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Published ahead of print on June 3, 2005, doi:10.1164/rccm.200411-1547OC

Am. J. Respir. Crit. Care Med., Volume 172, Number 4, August 2005, 470-479

A more recent version of this article appeared on August 15, 2005
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Submitted on November 19, 2004
Accepted on May 20, 2005

Inducible Nitric Oxide Synthase Contributes to Ventilator-Induced Lung Injury

Xinqi Peng1, Raja-Elie E Abdulnour1, Saad Sammani1, Shwu-Fan Ma1, Eugenia J Han1, Emile J Hasan1, Rubin Tuder2, Joe G.N. Garcia1, and Paul M Hassoun1*

1 Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA, 2 Department of Pathology and the Center for Translational Respiratory Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

* To whom correspondence should be addressed. 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 (VILI). Methods: C57BL/6J (WT) and iNOS-deficient mice (iNOS-/-) mice received spontaneous ventilation (control) or mechanical ventilation (MV, tidal volumes of 7 and 20 ml/kg) for 2h, after which NOS gene expression and activity were determined and pulmonary capillary leakage assessed by the Evans Blue Albumin assay (EBA). Results: iNOS mRNA and protein expression was absent in iNOS-/- mice, minimal in WT control mice, but significantly up-regulated in response to 2h of MV. In contrast, eNOS protein was decreased in WT mice, and non-significantly increased in iNOS-/- mice, as compared to controls. iNOS and eNOS activities followed similar patterns in WT and iNOS-/- mice. MV caused ALI as suggested by cell infiltration and nitrotyrosine accumulation in the lung, and a significant increase in BAL cell count in WT mice, findings that were reduced in iNOS-/- mice. Finally, EBA accumulation in lungs of WT mice was significant (50% versus 15% increase in iNOS-/- mice compared to controls) 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 up-regulated and contribute to lung edema in VILI.
Key words: Mechanical ventilation, inducible NOS, lung permeability




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