ADAM15 deficiency attenuates pulmonary hyperpermeability and acute lung injury in lipopolysaccharide-treated mice

• Published in: American journal of physiology. Lung cellular and molecular physiology Vol. 304; no. 3; pp. L135 - L142
• Main Authors: Sun, Chongxiu, Beard, Jr, Richard S, McLean, Danielle L, Rigor, Robert R, Konia, Thomas, Wu, Mack H, Yuan, Sarah Y
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.02.2013
• Subjects: Acute Lung Injury - chemically induced; Acute Lung Injury - genetics; Acute Lung Injury - metabolism; Acute Lung Injury - pathology; ADAM Proteins - deficiency; ADAM Proteins - genetics; Animals; Bronchoalveolar Lavage Fluid - cytology; Electric Impedance; Endothelial Cells - metabolism; Endothelial Cells - pathology; Lipopolysaccharides - pharmacology; Lung - metabolism; Lung - pathology; Membrane Proteins - deficiency; Membrane Proteins - genetics; Mice; Mice, Knockout; Neutrophil Infiltration; Neutrophils - metabolism; Neutrophils - pathology; Permeability; Peroxidase - genetics; Peroxidase - metabolism; Primary Cell Culture; Pulmonary Edema - chemically induced; Pulmonary Edema - genetics; Pulmonary Edema - metabolism; Pulmonary Edema - pathology; Transendothelial and Transepithelial Migration; Up-Regulation
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00133.2012

ADAM15 is a disintegrin and metalloprotease recently implicated in cancer and chronic immune disorders. We have recently characterized ADAM15 as a mediator of endothelial barrier dysfunction. Whether this molecule contributes to acute inflammation has not been evaluated. The purpose of this study was to investigate the role of ADAM15 in mediating pulmonary microvascular leakage during acute inflammatory injury. Immunofluorescent staining and Western blotting revealed that the endothelium was the main source of ADAM15 in lung tissue. In a mouse model of acute lung injury induced by lipopolysaccharide (LPS), upregulation of ADAM15 was observed in association with pulmonary edema and neutrophil infiltration. The LPS-induced inflammatory injury, as demonstrated by bronchoalveolar lavage neutrophil count, lung wet-to-dry weight ratio, and myeloperoxidase activity, was significantly attenuated in Adam15(-/-) mice. Studies with primary cell culture demonstrated abundant ADAM15 expression in endothelial cells (ECs) of mouse lung but not in neutrophils. Deficiency of ADAM15 in ECs had no obvious effect on basal permeability but significantly attenuated hyperpermeability response to LPS as evidenced by albumin flux assay and measurements of transendothelial electrical resistance, respectively. ADAM15 deficiency also reduced neutrophil chemotactic transmigration across endothelial barriers in the presence or absence of formyl-methionyl-leucyl-phenylalanine (fMLP). Rescue expression of ADAM15 in Adam15(-/-) ECs restored neutrophil transendothelial migration. These data indicate that ADAM15 upregulation contributes to inflammatory lung injury by promoting endothelial hyperpermeability and neutrophil transmigration.