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1 gene transfer to the mouse colon leads to intestinal fibrosis
1 Division of Gastroenterology, BC's Children's Hospital, Vancouver, British Columbia, Canada
2 Intestinal Disease Research Program, McMaster University, Hamilton, Ontario, Canada
3 Department of Pathology, McMaster University, Hamilton, Ontario, Canada
4 Intestinal Disease Research Program, McMaster University, Hamilton, Ontario, Canada; Department of Surgical and Gastroenterological Science, Section of Gastroenterology, University of Padova, Padova, Italy
5 Intestinal Disease Research Program, McMaster University, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada
* To whom correspondence should be addressed. E-mail: bvallance{at}cw.bc.ca.
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. Since
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. Since 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.
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