Anti-Fibrotic Agents for the Treatment of Crohn's Disease
Anti-Fibrotic Agents for the Treatment of Crohn's Disease
Background The current therapies for Crohn's disease (CD) are mainly focused on blockade of inflammation. Fibrosis remains one of the major complications of CD often leading to surgery, affecting patients' quality-of-life.
Aim To summarize the published data regarding the potential anti-fibrotic role of drugs commonly used in CD and the most effective anti-fibrotic drugs used in other diseases evaluating their potential use to treat intestinal fibrosis in CD.
Methods A literature search was performed in the PubMed, Medline, Cochrane and EMBASE databases, considering in vitro, animal and human studies on fibrosis in inflammatory bowel disease and other similar chronic pathologies.
Results Treatment of fibrosis in CD is limited to surgery or endoscopic dilatation, although some of the drugs currently used may have anti-fibrotic activity. In other diseases, anti-fibrotic agents are already used or are in preclinical or clinical trials. ACE inhibitors, Angiotensin Receptor Blockers, and HMG-CoA inhibitors merit further investigation in CD because of their role in preventing fibrosis in cardiovascular and renal diseases.
Conclusions Anti-fibrotic drugs are under evaluation or already used in clinical practice in other chronic inflammatory diseases. In CD, there is a great need for investigation into agents that may prevent, reduce or reverse intestinal fibrosis.
Although numerous findings in the field of immunopathology have identified dozens of possible target molecules for the treatment of the inflammatory bowel diseases (IBD), in this article, we concentrate on a less understood, but clinically highly relevant aspect: intestinal fibrosis in Crohn's disease (CD), one of the two major forms of IBD. Chronic inflammation plays a crucial role in fibrotic changes, by disrupting the natural balance of pro- and anti-fibrotic mechanisms. Transmural inflammation because of dysregulated wound healing mechanisms leads to fibrotic stenosis in one-third of patients with CD. In the absence of a reliable marker, ongoing fibrosis and consequent stricture development is often not diagnosed until the process is already irreversible. Being the most common indication for surgical intervention, this very frequent complication of CD can significantly influence the patients' quality-of-life.
The pathogenesis of fibrosis in CD remains poorly understood. Some studies have shown that transforming growth factor (TGF) β1, acting together with SMAD proteins and insulin growth factor (IGF) 1, plays a crucial role in promoting gene transcription for collagenous proteins, especially type III collagen and fibronectin. In addition, fibroblast contraction is facilitated by the hyperexpression of TGFβ1. Investigation into a possible linkage between fibrostenotic CD and gene mutations has demonstrated that any mutation of the NOD2/CARD15 gene concerning R702W, G908R and 3020InsC sequences is frequently associated with this particular phenotype. Fibrosis is also more frequent in patients presenting the V249 CX3CR1 allele polymorphism.
Chronic inflammation can affect almost every human tissue, causing fibrotic changes that significantly impair organ function, with associated therapeutic challenges. Fibrogenesis in every tissue, including the gut, is a complex process characterized by increased production of components of the extracellular matrix (ECM) by activated myofibroblasts. These may be the differentiation of stem cells, perycites, fibrocytes or stellate cells that are activated by cytokines, chemokines and growth factors (Figure 1). The possible inhibitory mechanisms have been examined in several pathologies affecting different organs, such as systemic sclerosis, liver cirrhosis, nephrosclerosis in diabetic and IgA nephropathy, rheumatoid arthritis, and chronic pancreatitis. In spite of all the progress that has been made in advancing our understanding of the pathophysiology of these conditions, clinical treatment remains a major challenge. The traditional medical interventions have focused on symptom control and the slowing down of disease progression. Although some of the currently available therapeutics display antifibrotic effects, they are unable to taper pro-fibrotic changes.
(Enlarge Image)
Figure 1.
Cell-types and inflammatory mediators involved in activation of intestinal myofibroblasts and extracellular matrix (ECM) deposition.
This article gives an overview of anti-fibrotic strategies in several chronic inflammatory disorders and their possible applications in the prevention or treatment of intestinal fibrosis in patients with CD.
Abstract and Introduction
Abstract
Background The current therapies for Crohn's disease (CD) are mainly focused on blockade of inflammation. Fibrosis remains one of the major complications of CD often leading to surgery, affecting patients' quality-of-life.
Aim To summarize the published data regarding the potential anti-fibrotic role of drugs commonly used in CD and the most effective anti-fibrotic drugs used in other diseases evaluating their potential use to treat intestinal fibrosis in CD.
Methods A literature search was performed in the PubMed, Medline, Cochrane and EMBASE databases, considering in vitro, animal and human studies on fibrosis in inflammatory bowel disease and other similar chronic pathologies.
Results Treatment of fibrosis in CD is limited to surgery or endoscopic dilatation, although some of the drugs currently used may have anti-fibrotic activity. In other diseases, anti-fibrotic agents are already used or are in preclinical or clinical trials. ACE inhibitors, Angiotensin Receptor Blockers, and HMG-CoA inhibitors merit further investigation in CD because of their role in preventing fibrosis in cardiovascular and renal diseases.
Conclusions Anti-fibrotic drugs are under evaluation or already used in clinical practice in other chronic inflammatory diseases. In CD, there is a great need for investigation into agents that may prevent, reduce or reverse intestinal fibrosis.
Introduction
Although numerous findings in the field of immunopathology have identified dozens of possible target molecules for the treatment of the inflammatory bowel diseases (IBD), in this article, we concentrate on a less understood, but clinically highly relevant aspect: intestinal fibrosis in Crohn's disease (CD), one of the two major forms of IBD. Chronic inflammation plays a crucial role in fibrotic changes, by disrupting the natural balance of pro- and anti-fibrotic mechanisms. Transmural inflammation because of dysregulated wound healing mechanisms leads to fibrotic stenosis in one-third of patients with CD. In the absence of a reliable marker, ongoing fibrosis and consequent stricture development is often not diagnosed until the process is already irreversible. Being the most common indication for surgical intervention, this very frequent complication of CD can significantly influence the patients' quality-of-life.
The pathogenesis of fibrosis in CD remains poorly understood. Some studies have shown that transforming growth factor (TGF) β1, acting together with SMAD proteins and insulin growth factor (IGF) 1, plays a crucial role in promoting gene transcription for collagenous proteins, especially type III collagen and fibronectin. In addition, fibroblast contraction is facilitated by the hyperexpression of TGFβ1. Investigation into a possible linkage between fibrostenotic CD and gene mutations has demonstrated that any mutation of the NOD2/CARD15 gene concerning R702W, G908R and 3020InsC sequences is frequently associated with this particular phenotype. Fibrosis is also more frequent in patients presenting the V249 CX3CR1 allele polymorphism.
Chronic inflammation can affect almost every human tissue, causing fibrotic changes that significantly impair organ function, with associated therapeutic challenges. Fibrogenesis in every tissue, including the gut, is a complex process characterized by increased production of components of the extracellular matrix (ECM) by activated myofibroblasts. These may be the differentiation of stem cells, perycites, fibrocytes or stellate cells that are activated by cytokines, chemokines and growth factors (Figure 1). The possible inhibitory mechanisms have been examined in several pathologies affecting different organs, such as systemic sclerosis, liver cirrhosis, nephrosclerosis in diabetic and IgA nephropathy, rheumatoid arthritis, and chronic pancreatitis. In spite of all the progress that has been made in advancing our understanding of the pathophysiology of these conditions, clinical treatment remains a major challenge. The traditional medical interventions have focused on symptom control and the slowing down of disease progression. Although some of the currently available therapeutics display antifibrotic effects, they are unable to taper pro-fibrotic changes.
(Enlarge Image)
Figure 1.
Cell-types and inflammatory mediators involved in activation of intestinal myofibroblasts and extracellular matrix (ECM) deposition.
This article gives an overview of anti-fibrotic strategies in several chronic inflammatory disorders and their possible applications in the prevention or treatment of intestinal fibrosis in patients with CD.
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