Ligation of protease-activated receptor 1 enhances alpha(v)beta6 integrin-dependent TGF-beta activation and promotes acute lung injury.
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.
Jenkins
R Gisli
RG
Lung Biology Center, UCSF, San Francisco, California 94158, USA.
Su
Xiao
X
Su
George
G
Scotton
Christopher J
CJ
Camerer
Eric
E
Laurent
Geoffrey J
GJ
Davis
George E
GE
Chambers
Rachel C
RC
Matthay
Michael A
MA
Sheppard
Dean
D
D000577:Amides / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism; D001761:Bleomycin / Q000378:metabolism; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D016023:Integrins / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D008168:Lung / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011654:Pulmonary Edema / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D011725:Pyridines / Q000378:metabolism; D044463:Receptor, PAR-1 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D012128:Respiratory Distress Syndrome / Q000378:metabolism* / Q000473:pathology; D013917:Thrombin / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
D000577:Amides; D000903:Antibiotics, Antineoplastic; D004791:Enzyme Inhibitors; D016023:Integrins; D047908:Intracellular Signaling Peptides and Proteins; D010455:Peptides; D011725:Pyridines; D044463:Receptor, PAR-1; D016212:Transforming Growth Factor beta; C403414:integrin alphavbeta8; D001761:Bleomycin; C108830:Y 27632; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D013917:Thrombin; D020742:rhoA GTP-Binding Protein