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Ligation of protease-activated receptor 1 enhances αv β6 integrin–dependent TGF-β activation and promotes acute lung injury
R. Gisli Jenkins, … , Michael A. Matthay, Dean Sheppard
R. Gisli Jenkins, … , Michael A. Matthay, Dean Sheppard
Published June 1, 2006
Citation Information: J Clin Invest. 2006;116(6):1606-1614. https://doi.org/10.1172/JCI27183.
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Research Article Pulmonology Article has an altmetric score of 3

Ligation of protease-activated receptor 1 enhances αv β6 integrin–dependent TGF-β activation and promotes acute lung injury

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Abstract

Activation of latent TGF-β by the αvβ6 integrin is a critical step in the development of acute lung injury. However, the mechanism by which αvβ6-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 αvβ6 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 αvβ6 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 αvβ6-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 αvβ6 integrin as potential therapeutic targets in this condition.

Authors

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

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Figure 7

Itgb6–/– mice instilled with TFLLRN and ventilated at high tidal volume are protected from lung edema and have reduced TGF-β activity in the lung compared with WT mice.

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                  Itgb6–/–
                  mice instilled with TFLLRN...
(A) WT mice (white bars) and Itgb6–/– mice (black bars) were ventilated and instilled with peptide and control, and lung edema was measured as described previously. WT, n = 6; and Itgb6–/–, n = 5. (B) Quantification of nuclear localized phospho-Smad2 immunostaining in WT mice instilled with Hank’s or PAR1-activating peptide or Itgb6–/– mice instilled with PAR1-activating peptide (black bar). WT mice, Hank’s, n = 3; WT mice, TFLLRN, n = 4; Itgb6–/– mice, n = 3; and Par1–/– mice, saline, n = 3. (C) Representative histological sections showing nuclear localized phospho-Smad2 immunostaining in the lung of WT or Itgb6–/– mice. Original magnification, ×400. Values are presented as mean + SEM. *P < 0.05.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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