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STAT3-Mediated signaling dysregulates lung Fibroblast-Myofibroblast activation and differentiation in UIP/IPF

Pechkovsky, D.V., Prêle, C.M., Wong, J., Hogaboam, C.M., McAnulty, R.J., Laurent, G.J., Zhang, S.S-M, Selman, M., Mutsaers, S.E. and Knight, D.A. (2012) STAT3-Mediated signaling dysregulates lung Fibroblast-Myofibroblast activation and differentiation in UIP/IPF. The American Journal of Pathology, 180 (4). pp. 1398-1412.

Link to Published Version: https://doi.org/10.1016/j.ajpath.2011.12.022
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Abstract

STAT3 is a latent transcription factor that plays a role in regulating fibroblast function in fibrotic lung diseases. To further understand the role of STAT3 in the phenotypic divergence and function of human lung fibroblasts (LFs), we investigated the effect of basal and cytokine-induced STAT3 activity on indices of LF differentiation and activation, including expression of α-smooth muscle actin (α-SMA), collagen, and adhesion molecules Thy-1/CD90 and αv β3 and β5 integrins. We identified a population of fibroblasts from usual interstitial pneumonia (UIP)/idiopathic pulmonary fibrosis (IPF) lungs characterized by constitutively phosphorylated STAT3, lower proliferation rates, and diminished expression of α-SMA, Thy-1/CD90, and β3 integrins compared with control LFs. Staining of UIP lung biopsy specimens demonstrated that phosphorylated STAT3 was not present in α-SMA–positive fibroblastic foci but was observed in the nuclei of cells located in the areas of dense fibrosis. STAT3 activation in LFs did not significantly influence basal or transforming growth factor β1–induced collagen I expression but inhibited expression of α-SMA, Thy-1/CD90, and αv β3 integrins. Suppression of STAT3 signaling diminished resistance of IPF LFs to staurosporine-induced apoptosis and responsiveness to transforming growth factor β1 but increased basal α-SMA and restored β3 integrin expression in LFs via an ALK-5–dependent, SMAD3/7-independent mechanism. These data suggest that STAT3 activation regulates several pathways in human LFs associated with normal wound healing, whereas aberrant STAT3 signaling plays a critical role in UIP/IPF pathogenesis.

Item Type: Journal Article
Publisher: Elsevier
Copyright: © 2012 American Society for Investigative Pathology.
URI: http://researchrepository.murdoch.edu.au/id/eprint/64360
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