title: Protective role of p70S6K in intestinal ischemia/reperfusion injury in mice.
abstract: The mTOR signaling pathway plays a crucial role in the regulation of cell growth, proliferation, survival and in directing immune responses. As the intestinal epithelium displays rapid cell growth and differentiation and is an important immune regulatory organ, we hypothesized that mTOR may play an important role in the protection against intestinal ischemia reperfusion (I/R)-induced injury. To better understand the molecular mechanisms by which the mTOR pathway is altered by intestinal I/R, p70S6K, the major effector of the mTOR pathway, was investigated along with the effects of rapamycin, a specific inhibitor of mTOR and an immunosuppressant agent used clinically in transplant patients. In vitro experiments using an intestinal epithelial cell line and hypoxia/reoxygenation demonstrated that overexpression of p70S6K promoted cell growth and migration, and decreased cell apoptosis. Inhibition of p70S6K by rapamycin reversed these protective effects. In a mouse model of gut I/R, an increase of p70S6K activity was found by 5 min and remained elevated after 6 h of reperfusion. Inhibition of p70S6K by rapamycin worsened gut injury, promoted inflammation, and enhanced intestinal permeability. Importantly, rapamycin treated animals had a significantly increased mortality. These novel results demonstrate a key role of p70S6K in protection against I/R injury in the intestine and suggest a potential danger in using mTOR inhibitors in patients at risk for gut hypoperfusion.
authors: Department of Surgery, University of Texas Health Science Center at Houston, Houston, Texas, United States of America. Kechen.Ban@uth.tmc.edu
authors: Kechen
authors: K
authors: Ban
authors: Rosemary A
authors: RA
authors: Kozar
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D004847:Epithelial Cells / Q000201:enzymology* / Q000473:pathology; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000494:pharmacology; D007410:Intestinal Diseases / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control; D007413:Intestinal Mucosa / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051379:Mice; D051381:Rats; D015427:Reperfusion Injury / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D015398:Signal Transduction; D020123:Sirolimus / Q000009:adverse effects / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors
chemical_list: D007166:Immunosuppressive Agents; C546843:mTOR protein, mouse; C546845:mTOR protein, rat; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus