Work

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

Year: 2006

Type: article

Abstract: Activation of latent TGF-beta by the alpha(v)beta6 integrin is a critical step in the development of acute lung injury. However, the mechanism by which alpha(v)beta6-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)beta6 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)beta6 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)beta6-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)beta6 integrin as potential therapeutic targets in this condition.

Source: Journal of Clinical Investigation

DOI: 10.1172/jci27183

Authors: R. G. Jenkins, Xiao Su, George Su, Christopher J Scotton, Eric Camerer, Geoffrey J Laurent, George E Davis, Rachel C Chambers, Michael A Matthay, Dean Sheppard

Institutions: University of California, San Francisco, University College London

Language: English

Topic: Blood Coagulation and Thrombosis Mechanisms

Subfield: Hematology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: bronze

Funders: Wellcome Trust, University of California, San Francisco, National Heart, Lung, and Blood Institute

Awards: In Vivo Function of Pulmonary Integrins, G2939202742, Interactions of Lymphocytes, Cytokines and Airway Cells, G3429402575, G358049942, RESOLUTION OF CLINICAL LUNG INJURY, The NHLBI-Bay Area Functional Genomics Consortium, Integrin-Mediated Development of the Thoracic Duct, SCCOR in translational research in Acute Lung Injury, Lung Fluid Balance and Mesenchymal Stem Cells, In Vivo Function of Pulmonary Integrins, Resolution of Clinical Lung Injury

OpenAlex ID: W2156036748

FWCI: 12.18

Cites: 32

Cited by: 322

Related to: 9