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Published ahead of print on June 3, 2005, doi:10.1164/rccm.200411-1547OC
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American Journal of Respiratory and Critical Care Medicine Vol 172. pp. 470-479, (2005)
© 2005 American Thoracic Society
doi: 10.1164/rccm.200411-1547OC

Original Article

Inducible Nitric Oxide Synthase Contributes to Ventilator-induced Lung Injury

Xinqi Peng*, Raja-Elie E. Abdulnour*, Saad Sammani, Shwu-Fan Ma, Eugenia J. Han, Emile J. Hasan, Rubin Tuder, Joe G. N. Garcia and Paul M. Hassoun

Division of Pulmonary and Critical Care Medicine, Department of Pathology, and the Center for Translational Respiratory Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland

Correspondence and requests for reprints should be addressed to Paul M. Hassoun, M.D., Division of Pulmonary and Critical Care Medicine, 5501 Hopkins Bayview Circle, Baltimore, MD 21224. E-mail: phassoun{at}jhmi.edu

Rationale: 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. Objectives: 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. Conclusion: Taken together, our results indicate that iNOS gene expression and activity are significantly upregulated and contribute to lung edema in ventilator-induced lung injury.

Key Words: inducible nitric oxide synthase • lung permeability • mechanical ventilation




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