Fig. 1.

Injury to the alveolar surface leads to release of thrombin and lysophosphatidic acid (LPA), which act through G protein-coupled receptors PAR1 and LPAr2 to signal via Gq/11, RhoA, and Rho kinase (ROCK) to activate transforming growth factor (TGF)-β via the α_vβ₆ integrin. This in turn leads to TGF-β receptor activation in neighboring cells and Smad2/3 phosphorylation, which translocates to the nucleus, leading to increased transcription of the ITGB6 gene and increased expression of the α_vβ₆ integrin on the cell surface. This is able to activate fibroblast TGF-β if the epithelial basement membrane is denuded, leading to activation via fibroblast RhoA signaling and mesenchymal integrin-mediated TGF-β activation (α_vβ₁ and α_vβ₅) leading to autonomous fibroblast TGF-β activation. A-kinase anchoring protein 13 (AKAP13) is a Rho guanine nucleotide exchange factor (GEF) that facilitates Gq/11 to RhoA signaling and may act as an amplification signal in epithelial cells, and ELK1 is a transcriptional repressor that is lost in pulmonary fibrosis. S1P, sphingosine-1 phosphate.