Inducible nitric oxide synthase contributes to ventilator-induced lung injury.
BACKGROUND
Inducible nitric oxide synthase (iNOS) has been implicated in the development of acute lung injury. Recent studies indicate a role for mechanical stress in iNOS and endothelial NOS (eNOS) regulation.


OBJECTIVE
This study investigated changes in lung NOS expression and activity in a mouse model of ventilator-induced lung injury.


METHODS
C57BL/6J (wild-type [WT]) and iNOS-deficient (iNOS(-/-)) mice received spontaneous ventilation (control) or mechanical ventilation (MV; VT of 7 and 20 ml/kg) for 2 hours, after which NOS gene expression and activity were determined and pulmonary capillary leakage assessed by the Evans blue albumin assay.


RESULTS
iNOS mRNA and protein expression was absent in iNOS(-/-) mice, minimal in WT control mice, but significantly upregulated in response to 2 hours of MV. In contrast, eNOS protein was decreased in WT mice, and nonsignificantly increased in iNOS(-/-) mice, as compared with control animals. iNOS and eNOS activities followed similar patterns in WT and iNOS(-/-) mice. MV caused acute lung injury as suggested by cell infiltration and nitrotyrosine accumulation in the lung, and a significant increase in bronchoalveolar lavage cell count in WT mice, findings that were reduced in iNOS(-/-) mice. Finally, Evans blue albumin accumulation in lungs of WT mice was significant (50 vs. 15% increase in iNOS(-/-) mice compared with control animals) in response to MV and was prevented by treatment of the animals with the iNOS inhibitor aminoguanidine.


CONCLUSIONS
Taken together, our results indicate that iNOS gene expression and activity are significantly upregulated and contribute to lung edema in ventilator-induced lung injury.
Peng
Xinqi
X
Division of Pulmonary and Critical Care Medicine, 5501 Hopkins Bayview Circle, Baltimore, MD 21224, USA.
Abdulnour
Raja-Elie E
RE
Sammani
Saad
S
Ma
Shwu-Fan
SF
Han
Eugenia J
EJ
Hasan
Emile J
EJ
Tuder
Rubin
R
Garcia
Joe G N
JG
Hassoun
Paul M
PM
D000818:Animals; D002199:Capillary Permeability; D015870:Gene Expression; D008168:Lung / Q000201:enzymology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D052247:Nitric Oxide Synthase Type II; D011654:Pulmonary Edema / Q000209:etiology; D012128:Respiratory Distress Syndrome / Q000201:enzymology / Q000209:etiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation; D012122:Ventilators, Mechanical / Q000009:adverse effects*
D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse