Neutrophil elastase promotes lung microvascular injury and proteolysis of endothelial cadherins.
Intestinal ischemia-reperfusion (I-R) is associated with lung injury and the acute respiratory distress syndrome. The hypothesis of this study was that intestinal I-R activates circulating neutrophils to promote elastase-mediated lung injury. Isolated rat lungs were perfused with blood or plasma obtained after intestinal I-R, and lung neutrophil retention and injury and bronchoalveolar lavage (BAL) elastase were measured. Perfusion with I-R blood caused lung neutrophil accumulation and injury and increased BAL elastase. These effects were attenuated by the elastase inhibitor L-658758. Interference with neutrophil adherence before gut reperfusion blocked BAL elastase accumulation. The role of endothelial junction proteins (cadherins) in I-R-elicited lung damage was also evaluated. Activated human neutrophils proteolyzed cadherins in human umbilical vein endothelial cells. Furthermore, plasma of patients with acute respiratory distress syndrome contained soluble cadherin fragments. The results of this study suggest that the elastase released by systemically activated neutrophils contributes to lung neutrophil accumulation and pulmonary microvascular injury. Elastase-mediated proteolysis of endothelial cell cadherins may represent the mechanism through which lung microvascular integrity is disrupted after intestinal I-R.
Department of Medicine, Louisiana State University Medical Center, Shreveport, Louisiana 71130, USA.
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Carden
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Xiao
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Moak
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Willis
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Robinson-Jackson
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Alexander
D000818:Animals; D001794:Blood Pressure; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D015820:Cadherins / Q000378:metabolism*; D002196:Capillaries / Q000502:physiology / Q000503:physiopathology; D002199:Capillary Permeability; D002478:Cells, Cultured; D002511:Cephalosporins / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007422:Intestines / Q000098:blood supply*; D007511:Ischemia / Q000503:physiopathology*; D019272:Leukocyte Elastase / Q000378:metabolism*; D008168:Lung / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D009504:Neutrophils / Q000502:physiology*; D009195:Peroxidase / Q000032:analysis; D011652:Pulmonary Circulation / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000503:physiopathology*; D012128:Respiratory Distress Syndrome / Q000097:blood / Q000473:pathology / Q000503:physiopathology*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D014471:Umbilical Veins
D015820:Cadherins; D002511:Cephalosporins; D015842:Serine Proteinase Inhibitors; C065332:L 658758; D009195:Peroxidase; D019272:Leukocyte Elastase