The role of endogenous nitric oxide in modulating ischemia-reperfusion injury in the isolated, blood-perfused rat lung.
Ischemia-reperfusion (IR) lung injury occurs after various clinical procedures, including cardiopulmonary bypass. It is not clear whether endogenous nitric oxide (NO) is protective or injurious in lungs subjected to IR. Thus, in this study we examined the contribution of endogenous NO to IR injury in isolated, blood-perfused rat lungs. Lungs of male Wistar rats (300 g) were subjected to 30 min ischemia and 180 min reperfusion (I30R180). Lungs were sampled for inducible nitric oxide synthase (i-NOS) mRNA expression (each n = 3) and NOS enzyme activity (each n = 4) at different time points. NOS inhibitors NG-nitro-L-arginine-methyl ester (10[-4] M) and aminoguanidine (10[-4] M) were used to study the contribution of NO to IR injury in lungs subjected to I30R30 and I30R180. The contribution of i-NOS to IR lung injury was studied by inducing i-NOS enzyme with Salmonella lipopolysaccharide, followed by I30R30. We found that ischemia-reperfusion alone can upregulate i-NOS mRNA and i-NOS enzyme activity (p < 0.05, ANOVA), but downregulate constitutive NOS enzyme activity over 180 min reperfusion. Endogenously produced NO is protective against lung injury in I30R180 in normal rats and lung injury in I30R30 in septic rats. NO is also pivotal in maintaining pulmonary vascular homeostasis in septic rat lungs undergoing IR.
Lu
Y T
YT
Division of Applied Pharmacology, Imperial College School of Medicine at the National Heart and Lung Institute, London, United Kingdom.
Liu
S F
SF
Mitchell
J A
JA
Malik
A B
AB
Hellewell
P G
PG
Evans
T W
TW
D000818:Animals; D004195:Disease Models, Animal; D006146:Guanidines / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000032:analysis* / Q000037:antagonists & inhibitors / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger / Q000032:analysis*; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000201:enzymology / Q000276:immunology*; D012128:Respiratory Distress Syndrome / Q000201:enzymology / Q000276:immunology*; D013997:Time Factors
D006146:Guanidines; D012333:RNA, Messenger; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C004479:pimagedine; D019331:NG-Nitroarginine Methyl Ester