Glutamine therapy improves outcome of in vitro and in vivo experimental colitis models.
BACKGROUND: Pharmacologic doses of glutamine (GLN) can improve clinical outcome following acute illness and injury. Recent studies indicate enhanced heat shock protein (HSP) expression is a key mechanism underlying GLN's protection. However, such a link has not yet been tested in chronic inflammatory states, such as experimental inflammatory bowel disease (IBD). METHODS: Experimental colitis was induced in Sprague-Dawley rats via oral 5% dextran sulfate sodium (DSS) for 7 days. GLN (0.75 g/kg/d) or sham was administered to rats by oral gavage during 7-day DSS treatment. In vitro inflammatory injury was studied using YAMC colonic epithelial cells treated with varying concentrations of GLN and cytokines (tumor necrosis factor-α/interferon-γ). RESULTS: Pharmacologic dose, bolus GLN attenuated DSS-induced colitis in vivo with decreased area under curve for bleeding (8.06 ± 0.87 vs 10.38 ± 0.79, P < .05) and diarrhea (6.97 ± 0.46 vs 8.53 ± 0.39, P < .05). This was associated with enhanced HSP25 and HSP70 in colonic mucosa. In vitro, GLN enhanced cell survival and reduced proapoptotic caspase3 and poly(ADP-ribose) polymerase cleavage postcytokine injury. Cytokine-induced inducible nitric oxide synthase expression and nuclear translocation of nuclear factor-κB p65 subunit were markedly attenuated at GLN concentrations above 0.5 mmol/L. GLN increased cellular HSP25 and HSP70 in a dose-dependent manner. CONCLUSIONS: These data demonstrate the therapeutic potential of GLN as a "pharmacologically acting nutrient" in the setting of experimental IBD. GLN sufficiency is crucial for the colonic epithelium to mount a cell-protective, antiapoptotic, and anti-inflammatory response against inflammatory injury. The enhanced HSP expression observed following GLN treatment may be responsible for this protective effect.
Xue, H; Sufit, AJD; Wischmeyer, PE
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