title: Neither fibrin nor plasminogen activator inhibitor-1 deficiency protects lung function in a mouse model of acute lung injury.
abstract: Fibrin impairs surfactant function in vitro, and inhibition of fibrinolysis by plasminogen activator inhibitor (PAI-1) is thought to promote fibrin accumulation in acute lung injury (ALI). This has led to speculation that impaired PAI-1 and fibrin accumulation should protect lung function in ALI. We tested this hypothesis by investigating ALI severity in fibrinogen-deficient (Fgn-/-) and PAI-1-deficient (PAI-1-/-) mice. PAI-1-/-, C57BL/6, Fgn-/-, and Fgn+/- females were anesthetized and allowed to aspirate 4 microl/g of hydrochloric acid (pH 1.0) and then reanesthetized and connected to a ventilator 48 h later. Naive C57BL/6 and Fgn+/- females served as controls. Following deep inflation (DI), forced oscillations were delivered periodically over 8 min to measure changes in elastance (H) as a surrogate of lung derecruitment, at positive end-expiratory pressures (PEEP) of 6, 3, and 1 cmH(2)O. Increases in H following DI in acid-injured mice were greater than naive strain-matched controls. Increases in H were no different between injured PAI-1-/- and C57BL/6, or between injured Fgn-/- and +/- mice, at any PEEP. Pressure-volume curves were no different between injured groups. Total lung fibrin was lower in injured PAI-1-/- and Fgn-/- mice relative to injured C57BL/6 and Fgn+/- mice, respectively, but indices of permeability were no different between strains. Unexpectedly, neither fibrin nor PAI-1 deficiency protects lung mechanical function in mice with acid-induced ALI. We speculate that in vivo lung function may be more closely tied to permeability and alveolar protein in general, rather than being linked specifically to fibrin.
authors.affiliation: School of Nutrition and Health Sciences, Taipei Medical University, Taipei, Taiwan.
authors.forename: Gilman B
authors.initials: GB
authors.lastname: Allen
authors.forename: Mary E
authors.initials: ME
authors.lastname: Cloutier
authors.forename: Yuna C
authors.initials: YC
authors.lastname: Larrabee
authors.forename: Konstantin
authors.initials: K
authors.lastname: Tetenev
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Smiley
authors.forename: Jason H T
authors.initials: JH
authors.lastname: Bates
mesh_terms: D055371:Acute Lung Injury / Q000209:etiology / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D000347:Afibrinogenemia / Q000235:genetics / Q000503:physiopathology; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D004195:Disease Models, Animal; D005260:Female; D005337:Fibrin / Q000172:deficiency* / Q000502:physiology; D005340:Fibrinogen / Q000235:genetics / Q000502:physiology; D018836:Inflammation Mediators / Q000502:physiology; D008168:Lung / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015656:Respiratory Mechanics / Q000235:genetics / Q000502:physiology; D058258:Serpin E2; D015843:Serpins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology
chemical_list: D018836:Inflammation Mediators; D058258:Serpin E2; C511869:Serpine2 protein, mouse; D015843:Serpins; D005337:Fibrin; D005340:Fibrinogen