BackgroundFibrosis is a serious consequence of Crohn’s disease (CD), often necessitating surgical resection. We examined the hypothesis that IL-13 may promote collagen accumulation within the CD muscle microenvironment.MethodsFactors potentially modulating collagen deposition were examined in intestinal tissue samples from fibrotic (f) CD and compared with cancer control (C), ulcerative colitis (UC) and uninvolved (u) CD. Mechanisms attributable to IL-13 were analysed using cell lines derived from uninvolved muscle tissue and tissue explants.ResultsIn fCD muscle extracts, collagen synthesis was significantly increased compared to other groups, but MMP-2 was not co-ordinately increased. IL-13 transcripts were highest in fCD muscle compared to muscle from other groups. IL-13 receptor (R) α1 was expressed by intestinal muscle smooth muscle, nerve and KIR+ cells. Fibroblasts from intestinal muscle expressed Rα1, phosphorylated STAT6 in response to IL-13, and subsequently down-regulated MMP-2 and TNF-α-induced MMP-1 and MMP-9 synthesis. Cells with the phenotype KIR+CD45+CD56+/−CD3− were significantly increased in fCD muscle compared to all other groups, expressed Rα1 and membrane IL-13, and transcribed high levels of IL-13. In explanted CD muscle, these cells did not phosphorylate STAT6 in response to exogenous IL-13.ConclusionsThe data indicate that in fibrotic intestinal muscle of Crohn’s patients, the IL-13 pathway is stimulated, involving a novel population of infiltrating IL-13Rα1+, KIR+ innate lymphoid cells, producing IL-13 which inhibits fibroblast MMP synthesis. Consequently, matrix degradation is down-regulated and this leads to excessive collagen deposition.

Proteinases are important at several phases of physiological and pathological inflammation, mediating cellular infiltration, cytokine activation, tissue damage, remodeling, and repair. However, little is known of their role in the pathogenesis of inflammatory bowel disease. The aim of this study was to assess the role of tissue proteases in a mouse model of colitis. Proteolytic activity was analyzed, using gel and in situ zymography, in colonic tissues from severe combined immunodeficient mice with colitis induced by transfer of CD4 ؉ T lymphocytes. Serine proteinase levels increased in colitic tissue, with major species of 23 kd, 30 kd, and 45 kd. Co-migration and inhibition studies indicated that the 23-kd proteinase was pancreatic trypsin and that the 30-kd species was neutrophil elastase. Matrix metalloproteinase (MMP)-9 expression, and MMP-2 and MMP-9 activation, was elevated in colitic tissues. Proteinase levels followed a decreasing concentration gradient from proximal to distal colon. Proteolysis was localized to infiltrating leukocytes in diseased severe combined immunodeficient mice. The inflammatory bowel diseases (IBD), Crohn's disease, and ulcerative colitis, probably share a common etiology, in terms of a dysregulation of mucosal T cell reactivity.

Dietary n-3 PUFAs reduced clinical colitis and colonic immunopathology in this model of colonic inflammation by decreasing proinflammatory cytokine synthesis, reducing myeloid cell recruitment and activation, and enhancing epithelial barrier function and mucosal wound healing mechanisms.

Up to one million people suffer from chronic skin ulcers in the US. Little is known of the mechanisms leading to tissue breakdown, although inadequate circulation and ischemia are common elements in most dermal ulcers. Collagen is the principal source of mechanical strength in most tissues, and its molecular and fibrillar stability is dependent on adequate oxygen supply. In wound repair, localized ischemia leads to fibrogenic responses culminating in elevated collagen synthesis and remodeling. This study examines factors influencing collagen turnover and stabilization before ulceration in "at risk" patients. Severely ischemic but uninjured ischemic skin (IS) was compared with patient- and site-matched non-ischemic skin. Biochemical mechanisms of tissue repair were activated in IS, with increased lactate, transforming growth factor-beta, vascular endothelial growth factor, collagen synthesis and matrix metalloproteinases (MMPs)-1 and 2. The absence of MMP-9 and inflammatory cells confirmed that this upregulation was inappropriate and not in response to injury. Molecular stability of collagen was reduced in IS, and there was increased susceptibility to enzymic degradation. In conclusion, chronic ischemia and long-term hypoxia result in elevated collagen remodeling in an oxygen-poor environment. Unstable collagen molecules are synthesized together with upregulated MMPs, resulting in collagen denaturation, defective angiogenesis, weaker skin, and predisposition to ulceration.

Introduction: Exacerbations of inflammatory bowel disease are thought to be related to concurrent infections. As infections are associated with elevated local and serum concentrations of chemokines, we have determined whether systemic administration of the CC chemokine macrophage inflammatory protein 1a (MIP-1a) exacerbates colitis in a mouse model. Methods: Colitis was induced in Balb/c mice using trinitrobenzene sulfonic acid (TNBS). Starting four days later, animals received daily intraperitoneal injections of recombinant MIP-1a. On day 7, mice were killed and pieces of colon taken for immunohistology and polymerase chain reaction analysis. The direct effects of MIP-1a on mucosal T cells and fibroblasts in vitro were also investigated. Results: Systemic administration of MIP-1a markedly enhanced colitis with mice developing large transmural ulcers filled with granulation tissue. Treatment resulted in increased numbers of CD4 cells infiltrating the colonic lamina propria, increased interferon c (IFN-c) levels, and increased transcripts for tumour necrosis factor a (TNF-a) and matrix metalloproteinase 3 (MMP3). Isolated lamina propria lymphocytes from mice with TNBS colitis contained increased numbers of IFN-c and TNF-a transcripts when stimulated with MIP-1a in vitro. Colonic lamina propria fibroblasts also responded to MIP-1a with increased proliferation and decreased collagen 1 synthesis but fibroblast proliferation was not seen in vivo. Conclusions: These experiments show that increasing serum concentrations of a chemokine, MIP-1a, exacerbates immune mediated colitis. The effect seems to be due to the ability of MIP-1a to boost Th1 responses in the gut wall. Our findings also suggest a potential pathway by which peripheral infections can exacerbate inflammatory bowel disease.