Neither fibrin nor plasminogen activator inhibitor-1 deficiency protects lung function in a mouse model of acute lung injury

• Published in: American journal of physiology. Lung cellular and molecular physiology Vol. 296; no. 3; pp. L277 - L285
• Main Authors: Allen, Gilman B, Cloutier, Mary E, Larrabee, Yuna C, Tetenev, Konstantin, Smiley, Stephen T, Bates, Jason H. T
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.03.2009
• Subjects: Acute Lung Injury - etiology; Acute Lung Injury - genetics; Acute Lung Injury - physiopathology; Acute Lung Injury - prevention & control; Afibrinogenemia - genetics; Afibrinogenemia - physiopathology; Animals; Biochemistry; Bronchoalveolar Lavage Fluid - chemistry; Disease Models, Animal; Female; Fibrin - deficiency; Fibrin - physiology; Fibrinogen - genetics; Fibrinogen - physiology; Hypotheses; Inflammation Mediators - physiology; Lung - pathology; Lung - physiopathology; Lung diseases; Lungs; Mice; Mice, Inbred C57BL; Mice, Knockout; Proteins; Respiratory Mechanics - genetics; Respiratory Mechanics - physiology; Rodents; Serpin E2; Serpins - deficiency; Serpins - genetics; Serpins - physiology
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.90475.2008

1 Vermont Lung Center, Department of Medicine, University of Vermont, and 2 Fletcher Allen Health Care, Burlington, Vermont; 3 Trudeau Institute, Saranac Lake, New York; and 4 Siberian State Medical University, Tomsk, Russia Submitted 8 September 2008 ; accepted in final form 2 December 2008 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 µl/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. lung mechanics; respiratory impedance; acid aspiration; coagulation Address for reprint requests and other correspondence: G. B. Allen, HSRF Rm. 220, 149 Beaumont Ave., Burlington, VT 05405-0075 (e-mail: Gil.Allen{at}uvm.edu )