Abstract
Intestinal fibrosis is one of the most threatening complications of Crohn’s disease. It occurs in more than a third of patients with this condition, is associated with increased morbidity and mortality, and surgery often represents the only available therapeutic option. The mechanisms underlying intestinal fibrosis are partly known. Studies conducted so far have shown a relevant pathogenetic role played by mesenchymal cells (especially myofibroblasts), cytokines (e.g., transforming growth factor-β), growth factors, microRNAs, intestinal microbiome, matrix stiffness, and mesenteric adipocytes. Further studies are still necessary to elucidate all the mechanisms involved in intestinal fibrosis, so that targeted therapies can be developed. Although several pre-clinical studies have been conducted so far, no anti-fibrotic therapy is yet available to prevent or reverse intestinal fibrosis. The aim of this review is to provide an overview of the main therapeutic targets currently identified and the most promising anti-fibrotic therapies, which may be available in the near future.
Highlights
IntroductionCrohn’s disease (CD) is a chronic-relapsing immune-mediated disorder [1], with a prevalent gastrointestinal involvement and a constantly increasing incidence worldwide, especially in Western countries [2], representing a major concern for the healthcare system
Crohn’s disease (CD) is a chronic-relapsing immune-mediated disorder [1], with a prevalent gastrointestinal involvement and a constantly increasing incidence worldwide, especially in Western countries [2], representing a major concern for the healthcare system.The main symptoms experienced by CD patients include abdominal pain, diarrhea and fever, with a severe impairment of their quality of life [3,4]
It was confirmed that flagellin derived from adherent-invasive Escherichia coli (AIEC), a micro-organism frequently isolated in the ileal tissue of CD, could bind the TLR5 expressed in intestinal epithelium, determining the expression of the IL-33 receptor (ST2), which is crucial for the development of intestinal fibrosis [42]
Summary
Crohn’s disease (CD) is a chronic-relapsing immune-mediated disorder [1], with a prevalent gastrointestinal involvement and a constantly increasing incidence worldwide, especially in Western countries [2], representing a major concern for the healthcare system. One of the most common and threatening complications of CD is intestinal fibrosis, which occurs in more than a third of patients and leads to intestinal obstruction due to strictures [5]. Intestinal fibrosis results in increased morbidity and mortality, causing prolonged hospitalization and a need for surgery [6]. The process of wound healing, which requires the intervention of a large number of molecular and cellular components, leads to the deposition of connective tissue in the extracellular matrix (ECM) in response to damage, resulting in tissue regeneration and repair [8]. When the stimulus to fibrogenesis becomes persistent or recurrent or even abnormal or exaggerated, as in the case of CD, this process may become uncontrolled [9], resulting in tissue fibrosis and scarring, with irreversible anatomical and/or functional alterations, eventually causing intestinal obstruction. In November 2021 we searched MEDLINE (PubMed) in a non-systematic manner by using the medical subject heading terms “fibrosis”, “strictures”, “intestinal fibrosis”,
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