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

Abstract

Allen GB, Cloutier ME, Larrabee YC, Tetenev K, Smiley ST, Bates JH. Neither fibrin nor plasminogen activator inhibitor-1 deficiency protects lung function in a mouse model of acute lung injury. Am J Physiol Lung Cell Mol Physiol 296: L277-L285, 2009. First published December 5, 2008 doi:10.1152/ajplung.90475.2008.-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 (FgnϪ/Ϫ) and PAI-1-deficient (PAI-1Ϫ/Ϫ) mice. PAI-1Ϫ/Ϫ, C57BL/6, FgnϪ/Ϫ, and Fgnϩ/Ϫ females were anesthetized and allowed to aspirate 4 l/g of hydrochloric acid (pH 1.0) and then reanesthetized and connected to a ventilator 48 h later. Naive C57BL/6 and Fgnϩ/Ϫ 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 2O. 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-1Ϫ/Ϫ and C57BL/6, or between injured FgnϪ/Ϫ and ϩ/Ϫ mice, at any PEEP. Pressure-volume curves were no different between injured groups. Total lung fibrin was lower in injured PAI-1Ϫ/Ϫ and FgnϪ/Ϫ mice relative to injured C57BL/6 and Fgnϩ/Ϫ 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 ACUTE LUNG INJURY (ALI) is a severe form of noncardiogenic pulmonary edema and hypoxemic respiratory failure stemming from numerous causes (60). Current treatment of ALI rests largely on supportive care with mechanical ventilation, and its prognosis remains poor with a mortality of 30 -40% in the general population, and higher in the elderly (49). The pathology of ALI typically progresses through an initial exudative phase characterized by neutrophil infiltration, edema, and accumulation of hyaline membranes, the latter consisting primarily of necrotic debris and fibrin (58). In this regard, the coagulation pathway and its end product fibrin have excited particular interest, in part due to the ability of fibrin to inhibit surfactant function in vitro (52,54), and the increasingly recognized interplay between coagulation and innate immunity (17,63). Fibrin formation and clearance in the lung are governed by the relative quantity and activity of fibrinolysis promoters such as plasminogen activators and fibrinolysis inh...

The complex role of fibrin in acute lung injury

“…Slofstra et al (16) showed that inhalation of APC could attenuate LPS-induced lung inflammation and that APC-treated mice had a decrease in thrombin-anti-thrombin complexes in the bronchoalveolar lavage fluid. Furthermore, the few studies that have only modulated fibrin formation without affecting thrombin formation have shown results similar to the work of Allen and colleagues (2). Hyperoxia in PAI-1Ϫ/Ϫ mice as mentioned above had no effect on lung vascular leak even though fibrin deposition in the lung was reduced.…”

“…In their recent article, Allen et al (2) report findings from a mouse model of ALI that challenge our current understanding of the role of fibrin deposition in ALI. In this study, the authors use two different transgenic mouse models to reduce fibrin deposition.…”

“…These studies raise the important issue that inhibiting a coagulation protease either locally or systemically may have differential effects. Allen et al (2) used mice that were deficient in PAI-1 or fibrinogen throughout the entire animal. Their findings may have been different if fibrin deposition had been inhibited only in the air space and not systemically.…”

Acute Lung Injury and Pulmonary Vascular Permeability: Use of Transgenic Models

“…Activation of Rho mobilized actin to form stress fibers and increased permeability, but activation of Rac prevented increases in endothelial permeability (54). Although coagulation factors significantly contribute to lung inflammation in many conditions, genetic deficiency in mice of either fibrin or PAI-1 did not protect against VILI (12).…”

Platelets induce endothelial tissue factor expression in a mouse model of acid-induced lung injury

“…ALTHOUGH ANTICOAGULANT PROPERTIES of the vascular endothelial lining protect against clot formation, coagulation, and abnormalities of fibrinolysis are features of acute lung injury (ALI) (1,11,24,31). Thus ALI is associated with increases in procoagulant markers in the lung including fibrin deposition and increase of plasminogen activator inhibitor (PAI-1) in the bronchoalveolar lavage (BAL) (1,24,31).…”