Selective inducible nitric oxide synthase (iNOS) inhibition attenuates remote acute lung injury in a model of ruptured abdominal aortic aneurysm.
OBJECTIVE
Abdominal aortic aneurysm rupture is associated with a systemic inflammatory response syndrome and acute lung injury. Using a selective inducible nitric oxide synthase (iNOS) inhibitor, N(6)-(iminoethyl)-lysine (L-NIL), we explored the role of iNOS in the early pro-inflammatory signaling and acute lung injury in experimental abdominal aortic aneurysm rupture.


METHODS
Anesthetized rats were randomized to sham control or shock and clamp (s + c) groups, which underwent one hour of hemorrhagic shock, followed by 45 minutes of supramesenteric aortic clamping, and then two hours resuscitated reperfusion. Animals in s + c were randomized to receive intravenous L-NIL at 50 microg/kg/h or saline at the start of reperfusion. Pulmonary permeability to (125)I-labeled albumin, myeloperoxidase (MPO) activity, cytokine levels, and semi-quantitative RT-PCR for mRNA were indicators of microvascular permeability, leuco-sequestration, and pro-inflammatory signaling, respectively.


RESULTS
Lung permeability index were significantly increased in s + c compared to sham (4.43 +/- 0.96 versus 1.30 +/- 0.17, P < 0.01), and attenuated by L-NIL treatment (2.14 +/- 0.70, P < 0.05). Lung tissue MPO activity was significantly increased in s + c compared to sham (2.80 +/- 0.32 versus 1.03 +/- 0.29, P < 0.002), and attenuated by L-NIL treatment (1.50 +/- 0.20, P < 0.007). Lung tissue iNOS activity was significantly increased in s + c compared to sham animals (P < 0.05), and attenuated by L-NIL treatment (P < 0.05). Lung tissue iNOS mRNA was upregulated 8-fold in s + c compared to sham (P < 0.05). Data represents mean +/- standard error mean, comparisons with ANOVA.


CONCLUSIONS
These data suggest that in our model of ruptured abdominal aortic aneurysm iNOS plays a crucial role in reperfusion lung injury. Selective inhibition of iNOS during early reperfusion prevents neutrophil mediated acute lung injury.
Harkin
Denis W
DW
Division of Vascular Surgery, Department of Surgery, The Toronto Hospital (General Division), Faculty of Medicine, University of Toronto, Toronto, Ontario M5C 2C4, Canada. D.W.Harkin@qub.ac.uk
Rubin
Barry B
BB
Romaschin
Alex
A
Lindsay
Thomas F
TF
D000208:Acute Disease; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy; D001019:Aortic Rupture / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy; D001794:Blood Pressure; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015850:Interleukin-6 / Q000235:genetics; D007413:Intestinal Mucosa / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008171:Lung Diseases / Q000209:etiology* / Q000378:metabolism; D008239:Lysine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009994:Osmolar Concentration; D010539:Permeability; D009195:Peroxidase / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044087:Receptor, Anaphylatoxin C5a / Q000235:genetics; D012151:Resuscitation; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D016207:Cytokines; D004791:Enzyme Inhibitors; D015850:Interleukin-6; C090663:N(6)-(1-iminoethyl)lysine; D012333:RNA, Messenger; D044087:Receptor, Anaphylatoxin C5a; D014409:Tumor Necrosis Factor-alpha; D009195:Peroxidase; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D008239:Lysine