]
  86. Rieder, F.; Fiocchi, C.; Rogler, G. Mechanisms, Management, and Treatment of Fibrosis in Patients with Inflammatory Bowel Diseases. Gastroenterology 2017, 152, 340–350.e6. [Google Scholar] [CrossRef]
  87. Budi, E.H.; Schaub, J.R.; Decaris, M.; Turner, S.; Derynck, R. TGF-β as a driver of fibrosis: Physiological roles and therapeutic opportunities. J. Pathol. 2021, 254, 358–373. [Google Scholar] [CrossRef]
  88. Wynn, T.A. Cellular and molecular mechanisms of fibrosis. J. Pathol. 2008, 214, 199–210. [Google Scholar] [CrossRef]
  89. Roberts, A.B.; A Anzano, M.; Lamb, L.C.; Smith, J.M.; Sporn, M.B. New class of transforming growth factors potentiated by epidermal growth factor: Isolation from non-neoplastic tissues. Proc. Natl. Acad. Sci. USA 1981, 78, 5339–5343. [Google Scholar] [CrossRef]
  90. Meng, X.-M.; Nikolic-Paterson, D.J.; Lan, H.Y. TGF-β: The master regulator of fibrosis. Nat. Rev. Nephrol. 2016, 12, 325–338. [Google Scholar] [CrossRef]
  91. Nickel, J.; Ten Dijke, P.; Mueller, T.D. TGF-β family co-receptor function and signaling. Acta Biochim. Biophys. Sin. 2018, 50, 12–36. [Google Scholar] [CrossRef]
  92. Gressner, A.M.; Weiskirchen, R. Modern pathogenetic concepts of liver fibrosis suggest stellate cells and TGF-beta as major players and therapeutic targets. J. Cell. Mol. Med. 2006, 10, 76–99. [Google Scholar] [CrossRef]
  93. Shull, M.M.; Ormsby, I.; Kier, A.B.; Pawlowski, S.; Diebold, R.J.; Yin, M.; Allen, R.; Sidman, C.; Proetzel, G.; Calvin, D.; et al. Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature 1992, 359, 693–699. [Google Scholar] [CrossRef]
  94. Hu, H.-H.; Chen, D.-Q.; Wang, Y.-N.; Feng, Y.-L.; Cao, G.; Vaziri, N.D.; Zhao, Y.-Y. New insights into TGF-β/Smad signaling in tissue fibrosis. Chem. Biol. Interact. 2018, 292, 76–83. [Google Scholar] [CrossRef]
  95. Zhang, Y.E. Non-Smad Signaling Pathways of the TGF-β Family. Cold Spring Harb. Perspect. Biol. 2017, 9, a022129. [Google Scholar] [CrossRef]
  96. Lodyga, M.; Hinz, B. TGF-β1—A truly transforming growth factor in fibrosis and immunity. Semin. Cell Dev. Biol. 2020, 101, 123–139. [Google Scholar] [CrossRef]
  97. Aoshiba, K.; Nagai, A. Differences in airway remodeling between asthma and chronic obstructive pulmonary disease. Clin. Rev. Allergy Immunol. 2004, 27, 35–43. [Google Scholar] [CrossRef]
  98. Davies, D.E. The role of the epithelium in airway remodeling in asthma. Proc. Am. Thorac. Soc. 2009, 6, 678–682. [Google Scholar] [CrossRef]
  99. Alyoussef, A. Blocking TGF-β type 1 receptor partially reversed skin tissue damage in experimentally induced atopic dermatitis in mice. Cytokine 2018, 106, 45–53. [Google Scholar] [CrossRef] [PubMed]
  100. Zhu, X.-J.; Lu, M.-P.; Chen, R.-X.; Bu, D.-Y.; Zhu, L.-P.; Wang, M.-L.; Yin, M.; Zhang, Z.-D.; Cheng, L. Polymorphism -509C/T in TGFB1 Promoter Is Associated with Increased Risk and Severity of Persistent Allergic Rhinitis in a Chinese Population. Am. J. Rhinol. Allergy 2020, 34, 597–603. [Google Scholar] [CrossRef] [PubMed]
  101. Liu, Y.; Shu, L.; Jiang, X.; Zhang, Y.; Chen, Q.; Shen, Y.; Yang, Y. The development of nasal polyps involves early middle meatus mucous remodeling via TGF-β1 mediated PAI-1 reduction. Braz. J. Otorhinolaryngol. 2023, 89, 366–373. [Google Scholar] [CrossRef]
  102. Katoh, S.; Matsumoto, N.; Tanaka, H.; Yasokawa, N.; Kittaka, M.; Kurose, K.; Abe, M.; Yoshioka, D.; Shirai, R.; Nakazato, M.; et al. Elevated levels of periostin and TGF-β1 in the bronchoalveolar lavage fluid of patients with idiopathic eosinophilic pneumonia. Asian Pac. J. Allergy Immunol. 2020, 38, 208–213. [Google Scholar]
  103. Aceves, S.S.; Newbury, R.O.; Dohil, R.; Bastian, J.F.; Broide, D.H. Esophageal remodeling in pediatric eosinophilic esophagitis. J. Allergy Clin. Immunol. 2007, 119, 206–212. [Google Scholar] [CrossRef]
  104. Rieder, F.; Nonevski, I.; Ma, J.; Ouyang, Z.; West, G.; Protheroe, C.; DePetris, G.; Schirbel, A.; Lapinski, J.; Goldblum, J.; et al. T-helper 2 cytokines, transforming growth factor beta1, and eosinophil products induce fibrogenesis and alter muscle motility in patients with eosinophilic esophagitis. Gastroenterology 2014, 146, 1266–1277. [Google Scholar] [CrossRef]
  105. Cho, J.Y.; Doshi, A.; Rosenthal, P.; Beppu, A.; Miller, M.; Aceves, S.; Broide, D. Smad3-deficient mice have reduced esophageal fibrosis and angiogenesis in a model of egg-induced eosinophilic esophagitis. J. Pediatr. Gastroenterol. Nutr. 2014, 59, 10–16. [Google Scholar] [CrossRef]
  106. Collison, A.M.; Sokulsky, L.A.; Sherrill, J.D.; Nightingale, S.; Hatchwell, L.; Talley, N.J.; Walker, M.M.; Rothenberg, M.E.; Mattes, J. TNF-related apoptosis-inducing ligand (TRAIL) regulates midline-1, thymic stromal lymphopoietin, inflammation, and remodeling in experimental eosinophilic esophagitis. J. Allergy Clin. Immunol. 2015, 136, 971–982. [Google Scholar] [CrossRef]
  107. Aceves, S.S.; Chen, D.; Newbury, R.O.; Dohil, R.; Bastian, J.F.; Broide, D.H. Mast cells infiltrate the esophageal smooth muscle in patients with eosinophilic esophagitis, express TGF-β1, and increase esophageal smooth muscle contraction. J. Allergy Clin. Immunol. 2010, 126, 1198–1204.e4. [Google Scholar] [CrossRef]
  108. Dohil, R.; Newbury, R.; Fox, L.; Bastian, J.; Aceves, S. Oral viscous budesonide is effective in children with eosinophilic esophagitis in a randomized, placebo-controlled trial. Gastroenterology 2010, 139, 418–429. [Google Scholar] [CrossRef] [PubMed]
  109. Straumann, A.; Conus, S.; Degen, L.; Felder, S.; Kummer, M.; Engel, H.; Bussmann, C.; Beglinger, C.; Schoepfer, A.; Simon, H. Budesonide is effective in adolescent and adult patients with active eosinophilic esophagitis. Gastroenterology 2010, 139, 1526–1537.e1. [Google Scholar] [CrossRef] [PubMed]
  110. Lucendo, A.J.; Arias, A.; De Rezende, L.C.; Yagüe-Compadre, J.L.; Mota-Huertas, T.; González-Castillo, S.; Cuesta, R.A.; Tenias, J.M.; Bellón, T. Subepithelial collagen deposition, profibrogenic cytokine gene expression, and changes after prolonged fluticasone propionate treatment in adult eosinophilic esophagitis: A prospective study. J. Allergy Clin. Immunol. 2011, 128, 1037–1046. [Google Scholar] [PubMed]
  111. Kagalwalla, A.F.; Akhtar, N.; Woodruff, S.A.; Rea, B.A.; Masterson, J.C.; Mukkada, V.; Parashette, K.R.; Du, J.; Fillon, S.; Protheroe, C.A.; et al. Eosinophilic esophagitis: Epithelial mesenchymal transition contributes to esophageal remodeling and reverses with treatment. J. Allergy Clin. Immunol. 2012, 129, 1387–1396. [Google Scholar] [CrossRef]
  112. Rajan, J.; Newbury, R.O.; Anilkumar, A.; Dohil, R.; Broide, D.H.; Aceves, S.S. Long-term assessment of esophageal remodeling in patients with pediatric eosinophilic esophagitis treated with topical corticosteroids. J. Allergy Clin. Immunol. 2016, 137, 147–156.e8. [Google Scholar] [CrossRef] [PubMed]
  113. Aceves, S.S.; Newbury, R.O.; Chen, D.; Mueller, J.; Dohil, R.; Hoffman, H.; Bastian, J.F.; Broide, D.H. Resolution of remodeling in eosinophilic esophagitis correlates with epithelial response to topical corticosteroids. Allergy 2010, 65, 109–116. [Google Scholar] [CrossRef]
  114. Rawson, R.; Yang, T.; Newbury, R.O.; Aquino, M.; Doshi, A.; Bell, B.; Broide, D.H.; Dohil, R.; Kurten, R.; Aceves, S.S. TGF-β1-induced PAI-1 contributes to a profibrotic network in patients with eosinophilic esophagitis. J. Allergy Clin. Immunol. 2016, 138, 791–800. [Google Scholar] [CrossRef] [PubMed]
  115. Arias, Á.; Lucendo, A.J.; Martínez-Fernández, P.; González-Castro, A.M.; Fortea, M.; González-Cervera, J.; Yagüe-Compadre, J.L.; Mota-Huertas, T.; Vicario, M. Dietary treatment modulates mast cell phenotype, density, and activity in adult eosinophilic oesophagitis. Clin. Exp. Allergy. 2016, 46, 78–91. [Google Scholar] [CrossRef] [PubMed]
  116. de Rooij, W.E.; Diks, M.A.P.; Warners, M.J.; Van Ampting, M.T.J.; van Esch, B.C.A.M.; Bredenoord, A.J. Gene expression and clinical outcomes after dietary treatment for eosinophilic esophagitis: A prospective study. Neurogastroenterol. Motil. 2022, 34, e14367. [Google Scholar] [CrossRef]
  117. Sarbinowska, J.; Wiatrak, B.; Waśko-Czopnik, D. Searching for Noninvasive Predictors of the Diagnosis and Monitoring of Eosinophilic Esophagitis—The Importance of Biomarkers of the Inflammatory Reaction Involving Eosinophils. Biomolecules 2021, 11, 890. [Google Scholar] [CrossRef]
  118. Pronio, A.; Covotta, F.; Pallotta, L.; Palma, R.; Badiali, D.; Sacchi, M.C.; Lamazza, A.; Severi, C. Eosinophilic Esophagitis: Cytokines Expression and Fibrotic Markers in Comparison to Celiac Disease. Diagnostics 2022, 12, 2092. [Google Scholar] [CrossRef]
  119. Cao, M.; Wang, Z.; Wang, Y.; Jing, H.; Meng, Y.; Geng, Y.; Li, X.-M.; Miao, M. Reduction of Th2 inflammation and fibrosis in eosinophilic esophagitis in a murine model by citri reticulatae pericarpium. J. Ethnopharmacol. 2023, 317, 116767. [Google Scholar] [CrossRef]
  120. Ossorio, M.; Bajo, M.A.; Del Peso, G.; Martínez, V.; Fernández, M.; Castro, M.J.; Rodríguez-Sanz, A.; Madero, R.; Bellón, T.; Selgas, R. Sustained low peritoneal effluent CCL18 levels are associated with preservation of peritoneal membrane function in peritoneal dialysis. PLoS ONE 2017, 12, e0175835. [Google Scholar] [CrossRef]
  121. Laky, K.; Kinard, J.L.; Li, J.M.; Moore, I.N.; Lack, J.; Fischer, E.R.; Kabat, J.; Latanich, R.; Zachos, N.C.; Limkar, A.R.; et al. Epithelial-intrinsic defects in TGFβR signaling drive local allergic inflammation manifesting as eosinophilic esophagitis. Sci. Immunol. 2023, 8, eabp9940. [Google Scholar] [CrossRef] [PubMed]
  122. Doré, J.J.; Edens, M.; Garamszegi, N.; Leof, E.B. Heteromeric and homomeric transforming growth factor-beta receptors show distinct signaling and endocytic responses in epithelial cells. J. Biol. Chem. 1998, 273, 31770–31777. [Google Scholar] [CrossRef]
  123. Dy, A.B.C.; Girkin, J.; Marrocco, A.; Collison, A.; Mwase, C.; O’sullivan, M.J.; Phung, T.-K.N.; Mattes, J.; Koziol-White, C.; Gern, J.E.; et al. Rhinovirus infection induces secretion of endothelin-1 from airway epithelial cells in both in vitro and in vivo models. Respir. Res. 2023, 24, 205. [Google Scholar] [CrossRef]
  124. Chen, M.; Zhang, W.; Shi, J.; Jiang, S. TGF-β1-Induced Airway Smooth Muscle Cell Proliferation Involves TRPM7-Dependent Calcium Influx via TGFβR/SMAD3. Mol. Immunol. 2018, 103, 173–181. [Google Scholar] [CrossRef] [PubMed]
  125. Arias, A.; González-Cervera, J.; Tenias, J.M.; Lucendo, A.J. Efficacy of dietary interventions for inducing histologic remission in patients with eosinophilic esophagitis: A systematic review and meta-analysis. Gastroenterology 2014, 146, 1639–1648. [Google Scholar] [CrossRef]
  126. Lucendo, A.J.; Navarro, M.; Comas, C.; Pascual, J.M.; Burgos, E.; Santamaría, L.; Larrauri, J. Immunophenotypic characterization and quantification of the epithelial inflammatory infiltrate in eosinophilic esophagitis through stereology: An analysis of the cellular mechanisms of the disease and the immunologic capacity of the esophagus. Am. J. Surg. Pathol. 2007, 31, 598–606. [Google Scholar] [CrossRef]
  127. Hata, A.; Chen, Y.-G. TGF-β Signaling from Receptors to Smads. Cold Spring Harb. Perspect. Biol. 2016, 8, a022061. [Google Scholar] [CrossRef]
  128. Wang, R.N.; Green, J.; Wang, Z.; Deng, Y.; Qiao, M.; Peabody, M.; Zhang, Q.; Ye, J.; Yan, Z.; Denduluri, S.; et al. Bone Morphogenetic Protein (BMP) signaling in development and human diseases. Genes. Dis. 2014, 1, 87–105. [Google Scholar] [CrossRef]
  129. Batts, L.E.; Polk, D.B.; Dubois, R.N.; Kulessa, H. Bmp signaling is required for intestinal growth and morphogenesis. Dev. Dyn. 2006, 235, 1563–1570. [Google Scholar] [CrossRef] [PubMed]
  130. Milano, F.; Van Baal, J.W.P.M.; Buttar, N.S.; Rygiel, A.M.; de Kort, F.; DeMars, C.J.; Rosmolen, W.D.; Bergman, J.J.; van Marle, J.; Wang, K.K.; et al. Bone Morphogenetic Protein 4 Expressed in Esophagitis Induces a Columnar Phenotype in Esophageal Squamous Cells. Gastroenterology 2007, 132, 2412–2421. [Google Scholar] [CrossRef] [PubMed]
  131. Gordon, S.; Taylor, P.R. Monocyte and macrophage heterogeneity. Nat. Rev. Immunol. 2005, 5, 953–964. [Google Scholar] [CrossRef]
  132. Braga, T.T.; Agudelo, J.S.H.; Camara, N.O.S. Macrophages During the Fibrotic Process: M2 as Friend and Foe. Front. Immunol. 2015, 6, 602. [Google Scholar] [CrossRef]
  133. Bellón, T.; Martínez, V.; Lucendo, B.; del Peso, G.; Castro, M.J.; Aroeira, L.S.; Rodríguez-Sanz, A.; Ossorio, M.; Sánchez-Villanueva, R.; Selgas, R.; et al. Alternative activation of macrophages in human peritoneum: Implications for peritoneal fibrosis. Nephrol. Dial. Transplant. 2011, 26, 2995–3005. [Google Scholar] [CrossRef]
  134. Kaviratne, M.; Hesse, M.; Leusink, M.; Cheever, A.W.; Davies, S.J.; McKerrow, J.H.; Wakefield, L.M.; Letterio, J.J.; Wynn, T.A. IL-13 activates a mechanism of tissue fibrosis that is completely TGF-beta independent. J. Immunol. 2004, 173, 4020–4029. [Google Scholar] [CrossRef]
  135. Jun, J.-I.; Lau, L.F. Resolution of organ fibrosis. J. Clin. Investig. 2018, 128, 97–107. [Google Scholar] [CrossRef]
  136. Navarro, P.; Laserna-Mendieta, E.J.; Guagnozzi, D.; Casabona, S.; Perelló, A.; Savarino, E.; de la Riva, S.; Olalla, J.M.; Ghisa, M.; Serrano-Moya, N.; et al. Proton pump inhibitor therapy reverses endoscopic features of fibrosis in eosinophilic esophagitis. Dig. Liver Dis. 2021, 53, 1479–1485. [Google Scholar] [CrossRef]
  137. Lieberman, J.A.; Morotti, R.A.; Konstantinou, G.N.; Yershov, O.; Chehade, M. Dietary therapy can reverse esophageal subepithelial fibrosis in patients with eosinophilic esophagitis: A historical cohort. Allergy 2012, 67, 1299–1307. [Google Scholar] [CrossRef]
  138. Abu-Sultaneh, S.M.A.; Durst, P.; Maynard, V.; Elitsur, Y. Fluticasone and food allergen elimination reverse sub-epithelial fibrosis in children with eosinophilic esophagitis. Dig. Dis. Sci. 2011, 56, 97–102. [Google Scholar] [CrossRef]
  139. Carlson, D.A.; Hirano, I.; Zalewski, A.; Gonsalves, N.; Lin, Z.; Pandolfino, J.E. Improvement in Esophageal Distensibility in Response to Medical and Diet Therapy in Eosinophilic Esophagitis. Clin. Transl. Gastroenterol. 2017, 8, e119. [Google Scholar] [CrossRef]
  140. Lee, C.J.; Dellon, E.S. Real-World Efficacy of Dupilumab in Severe, Treatment-Refractory, and Fibrostenotic Patients with Eosinophilic Esophagitis. Clin. Gastroenterol. Hepatol. 2023. online ahead of print. [Google Scholar] [CrossRef]
  141. Aceves, S.S.; Alexander, J.A.; Baron, T.H.; Bredenoord, A.J.; Day, L.; Dellon, E.S.; Falk, G.W.; Furuta, G.T.; Gonsalves, N.; Hirano, I.; et al. Endoscopic approach to eosinophilic esophagitis: American Society for Gastrointestinal Endoscopy Consensus Conference. Gastrointest. Endosc. 2022, 96, 576–592. [Google Scholar] [CrossRef]
Ijms 25 00927 g001
Figure 1. Design of studies reviewed. (A) Characteristics of study design. (B) Best design classification according to sample type and mRNA or protein of TGF-β1 detected [25,110,115,116,117]. (C) Classification of publications reviewed according to the groups of patients compared and the results obtained in the levels of TGF-β1 [25,110,115,116,117].
Figure 1. Design of studies reviewed. (A) Characteristics of study design. (B) Best design classification according to sample type and mRNA or protein of TGF-β1 detected [25,110,115,116,117]. (C) Classification of publications reviewed according to the groups of patients compared and the results obtained in the levels of TGF-β1 [25,110,115,116,117].
Ijms 25 00927 g001
Table 1. Characteristics of the reviewed manuscripts.
Table 1. Characteristics of the reviewed manuscripts.
Publication and YearSpeciesSampleMethodEoE Samples (n)OutcomeComparative Groupp Value
Aceves 2007 [103]HumanBiopsiesIHC7Increased numbers of TGF-β1(+) cells in LP from EoEGERD
Healthy		p = 0.02
p = 0.004
Misrha 2008 [25]Human
Mice		Biopsies
Tissue		RTqPCR8
7		Increased expression level of TGF-β1 from EoEHealthy
WT mice		p < 0.001
p < 0.001
Aceves 2010 [107]HumanBiopsiesIF21Increased numbers of TGF-β1(+) cells in SM from EoEHealthyp = 0.005
Aceves 2010 [113]HumanBiopsiesIHC16Increased numbers of TGF-β1(+) cells in LP from EoEREoEpostRp = 0.01
Dohil 2010 [108]HumanBiopsiesIHC15Increased numbers of TGF-β1(+) cells in LP from EoEpEoEpostNA
Straumann 2010 [109]HumanBiopsiesIF18Increased numbers of TGF-β1(+) cells from EoEpreEoEpostNA
Lucendo 2011 [110]HumanBiopsiesRTqPCR10No significant increased expression levels of TGF-β1 from EoEGERD
Healthy
EoEpost		p = 0.11
Kagalwalla 2012 [111]HumanBiopsiesIHC18Increased score of TGF-β1 index of EoE, and correlate with EMT scores index (r = 0.520, p < 0.01)GERD
Healthy		p < 0.01
p < 0.001
Cho 2014 [105]MiceTissueIHC
RTqPCR		12 (sensitized mice)Increased numbers of TGF-β1(+) cells and expression levels in sensitized mice.
No difference in numbers of TGFβ1 positive cells in sensitized mice Smad3 KO compared to sensitized WT mice (p = NS)		WT mice
SMAD−/− mice		p < 0.01
(IHC)
p < 0.001
(qPCR)
Rieder 2015 [104]HumanOCSELISA14Increased protein level of TGF-β1 from EoEHealthyp = 0.006
Collison 2015 [106]MiceTissueRTqPCRNAIncreased expression level of TGF-β1 in sensitized mice.WT micep < 0.05
Rajan 2015 [112]HumanBiopsiesIHC32Increased numbers of TGF-β1(+) cells from EoER over time.
(No alignment with fibrosis is found, except in the early stages of the disease course and only in responders)		EoER over timep = NS
Rawson 2016 [114]HumanBiopsiesIHC14Increased numbers of TGF-β1(+) cells in LP from EoEHealthyNA
Arias 2016 [115]HumanBiopsiesRTqPCR10No significant increased expression levels of TGF-β1 from EoEpreHealthy
EoE post		p = 0.740
p = 0.386
Sarbinowska 2021 [117]HumanSerumELISA16Increased protein level of TGF-β1 from EoE compared to controls but not significant differences to EoEpost.Healthy
EoE post		p = 0.04
p = 0.12
de Rooij 2022 [116]HumanBiopsiesRTqPCR40Significant decreased expression levels of TGF-β1 from EoE after combined treatment, but no differences were observed after FFED treatment alone.EoE post
EoE post FFED		p < 0.01
p > 0.05
Pronio 2022 [118]HumanBiopsiesRTqPCR5TGF-β expression was similar to the control in the mid-esophagus but reduced the distal EoE esophagusHealthyNA
Cao 2023 [119]MiceTissueWB6Compared with naïve mice, TGF-β1 protein levels in sham-treated mice increased and decreased significantly after treatment, comparing before and after treatment.WT mice
EoE mice post		p < 0.001
p < 0.01
Species: species of origin of the sample used in the study. Samples: type of samples used in the study. Method: technique used to measure TGF-β1 levels. Comparative groups: samples compared to those in the EoE group (GERD group/Healthy group or WT in mice). EoE samples (n): number of samples obtained from patients with EoE. Outcome: result of the statistical comparison of TGF-β1 levels. p value: statistical significance of comparative analysis. OSC: organ culture system. LP: lamina propria. SM: smooth muscle. IHC: immunohistochemistry. NA: not available; RTqPCR: quantitative reverse transcription polymerase chain reaction. ELISA: enzyme-linked immunosorbent assay. IF: immunofluorescence. GERD: gastroesophageal reflux disease. WT: wild type. EoER: responder patients to corticoids. EoENR: non-responders patients to corticoids. FFED: four-food elimination diet. EoEpost: EoE after effective treatment. EoEp: EoE placebo group/not treated. EoEpre: EoE before treatment, NS: not significant. Statistical significance p < 0.05.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Arias-González, L.; Rodríguez-Alcolado, L.; Laserna-Mendieta, E.J.; Navarro, P.; Lucendo, A.J.; Grueso-Navarro, E. Fibrous Remodeling in Eosinophilic Esophagitis: Clinical Facts and Pathophysiological Uncertainties. Int. J. Mol. Sci. 2024, 25, 927. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25020927

AMA Style

Arias-González L, Rodríguez-Alcolado L, Laserna-Mendieta EJ, Navarro P, Lucendo AJ, Grueso-Navarro E. Fibrous Remodeling in Eosinophilic Esophagitis: Clinical Facts and Pathophysiological Uncertainties. International Journal of Molecular Sciences. 2024; 25(2):927. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25020927

Chicago/Turabian Style

Arias-González, Laura, Leticia Rodríguez-Alcolado, Emilio J. Laserna-Mendieta, Pilar Navarro, Alfredo J. Lucendo, and Elena Grueso-Navarro. 2024. "Fibrous Remodeling in Eosinophilic Esophagitis: Clinical Facts and Pathophysiological Uncertainties" International Journal of Molecular Sciences 25, no. 2: 927. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25020927

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop