Themes in fibrosis and gastrointestinal inflammation

1Cleveland Clinic Foundation.
AJP Gastrointestinal and Liver Physiology (Impact Factor: 3.65). 03/2011; 300(5):G677-83. DOI: 10.1152/ajpgi.00104.2011
Source: PubMed

ABSTRACT Wound healing is an appropriate response to inflammation and tissue injury in the gastrointestinal tract. If wound healing responses are excessive, perpetuated, or prolonged, they lead to fibrosis, distortion of tissue architecture, and loss of function. This introductory editorial and the minireviews or reviews in this themes series highlight the diversity in severity and location of fibrosis in response to gastrointestinal inflammation. The multiplicity of cellular and molecular mediators and new players, including stem cells or extracellular matrix-producing cells derived from nonmesenchymal cell types, is reviewed. Comparisons of inflammation-induced fibrosis across organ systems and the need for integrated and systems-based molecular approaches, new imaging modalities, well-characterized animal models, cell culture models, and improved diagnostic or predictive markers are reviewed. To date, intestinal fibrosis has received much less attention than inflammation in terms of defining mechanisms and underlying causes. This themes series aims to illustrate the importance of research in this area in gastrointestinal health and disease.

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    ABSTRACT: BackgroundMagnetic resonance colonography (MRC) has been developed to assess inflammatory bowel diseases. We aimed to assess the feasibility of MRC in rats with TNBS-induced chronic colitis and to confront imaging results with fibrosis and stenosing features of the model.Materials and MethodsChronic colitis was induced in 12 rats by weekly intra-rectal injection of increasing doses of TNBS for 6 weeks, while 8 control rats received the vehicle. At week 7, MRC was performed. Fibrosis scores were assessed and fibrosis mediators measured.ResultsChronic colitis was associated with significant body weight loss (p<0.0001) and higher colon weight/length compared to controls (p = 0.0004). Fibrosis mediators and histological scores were significantly higher in rats with TNBS than in controls: α-SMA expression (0.9 versus 0.61, p = 0.0311) and fibrosis score (p = 0.0308). Colon wall thickness was higher in rats with TNBS than in controls: maximal thickness (2.38 versus 0.74 mm, p<0.0001) and minimal thickness (1.33 versus 0.48 mm, p<0.0001). Wall signal intensity on T2w images was higher in rats with TNBS than in controls (9040 versus 6192, p = 0.0101) and correlated with fibrosis score (r = 0.5214; p = 0.04). Luminal narrowing was higher in rats with TNBS (50.08 versus 10.33%, p<0.0001) and correlated with α-SMA expression (r = 0.5618; p = 0.01). Stenosis was observed in 7/9 rats with TNBS and in no controls (p = 0.0053).ConclusionsMRC is feasible and easily distinguishes rats with colitis from controls. MRC signs correlated with fibrosis parameters. MRC evaluation may be part of a new anti-fibrosis drug assessment in experimental models of chronic colitis.
    PLoS ONE 07/2014; 9(7):e100921. DOI:10.1371/journal.pone.0100921 · 3.53 Impact Factor
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    ABSTRACT: Tissue injury can occur for a variety of reasons including physical damage, infection and ischemia. The ability of tissues to effectively recover from injury is a cornerstone of human health. The healing response in tissues is conserved across organs and typically involves distinct but overlapping inflammatory, proliferative and maturation/resolution phases. If the inflammatory phase is not successfully controlled and appropriately resolved, an excessive healing response characterized by scar formation can lead to tissue fibrosis, a major clinical complication in disorders such as Crohn's Disease (CD). As a result of enhanced metabolic and inflammatory processes during chronic inflammation, profound changes in tissue oxygen levels occur leading to localized tissue hypoxia. Therefore, inflammation, fibrosis and hypoxia are co-incidental events during inflammation-driven fibrosis. Our current understanding of the mechanism(s) underpinning fibrosis is limited as are the therapeutic options available. In this review, we discuss what is known about the cellular and molecular mechanisms underpinning inflammation-driven fibrosis and how hypoxia may play a role in shaping this process.
    AJP Regulatory Integrative and Comparative Physiology 10/2014; DOI:10.1152/ajpregu.00349.2014 · 3.53 Impact Factor
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    ABSTRACT: Abstract Intestinal fibrosis is a common complication of the inflammatory bowel diseases (IBDs). It becomes clinically apparent in >30% of patients with Crohn's disease (CD) and in about 5% with ulcerative colitis (UC). Fibrosis is a consequence of local chronic inflammation and is characterized by excessive extracellular matrix (ECM) protein deposition. ECM is produced by activated myofibroblasts, which are modulated by both, profibrotic and antifibrotic factors. Fibrosis depends on the balance between the production and degradation of ECM proteins. This equilibrium can be impacted by a complex and dynamic interaction between profibrotic and antifibrotic mediators. Despite the major therapeutic advances in the treatment of active inflammation in IBD over the past two decades, the incidence of intestinal strictures in CD has not significantly changed as the current anti-inflammatory therapies neither prevent nor reverse the established fibrosis and strictures. This implies that control of intestinal inflammation does not necessarily affect the associated fibrotic process. The conventional view that intestinal fibrosis is an inevitable and irreversible process in patients with IBD is also gradually changing in light of an improved understanding of the cellular and molecular mechanisms that underline the pathogenesis of fibrosis. Comprehension of the mechanisms of intestinal fibrosis is thus vital and may pave the way for the developments of antifibrotic agents and new therapeutic approaches in IBD.
    Scandinavian Journal of Gastroenterology 01/2015; 50(1):53-65. DOI:10.3109/00365521.2014.968863 · 2.33 Impact Factor