This Article Full Text Full Text (PDF) Online Supplement All Versions of this Article: 2007-0315OCv1 39/1/53    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 Kaynar, A. M. Articles by Shapiro, S. D. Search for Related Content PubMed PubMed Citation Articles by Kaynar, A. M. Articles by Shapiro, S. D.

Neutrophil Elastase Is Needed for Neutrophil Emigration into Lungs in Ventilator-Induced Lung Injury

¹ Department of Critical Care Medicine, ² Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; ³ Washington University School of Medicine, St. Louis, Missouri; and ⁴ Department of Environmental and Occupational Health, University of Pittsburgh, Graduate School Public Health, Pittsburgh, Pennsylvania

Correspondence and requests for reprints should be addressed to A. Murat Kaynar, MD, Department of Critical Care Medicine, Scaife Hall 639, University of Pittsburgh School of Medicine, 3550 Terrace Street, Pittsburgh, PA 15261. E-mail: kaynarm{at}upmc.edu

Mechanical ventilation, often required to maintain normal gas exchange in critically ill patients, may itself cause lung injury. Lung-protective ventilatory strategies with low tidal volume have been a major success in the management of acute respiratory distress syndrome (ARDS). Volutrauma causes mechanical injury and induces an acute inflammatory response. Our objective was to determine whether neutrophil elastase (NE), a potent proteolytic enzyme in neutrophils, would contribute to ventilator-induced lung injury. NE-deficient (NE^–/–) and wild-type mice were mechanically ventilated at set tidal volumes (10, 20, and 30 ml/kg) with 0 cm H₂O of positive end-expiratory pressure for 3 hours. Lung physiology and markers of lung injury were measured. Neutrophils from wild-type and NE^–/– mice were also used for in vitro studies of neutrophil migration, intercellular adhesion molecule (ICAM)-1 cleavage, and endothelial cell injury. Surprisingly, in the absence of NE, mice were not protected, but developed worse ventilator-induced lung injury despite having lower numbers of neutrophils in alveolar spaces. The possible explanation for this finding is that NE cleaves ICAM-1, allowing neutrophils to egress from the endothelium. In the absence of NE, impaired neutrophil egression and prolonged contact between neutrophils and endothelial cells leads to tissue injury and increased permeability. NE is required for neutrophil egression from the vasculature into the alveolar space, and interfering with this process leads to neutrophil-related endothelial cell injury.

Key Words: neutrophil elastase • ventilator-induced lung injury • endothelial injury • emigration

CLINICAL RELEVANCE This study suggests a role for neutrophil elastase in neutrophil emigration out of vasculature during mechanical ventilation. The lack of the enzyme caused prolonged interaction between neutrophils and endothelium leading to endothelial injury.

 

This article has been cited by other articles:

				R. Cockeran, T. J. Mitchell, C. Feldman, and R. Anderson Pneumolysin induces release of matrix metalloproteinase-8 and -9 from human neutrophils Eur. Respir. J., November 1, 2009; 34(5): 1167 - 1170. [Abstract] [Full Text] [PDF]

				G. R. Zosky, V. Cannizzaro, Z. Hantos, and P. D. Sly Protective mechanical ventilation does not exacerbate lung function impairment or lung inflammation following influenza A infection J Appl Physiol, November 1, 2009; 107(5): 1472 - 1478. [Abstract] [Full Text] [PDF]

				K. B. Adler and S. Matalon Highlights of the August Issue Am. J. Respir. Cell Mol. Biol., August 1, 2009; 41(2): 125 - 126. [Full Text] [PDF]

				P. J. Shaw, P. E. Ganey, and R. A. Roth Trovafloxacin Enhances the Inflammatory Response to a Gram-Negative or a Gram-Positive Bacterial Stimulus, Resulting in Neutrophil-Dependent Liver Injury in Mice J. Pharmacol. Exp. Ther., July 1, 2009; 330(1): 72 - 78. [Abstract] [Full Text] [PDF]

				P. J. Wolters, C. Wray, R. E. Sutherland, S. S. Kim, J. Koff, Y. Mao, and J. A. Frank Neutrophil-Derived IL-6 Limits Alveolar Barrier Disruption in Experimental Ventilator-Induced Lung Injury J. Immunol., June 15, 2009; 182(12): 8056 - 8062. [Abstract] [Full Text] [PDF]

				K. B. Adler and S. Matalon Highlights of the May Issue Am. J. Respir. Cell Mol. Biol., May 1, 2009; 40(5): 505 - 506. [Full Text] [PDF]

				E. Kolaczkowska, W. Grzybek, N. van Rooijen, H. Piccard, B. Plytycz, B. Arnold, and G. Opdenakker Neutrophil elastase activity compensates for a genetic lack of matrix metalloproteinase-9 (MMP-9) in leukocyte infiltration in a model of experimental peritonitis J. Leukoc. Biol., March 1, 2009; 85(3): 374 - 381. [Abstract] [Full Text] [PDF]