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-1beta, IFN-gamma, nitrite, TNF-alpha, IL-4, TGF-beta1, inducible form of nitric oxide synthase (iNOS), and corticosterone significantly increased compared to the sham group. The elevated levels of Th(1) cytokines, namely TNF-alpha, IL-1beta, IFN-gamma, 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 Th(2) cytokines, namely IL-4 and TGF-beta1, in WBH mice at +4 h of WBH. L-arg administration significantly increased the levels of Th(2) 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-beta 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.
Chatterjee
Saurabh
S
Immunology and Hyperthermia Section, Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400 085, India.
Premachandran
Sudha
S
Bagewadikar
Raghavendra S
RS
Bhattacharya
Sayanti
S
Chattopadhyay
Subrata
S
Poduval
T B
TB
D000818:Animals; D000906:Antibodies / Q000627:therapeutic use; D001120:Arginine / Q000378:metabolism*; D003345:Corticosterone / Q000097:blood; D016207:Cytokines / Q000097:blood*; D003907:Dexamethasone / Q000627:therapeutic use; D018883:Heat Stroke / Q000097:blood* / Q000188:drug therapy / Q000628:therapy; D008099:Liver / Q000201:enzymology; D051379:Mice; D019331:NG-Nitroarginine Methyl Ester / Q000627:therapeutic use; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009573:Nitrites / Q000097:blood; D018417:Th1 Cells / Q000378:metabolism*; D018418:Th2 Cells / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000276:immunology
D000906:Antibodies; D016207:Cytokines; D009573:Nitrites; D016212:Transforming Growth Factor beta; D003907:Dexamethasone; D001120:Arginine; D052247:Nitric Oxide Synthase Type II; D019331:NG-Nitroarginine Methyl Ester; D003345:Corticosterone