Ligation of protease-activated receptor 1 enhances [alpha]v [beta]6 integrin-dependent TGF-[beta] activation and promotes acute lung injury.
Jenkins, R. Gisli 1,2; Su, Xiao 3; Su, George 1; Scotton, Christopher J. 2; Camerer, Eric 3; Laurent, Geoffrey J. 2; Davis, George E. 4; Chambers, Rachel C. 2; Matthay, Michael A. 3; Sheppard, Dean 1
[Article]
Journal of Clinical Investigation.
116(6):1606-1614, June 2006.
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Activation of latent TGF-[beta] by the [alpha]v[beta]6 integrin is a critical step in the development of acute lung injury. However, the mechanism by which [alpha]v[beta]6-mediated TGF-[beta] activation is regulated has not been identified. We show that thrombin, and other agonists of protease-activated receptor 1 (PAR1), activate TGF-[beta] in an [alpha]v[beta]6 integrin-specific manner. This effect is PAR1 specific and is mediated by RhoA and Rho kinase. Intratracheal instillation of the PAR1-specific peptide TFLLRN increases lung edema during high-tidal-volume ventilation, and this effect is completely inhibited by a blocking antibody against the [alpha]v[beta]6 integrin. Instillation of TFLLRN during high-tidal-volume ventilation is associated with increased pulmonary TGF-[beta] activation; however, this is not observed in Itgb6-/- mice. Furthermore, Itgb6-/- mice are also protected from ventilator-induced lung edema. We also demonstrate that pulmonary edema and TGF-[beta] activity are similarly reduced in Par1-/- mice following bleomycin-induced lung injury. These results suggest that PAR1-mediated enhancement of [alpha]v[beta]6-dependent TGF-[beta] activation could be one mechanism by which activation of the coagulation cascade contributes to the development of acute lung injury, and they identify PAR1 and the [alpha]v[beta]6 integrin as potential therapeutic targets in this condition.
Copyright (C) 2006 The American Society for Clinical Investigation, Inc.