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Ligation of protease-activated receptor 1 enhances v 6 integrin-dependent TGF- activation and promotes acute lung injury
Open accessAbstract
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.
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Cited by
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Wipff, P.-J., Rifkin, D. B., Meister, J.-J., & Hinz, B. (2007) · The Journal of Cell Biology · doi:10.1083/jcb.200704042 · Cited by 1,346
Pulmonary fibrosis and COVID-19: the potential role for antifibrotic therapy
George, P. M., Wells, A. U., & Jenkins, R. G. (2020) · The Lancet Respiratory Medicine · doi:10.1016/s2213-2600(20)30225-3 · Cited by 1,085
TGF-β1 Signaling and Tissue Fibrosis
Kim, K. K., Sheppard, D., & Chapman, H. A. (2018) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a022293 · Cited by 800
Integrin–TGF‐β crosstalk in fibrosis, cancer and wound healing
Margadant, C., & Sonnenberg, A. (2010) · The EMBO Reports · doi:10.1038/embor.2009.276 · Cited by 653
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Metadata
- Authors
- Jenkins, R. G.
- Venue
- Journal of Clinical Investigation
- Published
- 2006-06-01
- Volume
- 116
- Issue
- 6
- Pages
- 1606-1614
- ISSN
- 0021-9738 (ISSN-L)
- OpenAlex
- W2156036748
- Cited by
- 314
- References
- 0
- FWCI
- 10.63
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Jenkins, R. G. (2006). Ligation of protease-activated receptor 1 enhances v 6 integrin-dependent TGF- activation and promotes acute lung injury. Journal of Clinical Investigation. https://doi.org/10.1172/jci27183
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