This Article Full Text Full Text (PDF) Online Supplement All Versions of this Article: 200411-1547OCv1 172/4/470    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Peng, X. Articles by Hassoun, P. M. Search for Related Content PubMed PubMed Citation Articles by Peng, X. Articles by Hassoun, P. M.

Inducible Nitric Oxide Synthase Contributes to Ventilator-induced Lung Injury

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

This article has been cited by other articles:

				J. H. Finigan, A. Boueiz, E. Wilkinson, R. Damico, J. Skirball, H. H. Pae, M. Damarla, E. Hasan, D. B. Pearse, S. P. Reddy, et al. Activated protein C protects against ventilator-induced pulmonary capillary leak Am J Physiol Lung Cell Mol Physiol, June 1, 2009; 296(6): L1002 - L1011. [Abstract] [Full Text] [PDF]

				J. M. Dodd-o, M. Hristopoulos, D. Scharfstein, R. Brower, P. Hassoun, L. S. King, P. Becker, M. Liu, W. Wang, H. T. Hassoun, et al. Interactive effects of mechanical ventilation and kidney health on lung function in an in vivo mouse model Am J Physiol Lung Cell Mol Physiol, January 1, 2009; 296(1): L3 - L11. [Abstract] [Full Text] [PDF]

				E. P. Schmidt, M. Damarla, O. Rentsendorj, L. E. Servinsky, B. Zhu, A. Moldobaeva, A. Gonzalez, P. M. Hassoun, and D. B. Pearse Soluble guanylyl cyclase contributes to ventilator-induced lung injury in mice Am J Physiol Lung Cell Mol Physiol, December 1, 2008; 295(6): L1056 - L1065. [Abstract] [Full Text] [PDF]

				A. Le, R. Damico, M. Damarla, A. Boueiz, H. H. Pae, J. Skirball, E. Hasan, X. Peng, A. Chesley, M. T. Crow, et al. Alveolar cell apoptosis is dependent on p38 MAP kinase-mediated activation of xanthine oxidoreductase in ventilator-induced lung injury J Appl Physiol, October 1, 2008; 105(4): 1282 - 1290. [Abstract] [Full Text] [PDF]

				J A Frank, J-F Pittet, C Wray, and M A Matthay Protection from experimental ventilator-induced acute lung injury by IL-1 receptor blockade Thorax, February 1, 2008; 63(2): 147 - 153. [Abstract] [Full Text] [PDF]

				S. Papaiahgari, A. Yerrapureddy, S. R. Reddy, N. M. Reddy, J. M. Dodd-O, M. T. Crow, D. N. Grigoryev, K. Barnes, R. M. Tuder, M. Yamamoto, et al. Genetic and Pharmacologic Evidence Links Oxidative Stress to Ventilator-induced Lung Injury in Mice Am. J. Respir. Crit. Care Med., December 15, 2007; 176(12): 1222 - 1235. [Abstract] [Full Text] [PDF]

				R. Liu, Y. Hotta, A. R. Graveline, O. V. Evgenov, E. S. Buys, K. D. Bloch, F. Ichinose, and W. M. Zapol Congenital NOS2 deficiency prevents impairment of hypoxic pulmonary vasoconstriction in murine ventilator-induced lung injury Am J Physiol Lung Cell Mol Physiol, November 1, 2007; 293(5): L1300 - L1305. [Abstract] [Full Text] [PDF]

				T. Miyahara, K. Hamanaka, D. S. Weber, D. A. Drake, M. Anghelescu, and J. C. Parker Phosphoinositide 3-kinase, Src, and Akt modulate acute ventilation-induced vascular permeability increases in mouse lungs Am J Physiol Lung Cell Mol Physiol, July 1, 2007; 293(1): L11 - L21. [Abstract] [Full Text] [PDF]

				H. T. Hassoun, D. N. Grigoryev, M. L. Lie, M. Liu, C. Cheadle, R. M. Tuder, and H. Rabb Ischemic acute kidney injury induces a distant organ functional and genomic response distinguishable from bilateral nephrectomy Am J Physiol Renal Physiol, July 1, 2007; 293(1): F30 - F40. [Abstract] [Full Text] [PDF]

				R.-E. E. Abdulnour, X. Peng, J. H. Finigan, E. J. Han, E. J. Hasan, K. G. Birukov, S. P. Reddy, J. E. Watkins III, U. S. Kayyali, J. G. N. Garcia, et al. Mechanical stress activates xanthine oxidoreductase through MAP kinase-dependent pathways Am J Physiol Lung Cell Mol Physiol, September 1, 2006; 291(3): L345 - L353. [Abstract] [Full Text] [PDF]

				H. Grasemann, F. Kurtz, and F. Ratjen Inhaled L-Arginine Improves Exhaled Nitric Oxide and Pulmonary Function in Patients with Cystic Fibrosis Am. J. Respir. Crit. Care Med., July 15, 2006; 174(2): 208 - 212. [Abstract] [Full Text] [PDF]

				N. G. Hall, Y. Liu, J. M. Hickman-Davis, G. C. Davis, C. Myles, E. J. Andrews, S. Matalon, and J. D. Lang Jr. Bactericidal Function of Alveolar Macrophages in Mechanically Ventilated Rabbits Am. J. Respir. Cell Mol. Biol., June 1, 2006; 34(6): 719 - 726. [Abstract] [Full Text] [PDF]

				K. Takenaka, Y. Nishimura, T. Nishiuma, A. Sakashita, T. Yamashita, K. Kobayashi, M. Satouchi, T. Ishida, S. Kawashima, and M. Yokoyama Ventilator-induced lung injury is reduced in transgenic mice that overexpress endothelial nitric oxide synthase Am J Physiol Lung Cell Mol Physiol, June 1, 2006; 290(6): L1078 - L1086. [Abstract] [Full Text] [PDF]

				E. B. Milbrandt, A. Ishizaka, and D. C. Angus Update in critical care 2005. Am. J. Respir. Crit. Care Med., April 15, 2006; 173(8): 833 - 841. [Full Text] [PDF]