title: Neutrophil elastase is needed for neutrophil emigration into lungs in ventilator-induced lung injury.
abstract: 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.
authors.affiliation: Department of Critical Care Medicine, Scaife Hall 639, University of Pittsburgh School of Medicine, 3550 Terrace Street, Pittsburgh, PA 15261, USA. kaynarm@upmc.edu
authors.forename: A Murat
authors.initials: AM
authors.lastname: Kaynar
authors.forename: A McGarry
authors.initials: AM
authors.lastname: Houghton
authors.forename: Esther H
authors.initials: EH
authors.lastname: Lum
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Pitt
authors.forename: Steven D
authors.initials: SD
authors.lastname: Shapiro
mesh_terms: D000818:Animals; D002634:Chemotaxis, Leukocyte; D004730:Endothelium, Vascular / Q000503:physiopathology; D019272:Leukocyte Elastase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008168:Lung / Q000033:anatomy & histology; D008171:Lung Diseases / Q000201:enzymology / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000201:enzymology / Q000502:physiology*; D009929:Organ Size; D011667:Pulmonary Veins / Q000503:physiopathology; D012128:Respiratory Distress Syndrome / Q000209:etiology* / Q000473:pathology; D013990:Tidal Volume; D012122:Ventilators, Mechanical / Q000009:adverse effects*
chemical_list: D019272:Leukocyte Elastase