title: Plasminogen activator inhibitor-1 deficiency augments visceral mesothelial organization, intrapleural coagulation, and lung restriction in mice with carbon black/bleomycin-induced pleural injury.
abstract: Local derangements of fibrin turnover and plasminogen activator inhibitor (PAI)-1 have been implicated in the pathogenesis of pleural injury. However, their role in the control of pleural organization has been unclear. We found that a C57Bl/6j mouse model of carbon black/bleomycin (CBB) injury demonstrates pleural organization resulting in pleural rind formation (14 d). In transgenic mice overexpressing human PAI-1, intrapleural fibrin deposition was increased, but visceral pleural thickness, lung volumes, and compliance were comparable to wild type. CBB injury in PAI-1(-/-) mice significantly increased visceral pleural thickness (P < 0.001), elastance (P < 0.05), and total lung resistance (P < 0.05), while decreasing lung compliance (P < 0.01) and lung volumes (P < 0.05). Collagen, α-smooth muscle actin, and tissue factor were increased in the thickened visceral pleura of PAI-1(-/-) mice. Colocalization of α-smooth muscle actin and calretinin within pleural mesothelial cells was increased in CBB-injured PAI-1(-/-) mice. Thrombin, factor Xa, plasmin, and urokinase induced mesothelial-mesenchymal transition, tissue factor expression, and activity in primary human pleural mesothelial cells. In PAI-1(-/-) mice, D-dimer and thrombin-antithrombin complex concentrations were increased in pleural lavage fluids. The results demonstrate that PAI-1 regulates CBB-induced pleural injury severity via unrestricted fibrinolysis and cross-talk with coagulation proteases. Whereas overexpression of PAI-1 augments intrapleural fibrin deposition, PAI-1 deficiency promotes profibrogenic alterations of the mesothelium that exacerbate pleural organization and lung restriction.
authors.affiliation: 1 The Texas Lung Injury Institute.
authors.forename: Torry A
authors.initials: TA
authors.lastname: Tucker
authors.forename: Ann
authors.initials: A
authors.lastname: Jeffers
authors.forename: Alexia
authors.initials: A
authors.lastname: Alvarez
authors.forename: Shuzi
authors.initials: S
authors.lastname: Owens
authors.forename: Kathleen
authors.initials: K
authors.lastname: Koenig
authors.forename: Brandon
authors.initials: B
authors.lastname: Quaid
authors.forename: Andrey A
authors.initials: AA
authors.lastname: Komissarov
authors.forename: Galina
authors.initials: G
authors.lastname: Florova
authors.forename: Hema
authors.initials: H
authors.lastname: Kothari
authors.forename: Usha
authors.initials: U
authors.lastname: Pendurthi
authors.forename: L Vijaya
authors.initials: LV
authors.lastname: Mohan Rao
authors.forename: Steven
authors.initials: S
authors.lastname: Idell
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000494:pharmacology; D001777:Blood Coagulation / Q000502:physiology*; D004848:Epithelium / Q000378:metabolism*; D005337:Fibrin / Q000378:metabolism / Q000494:pharmacology; D006474:Hemorrhagic Disorders / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000378:metabolism; D055370:Lung Injury / Q000139:chemically induced / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017395:Plasminogen Activator Inhibitor 1 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D010994:Pleura / Q000473:pathology*; D053260:Soot / Q000494:pharmacology; D013917:Thrombin / Q000378:metabolism / Q000494:pharmacology
chemical_list: D017395:Plasminogen Activator Inhibitor 1; C051321:SERPINE1 protein, human; D053260:Soot; D001761:Bleomycin; D005337:Fibrin; D013917:Thrombin
references.citation: Respirology. 2004 Nov;9(4):428-40
references.pmid: 15612953
references.citation: Semin Thromb Hemost. 2013 Jun;39(4):373-81
references.pmid: 23504608
references.citation: Am J Respir Crit Care Med. 2002 Oct 1;166(7):920-6
references.pmid: 12359647
references.citation: Am J Physiol Cell Physiol. 2005 Jul;289(1):C217-23
references.pmid: 15716324
references.citation: Chest. 2009 Oct;136(4):1148-1159
references.pmid: 19809058
references.citation: J Clin Invest. 2009 Sep;119(9):2550-63
references.pmid: 19652365
references.citation: J Clin Invest. 2000 Dec;106(11):1341-50
references.pmid: 11104787
references.citation: Am J Respir Cell Mol Biol. 1996 Aug;15(2):252-9
references.pmid: 8703482
references.citation: J Pathol. 2012 Oct;228(2):170-80
references.pmid: 22262246
references.citation: J Clin Invest. 2003 Dec;112(12):1776-84
references.pmid: 14679171
references.citation: Circulation. 2010 Sep 21;122(12):1200-9
references.pmid: 20823384
references.citation: Curr Opin Infect Dis. 2013 Apr;26(2):196-202
references.pmid: 23286936
references.citation: J Biol Chem. 2006 Jun 2;281(22):15345-51
references.pmid: 16554301
references.citation: Respiration. 1976;33(5):396-402
references.pmid: 935693
references.citation: J Clin Invest. 1996 Jan 1;97(1):232-7
references.pmid: 8550840
references.citation: Acta Pharmacol Sin. 2012 Jul;33(7):897-908
references.pmid: 22659625
references.citation: Am J Pathol. 2003 Aug;163(2):445-52
references.pmid: 12875966
references.citation: Am J Respir Cell Mol Biol. 2012 Feb;46(2):173-9
references.pmid: 21852688
references.citation: Am J Physiol. 1991 Oct;261(4 Pt 1):L240-8
references.pmid: 1928357
references.citation: Arterioscler Thromb Vasc Biol. 1997 Mar;17(3):483-9
references.pmid: 9102166
references.citation: Respir Res. 2007 Apr 16;8:31
references.pmid: 17433115
references.citation: Kidney Int. 2006 Mar;69(6):1064-72
references.pmid: 16528256
references.citation: Am J Physiol Lung Cell Mol Physiol. 2009 Jul;297(1):L115-24
references.pmid: 19411308
references.citation: Am J Pathol. 2000 Jul;157(1):177-87
references.pmid: 10880388
references.citation: Kidney Int. 2010 Feb;77(4):319-28
references.pmid: 19956083
references.citation: Clin Chest Med. 2006 Jun;27(2):181-91
references.pmid: 16716812
references.citation: Am J Physiol Lung Cell Mol Physiol. 2007 Jan;292(1):L25-32
references.pmid: 16980376
references.citation: Hum Pathol. 2003 Oct;34(10):994-1000
references.pmid: 14608532
references.citation: Am J Respir Cell Mol Biol. 2013 Jan;48(1):44-52
references.pmid: 23002099
references.citation: FASEB J. 2003 Oct;17(13):1904-6
references.pmid: 12897066
references.citation: J Immunol. 2007 Nov 1;179(9):6043-51
references.pmid: 17947678
references.citation: Curr Opin Pulm Med. 2008 Jul;14(4):310-5
references.pmid: 18520264
references.citation: Eur Respir J. 2010 Jan;35(1):176-85
references.pmid: 19574324