Up-regulation of endothelial nitric oxide synthase inhibits pulmonary leukocyte migration following lung ischemia-reperfusion in mice.
Endogenous nitric oxide (NO) is known to modulate post-ischemic inflammatory response in various organs. However, the role of nitric oxide synthase isoforms (NOS) in mediating pulmonary post-ischemic inflammatory response is poorly understood. We therefore studied post-ischemic endothelial adhesion molecule expression and leukocyte migration in endothelial NOS knockout (eNOS-KO) mice subjected to pulmonary ischemia and reperfusion in vivo. Under anesthesia and mechanical ventilation, the left pulmonary hilum in wild-type (WT) and eNOS-KO mice was clamped for 1 hour, followed by reperfusion for up to 24 hours. In WT mice, we observed a selective up-regulation of both eNOS mRNA and protein in lung tissue, while inducible NOS (iNOS) and neuronal NOS (nNOS) remained unchanged. Survival in eNOS-KO mice was reduced due to severe pulmonary edema, underlining an increased susceptibility to ischemia-reperfusion (I/R) injury. Interstitial tissue infiltration by CD18- and CD11a-positive white blood cells as well as lung tissue water content peaked at 5 hours of reperfusion and were found significantly higher than in WT mice. Enhanced leukocyte-endothelial interaction was associated with pronounced up-regulation of vascular cell adhesion molecule (VCAM) in eNOS-KO mice during post-ischemic reperfusion. We conclude that eNOS attenuates post-ischemic inflammatory injury to the lung most probably via inhibition of endothelial adhesion molecule expression.
Kaminski
Alexander
A
Department of Cardiac Surgery, University of Rostock, Rostock, Germany.
Pohl
Christiane Backhaus
CB
Sponholz
Christoph
C
Ma
Nan
N
Stamm
Christof
C
Vollmar
Brigitte
B
Steinhoff
Gustav
G
D000818:Animals; D001834:Body Water / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics*; D007150:Immunohistochemistry; D007249:Inflammation; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D007511:Ischemia / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D007527:Isoenzymes / Q000172:deficiency / Q000235:genetics; D008168:Lung / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000172:deficiency / Q000235:genetics*; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D009195:Peroxidase / Q000378:metabolism; D015424:Reperfusion; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics
D007527:Isoenzymes; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D009195:Peroxidase; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse