Crohn's disease (CD) is a chronic, relapsing inflammatory bowel disease, characterized by transmural inflammation. In CD, the recurrent inflammatory injury and tissue repair that occurs in the intestine can progress uncontrollably, leading to the proliferation of mesenchymal cells as well as fibrosis, characterized by excessive extracellular matrix deposition. These processes thicken the bowel wall, reducing flexibility, and often culminate in obstructive strictures. Because no effective measures are currently available to specifically treat or prevent intestinal stricturing, we sought to gain a better understanding of its pathogenesis by developing a mouse model of intestinal fibrosis. Because transforming growth factor (TGF)-beta1 can mediate both fibrosis and mesenchymal cell proliferation; we studied the effects of delivering adenoviral vectors encoding spontaneously active TGF-beta1 into the colons of mice. We first demonstrated that enema delivery of marker adenoviral vectors led to the transfection of the colonic epithelium and transient transgene expression. Histologically, control vectors caused an acute inflammatory response, involving the recruitment of neutrophils and mononuclear cells into the colonic lamina propria; however, infection caused little if any fibrosis. In contrast, the TGF-beta1 vector caused a more severe and prolonged inflammatory response as well as localized collagen deposition, leading to severe and progressive fibrosis. This was accompanied by the emergence of cells with a myofibroblast phenotype. Ultimately the fibrosis resulted in many of the TGF-beta1-transfected mice developing profound colonic obstruction. Through adenoviral gene transfer technology, we describe a novel mouse model of colitis and implicate TGF-beta1 in the pathogenesis of obstructive intestinal fibrosis.
"However, given the pleiotropic nature of TGF-β1 and its central role in coordinating almost every aspect of normal tissue repair and homeostasis, special security measures may have evolved to protect us against the disastrous consequences of dysregulated TGF-β1 signalling. Temporal overexpression of active TGF-β1 using a viral expression alone is sufficient to cause persistent fibrosis in multiple organs, including skin , lung , and intestine . Conversely, TGF-β1 knockout mice exhibit defective vasculogenesis and spontaneously develop skin and lung inflammation . "
"Adenovirus-mediated overexpression of TGF-b in the murine colon leads to colonic fibrosis ; conversely , the loss of Smad3 confers resistance to trinitrobenzene sulfonic acid-induced colorectal fibrosis . Disruption of the TGF-b/Smad signaling pathway, either by the loss of Smad3, or increase of Smad7 expression, can reduce fibrosis in several organs including the intestine . "
[Show abstract][Hide abstract] 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.
"Mutations involved in LoeyseDietz syndrome, particularly the TGF- Beta pathway, may have a key role. Studies have implicated the overexpression of TGF-beta in localized collagen deposition in mouse colon, leading to the development of severe fibrosis and intestinal obstruction . Moreover, increased expression of TGF- Beta was observed in patients with collagenous colitis, marked by typical thickening of the submucosal collagen layer  "
[Show abstract][Hide abstract] ABSTRACT: Congenital colonic stenosis is an exceptionally rare condition, with less than 15 cases in the literature. Although it has some similarities to small intestinal atresia and small intestinal stenosis, colonic atresia and colonic stenosis has been found in association with other anomalies such as Hirschsprung's disease, craniofacial abnormalities, and musculoskeletal anomalies. In this case report, we present a 6 month old male with suspected Loeys–Dietz syndrome (a connective tissue disorder), who presented with colonic stenosis.
Journal of Pediatric Surgery Case Reports 10/2013; 1(10):340–342. DOI:10.1016/j.epsc.2013.09.004
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