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Title: Plasminogen Activator Inhibitor-1 Is Critical in Alcohol-Enhanced Acute Lung Injury in Mice.

Authors: Poole, Lauren G; Massey, Veronica L; Siow, Deanna L; Torres-Gonzáles, Edilson; Warner, Nikole L; Luyendyk, James P; Ritzenthaler, Jeffrey D; Roman, Jesse; Arteel, Gavin E

Published In Am J Respir Cell Mol Biol, (2017 Sep)

Abstract: Chronic alcohol exposure is a clinically important risk factor for the development of acute respiratory distress syndrome, the most severe form of acute lung injury (ALI). However, the mechanisms by which alcohol sensitizes the lung to development of this disease are poorly understood. We determined the role of the antifibrinolytic protein plasminogen activator inhibitor-1 (PAI-1) in alcohol enhancement of experimental endotoxin-induced ALI. Wild-type, PAI-1-/-, and integrin β3-/- mice were fed ethanol-containing Lieber-DeCarli liquid or a control diet for 6 weeks, followed by systemic LPS challenge. LPS administration triggered coagulation cascade activation as evidenced by increased plasma thrombin-antithrombin levels and pulmonary fibrin deposition. Ethanol-exposed animals showed enhanced PAI-1 expression and pulmonary fibrin deposition with coincident exaggeration of pulmonary inflammatory edematous injury. PAI-1 deficiency markedly reduced pulmonary fibrin deposition and greatly reduced inflammation and injury without impacting upstream coagulation. Interestingly, pulmonary platelet accumulation was effectively abolished by PAI-1 deficiency in ethanol/LPS-challenged mice. Moreover, mice lacking integrin αIIBβ3, the primary platelet receptor for fibrinogen, displayed a dramatic reduction in early inflammatory changes after ethanol/LPS challenge. These results indicate that the mechanism whereby alcohol exaggerates LPS-induced lung injury requires PAI-1-mediated pulmonary fibrin accumulation, and suggest a novel mechanism whereby alcohol contributes to inflammatory ALI by enhancing fibrinogen-platelet engagement.

PubMed ID: 28445073 Exiting the NIEHS site

MeSH Terms: Acute Lung Injury/complications; Acute Lung Injury/metabolism*; Acute Lung Injury/pathology*; Acute Lung Injury/prevention & control; Animals; Blood Platelets/metabolism; Ethanol/adverse effects*; Fibrin/metabolism; Hemorrhagic Disorders/complications; Hemorrhagic Disorders/pathology; Integrin beta3/metabolism; Lipopolysaccharides; Mice, Inbred C57BL; Models, Biological; Plasminogen Activator Inhibitor 1/deficiency; Plasminogen Activator Inhibitor 1/metabolism*; Pulmonary Edema/complications; Pulmonary Edema/pathology; Pulmonary Edema/prevention & control

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