Ligation of protease-activated receptor 1 enhances alpha(v)beta6 integrin-dependent TGF-beta activation and promotes acute lung injury

J Clin Invest. 2006 Jun;116(6):1606-14. doi: 10.1172/JCI27183. Epub 2006 May 18.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / metabolism
  • Animals
  • Antibiotics, Antineoplastic / metabolism
  • Bleomycin / metabolism
  • Cells, Cultured
  • Enzyme Inhibitors / metabolism
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism
  • Humans
  • Integrins / genetics
  • Integrins / metabolism*
  • Intracellular Signaling Peptides and Proteins
  • Lung / cytology
  • Lung / metabolism
  • Lung / pathology
  • Mice
  • Mice, Knockout
  • Peptides / genetics
  • Peptides / metabolism
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Pulmonary Edema / etiology
  • Pulmonary Edema / metabolism
  • Pulmonary Edema / pathology
  • Pyridines / metabolism
  • Receptor, PAR-1 / agonists
  • Receptor, PAR-1 / genetics
  • Receptor, PAR-1 / metabolism*
  • Respiratory Distress Syndrome, Adult / metabolism*
  • Respiratory Distress Syndrome, Adult / pathology
  • Thrombin / metabolism
  • Transforming Growth Factor beta / metabolism*
  • rho-Associated Kinases
  • rhoA GTP-Binding Protein / genetics
  • rhoA GTP-Binding Protein / metabolism

Substances

  • Amides
  • Antibiotics, Antineoplastic
  • Enzyme Inhibitors
  • Integrins
  • Intracellular Signaling Peptides and Proteins
  • Peptides
  • Pyridines
  • Receptor, PAR-1
  • Transforming Growth Factor beta
  • integrin alphavbeta8
  • Bleomycin
  • Y 27632
  • Protein-Serine-Threonine Kinases
  • rho-Associated Kinases
  • Thrombin
  • rhoA GTP-Binding Protein