Peroxynitrite inhibits enterocyte proliferation and modulates Src kinase activity in vitro

Douglas A. Potoka, Jeffrey S. Upperman, Xiao Ru Zhang, Joshua R. Kaplan, Seth J. Corey, Anatoly Grishin, Ruben Zamora, Henri R. Ford

Research output: Contribution to journalArticle

51 Scopus citations

Abstract

Overproduction of nitric oxide (NO) or its toxic metabolite, peroxynitrite (ONOO-), after 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, whereas intestinal epithelial cell line cells were treated with ONOO- or decomposed ONOO- in vitro. Enterocyte proliferation in vivo and in vitro was measured by 5-bromo-2′-deoxyuridine (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, focal adhesion kinase, 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.

Original languageEnglish (US)
Pages (from-to)G861-G869
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume285
Issue number5 48-5
DOIs
StatePublished - Nov 2003

Keywords

  • Cell signaling
  • Focal adhesion kinase
  • Lipopolysaccharide
  • Nitrotyrosine

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

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