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1 Department of Surgery, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
2 Department of Hematology and Oncology, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
* To whom correspondence should be addressed. E-mail: Henri.Ford{at}chp.edu.
Overproduction of nitric oxide (NO) or its toxic metabolite, peroxynitrite (ONOO-), following endotoxemia promotes gut barrier failure, in part, by inducing enterocyte apoptosis. We hypothesized that ONOO- may also inhibit enterocyte proliferation by disrupting the Src tyrosine kinase signaling pathway, thereby blunting repair of the damaged mucosa. We examined the effect of ONOO- on enterocyte proliferation and Src kinase activity. Sprague-Dawley rats were challenged with LPS or saline, while IEC-6 cells were treated with ONOO- or decomposed ONOO- in vitro. Enterocyte proliferation in vivo and in vitro was measured by BrdU or 3H-thymidine incorporation. Src kinase activity in cell lysates was determined at various times. LPS challenge in vivo, and ONOO- treatment in vitro inhibited enterocyte proliferation. ONOO- treatment blunted the activity of Src and its downstream target, FAK in a time dependent manner. ONOO- blocked mitogen (FBS, EGF)-induced enterocyte proliferation and Src phosphorylation while increasing Src nitration. Thus, ONOO- may promote gut barrier failure not only by inducing enterocyte apoptosis, but also by disrupting signaling pathways involved in enterocyte proliferation.
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