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INFLAMMATION/IMMUNITY/MEDIATORS

TGF-1 gene transfer to the mouse colon leads to intestinal fibrosis

¹Division of Gastroenterology, British Columbia's Children's Hospital, Vancouver, British Columbia, Canada; ²Intestinal Disease Research Program and Departments of ³Pathology and ⁴Medicine, McMaster University, Hamilton, Ontario, Canada; and ⁵Department of Surgical and Gastroenterological Science, Section of Gastroenterology, University of Padova, Italy

Submitted 8 February 2005 ; accepted in final form 21 February 2005

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)-1 can mediate both fibrosis and mesenchymal cell proliferation; we studied the effects of delivering adenoviral vectors encoding spontaneously active TGF-1 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-1 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-1-transfected mice developing profound colonic obstruction. Through adenoviral gene transfer technology, we describe a novel mouse model of colitis and implicate TGF-1 in the pathogenesis of obstructive intestinal fibrosis.

colitis; Crohn's disease; myofibroblast; adenovirus; epithelial cells

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