Arginine metabolic pathways determine its therapeutic benefit in experimental heatstroke: Role of Th1/Th2 cytokine balance

We have demonstrated that therapeutic administration of l-arginine (l-arg) (120 mg/kg) at +2 h of whole body hyperthermia (WBH) could rescue the mice from heatstroke-induced death. Studies were undertaken to elucidate the role of l-arg in the immunomodulation of the heat-stressed mice. Administration of l-arginine (l-arg), (120 mg/kg, i.p.), at +2 h of WBH, rescued the mice from heat-induced death and reduced the hypothermia. At +4 and +24 h of WBH, levels of IL-1β, IFN-γ, nitrite, TNF-α, IL-4, TGF-β1, inducible form of nitric oxide synthase (iNOS), and corticosterone significantly increased compared to the sham group. The elevated levels of Th1 cytokines, namely TNF-α, IL-1β, IFN-γ, nitrite, and iNOS, decreased significantly both at +4 and +24 h of WBH, following l-arg administration. However, l-arg administration did not reduce the increased levels of Th2 cytokines, namely IL-4 and TGF-β1, in WBH mice at +4 h of WBH. l-arg administration significantly increased the levels of Th2 cytokines at +24 h of WBH, compared to the saline-treated WBH mice. l-arg administration significantly increased both the splenic and hepatic arginase activity at +4 and +24 h of WBH compared to the saline-treated WBH mice. l-NAME treatment at +2 h of WBH and anti-TGF-β antibody treatment at 0 h of WBH significantly increased the mortality compared to the saline-treated WBH mice. Altered liver histopathology was attenuated following the administration of l-arg at +2 h of WBH. These results suggest that therapeutic administration of l-arg at appropriate concentration and time attenuates the acute inflammatory response, leading to the rescue of mice from heatstroke.