Ligation of protease-activated receptor 1 enhances  v 6 integrin-dependent TGF-  activation and promotes acute lung injury

Abstract

Activation of latent TGF-β by the α v β 6 integrin is a critical step in the development of acute lung injury. However, the mechanism by which α v β 6 -mediated TGF-β activation is regulated has not been identified. We show that thrombin, and other agonists of protease-activated receptor 1 (PAR1), activate TGF-β in an α v β 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 α v β 6 integrin. Instillation of TFLLRN during high-tidal-volume ventilation is associated with increased pulmonary TGF-β 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-β activity are similarly reduced in Par1 -/-mice following bleomycin-induced lung injury. These results suggest that PAR1-mediated enhancement of α v β 6 -dependent TGF-β 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 α v β 6 integrin as potential therapeutic targets in this condition.

Cross Talk among TGF- Signaling Pathways, Integrins, and the Extracellular Matrix

“…Therefore, more support for the traction model comes from the finding that LAP-and ECM-binding components of LTBP-1 are required for activation (Annes et al 2004). Also relevant is the observation that protease-activated receptor-1 (PAR1) signaling enhances avb6-mediated TGF-b activation (Jenkins et al 2006). Rho A and Rho kinase, which mediate PAR1 effects on actin reorganization, are required for the PAR1 effect on avb6-mediated activation.…”

The Roles of Proteinase-Activated Receptors in the Vascular Physiology and Pathophysiology

“…Proteinases in the coagulation-fibrinolysis system and other proteinases including those derived from inflammatory and immune cells, are activated under pathological conditions such as thrombus formation, hemorrhage, inflammation, or Growth retardation with a delay in placental development at embryonic days 9-10 43 Defect in the yolk sac vasculature, multiple bleeding and embryonic death in Ϸ50 % of Par1 Ϫ/Ϫ , at gestational days 9-10 [43][44][45] Survivors develop to the level indistinguishable to Par1 ϩ/Ϫ and wild-type 43,44 Normal bleeding time, normal platelet response to thrombin 43,44 Partial defect in thrombin-induced endothelium-dependent relaxation 18 Attenuation of the vascular lesions development after arterial injury 94 Attenuated inflammation in experimental colitis 118 Tenuation of pulmonary edema in bleomycin lung injury 119 Reduced cerebral infarction size in experimental transient focal cerebral ischemia 120…”

Influenza Promotes Collagen Deposition via αvβ6 Integrin-mediated Transforming Growth Factor β Activation

“…These animals phenocopy the major abnormalities of TGF␤1 Ϫ/Ϫ mice, suggesting that TGF␤ activation in vivo is predominantly mediated by integrins (14), at least during development. The ␣v␤8 integrin, in association with matrix metalloproteinase-14 (MMP14), activates TGF␤ by proteolysis of LAP (13), whereas ␣v␤3, ␣v␤5, and ␣v␤6 integrins activate TGF␤ by a process involving cell traction (15)(16)(17). The ␣v␤6 integrin is an epithelium-restricted molecule expressed at low levels in the skin and lungs of healthy individuals and is rapidly up-regulated in response to inflammation and injury (4,18).…”

“…The ␣v␤6 integrin is an epithelium-restricted molecule expressed at low levels in the skin and lungs of healthy individuals and is rapidly up-regulated in response to inflammation and injury (4,18). Previous work by this group identified a mechanism of TGF␤ activation via the ␣v␤6 integrin involving stimulation of the GTPase RhoA and its major downstream effector Rho kinase (15,19).…”