title: Wood bark smoke induces lung and pleural plasminogen activator inhibitor 1 and stabilizes its mRNA in porcine lung cells.
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.
authors.affiliation: The Texas Lung Injury Institute, The University of Texas Health Science Center at Tyler, Tyler, TX 75708, USA.
authors.forename: Krishna K
authors.initials: KK
authors.lastname: Midde
authors.forename: Andriy I
authors.initials: AI
authors.lastname: Batchinsky
authors.forename: Leopoldo C
authors.initials: LC
authors.lastname: Cancio
authors.forename: Sreerama
authors.initials: S
authors.lastname: Shetty
authors.forename: Andrey A
authors.initials: AA
authors.lastname: Komissarov
authors.forename: Galina
authors.initials: G
authors.lastname: Florova
authors.forename: Kerfoot P
authors.initials: KP
authors.lastname: Walker
authors.forename: Kathy
authors.initials: K
authors.lastname: Koenig
authors.forename: Zissis C
authors.initials: ZC
authors.lastname: Chroneos
authors.forename: Tim
authors.initials: T
authors.lastname: Allen
authors.forename: Kevin
authors.initials: K
authors.lastname: Chung
authors.forename: Michael
authors.initials: M
authors.lastname: Dubick
authors.forename: Steven
authors.initials: S
authors.lastname: Idell
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D005337:Fibrin / Q000378:metabolism; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism*; D010994:Pleura / Q000378:metabolism*; D011897:Random Allocation; D012906:Smoke / Q000009:adverse effects*; D013552:Swine
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D012906:Smoke; D005337:Fibrin