Proposed model of miR-199a-5p profibrotic function in lung fibrogenesis.

<p>Persistent injury of the respiratory epithelium causes release of profibrotic factors such as TGFβ. In lung fibroblasts, TGFβ binds to TGFβR I (RI) and II (RII) and the resultant complex can be internalized via two distinct endocytic pathways. The clathrin-coated pit pathway (red arrows) increases TGFβ signal transduction leading to the activation of lung fibroblasts and ultimately lung fibrosis whereas the CAV1 lipid raft pathway (green arrows) mediates TGFβ/TGFβR complex degradation, thus decreasing TGFβ signaling and preventing lung fibrosis <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003291#pgen.1003291-Rosenbloom1" target="_blank">[73]</a>. Production of miR-199a-5p in response to TGFβ in lung fibroblasts results in CAV1 downregulation and subsequently, impaired TGFβ/TGFβR complex degradation. This miRNA-mediated mechanism for low CAV1 expression promotes TGFβ signaling and the pathogenic activation of lung fibroblasts. CAV1 = caveolin-1, TGFβ = Transforming Growth factor-β, TGFβR = Transforming Growth factor-β Receptor, SBE = SMAD Binding Element, ECM = Extracellular Matrix.