Work

Wood Bark Smoke Induces Lung and Pleural Plasminogen Activator Inhibitor 1 and Stabilizes Its mRNA in Porcine Lung Cells

Year: 2011

Type: article

Abstract: Although aberrant fibrinolysis and plasminogen activator inhibitor 1 (PAI-1) are implicated in acute lung injury, the role of this serpin in the pathogenesis of wood bark smoke (WBS)-induced acute lung injury (SIALI) and its regulation in resident lung cells after exposure to smoke are unclear. A total of 22 mechanically ventilated pigs were included in this study. Immunohistochemical analyses were used to assess fibrin and PAI-1 in the lungs of pigs with SIALI in situ. Plasminogen activator inhibitor 1 was measured in bronchoalveolar lavage fluids by Western blotting. Induction of PAI-1 was determined at the protein and mRNA levels by Western and polymerase chain reaction analyses in primary porcine alveolar type II cells, fibroblasts, and pleural mesothelial cells. Plasminogen activator inhibitor 1 mRNA stability was determined by transcription chase studies. Gel shift analyses were used to characterize the mechanism regulating PAI-1 mRNA stability. Smoke-induced ALI induced PAI-1, with prominent extravascular fibrin deposition in large and small airways as well as alveolar and subpleural compartments. In pleural mesothelial cells, lung fibroblasts, and alveolar type II cells, PAI-1 mRNA was stabilized by WBS extract and contributed to induction of PAI-1. The mechanism involves dissociation of a novel 6-phospho-d-gluconate-NADP oxidoreductase-like PAI-1 mRNA binding protein from PAI-1 mRNA. Exposure to WBS induces prominent airway and mesothelial expression of PAI-1, associated with florid distribution of fibrin in SIALI in vivo Wood bark smoke components induce PAI-1 in vitro in part by stabilization of PAI-1 mRNA, a newly recognized pathway that may promote extravascular fibrin deposition and lung dysfunction in SIALI. ABBREVIATIONS-3′ UTR-3′ Untranslated region; 6-PGD-6-phospho-d-gluconate-NADP oxidoreductase; ARDS-Acute respiratory distress syndrome; APRV-Airway-pressure-release ventilation; ATII-Alveolar type II cells; AU-Arbitrary fluorescence emission units; BAL-Bronchoalveolar lavage; BALF-BAL fluid; CMV-Conventional mechanical ventilation; Fio2-Fraction of inspired oxygen; HBSS-Hanks balanced salt solution; ICU-Intensive care unit; PBS-Phosphate-buffered saline; PL-Plasmin; PGN-Plasminogen; PA-PGN activator; PAI-1-Plasminogen activator inhibitor 1; PMCs-Pleural mesothelial cells; PEEP-Positive end-expiratory pressure; Paco2-Partial pressure of carbon dioxide in arterial blood; Pao2-Partial pressure of oxygen in arterial blood; PIP-Peak inspiratory pressure; PFs-Pleural fluids; PFR-Pao2-to-Fio2 ratio; scuPA-Single-chain urokinase; SIALI-Smoke-induced acute lung injury; TV-tidal volume; uPA-Urokinase-type plasminogen activator; WBSE-Wood bark smoke extract

Source: Shock

DOI: 10.1097/shk.0b013e31821d60a4