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bioRxiv · 10.1101/2020.07.04.187492

Connective-Tissue Growth Factor (CTGF/CCN2) Contributes to TGF-β1-Induced Lung Fibrosis

Yanagihara, T.·Chong, S. G.·Gholiof, M.·Lipson, K. E.·Zhou, Q.·Scallan, C.·Upagupta, C.·Tikkanen, J.·Keshavjee, S.·Ask, K.·Kolb, M. R.
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Abstract

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by progressive and excessive accumulation of myofibroblasts and extracellular matrix in the lung. Connective-tissue growth factor (CTGF) is known to exacerbate pulmonary fibrosis in radiation-induced lung fibrosis, and in this study, we show the upregulation of CTGF from a rat lung fibrosis model induced by adenovirus vector encoding active TGF-β1 (AdTGF-β1), and also in patients with IPF. The expression of CTGF was upregulated in vascular smooth muscle cells cultured from fibrotic lungs on days 7 or 14 as well as endothelial cells sorted from fibrotic lungs on day 14 or 28 respectively. These findings suggest the role of different cells in maintaining the fibrotic phenotype during fibrogenesis. Treatment of fibroblasts with recombinant CTGF along with TGF-β increases pro-fibrotic markers in fibroblasts, confirming the synergistic effect of recombinant CTGF with TGF-β in inducing pulmonary fibrosis. Also, fibrotic extracellular matrix upregulated the expression of CTGF, as compared to normal extracellular matrix, suggesting that not only profibrotic mediators but also a profibrotic environment contributes to fibrogenesis. We also showed that pamrevlumab, a CTGF inhibitory antibody, partially attenuates fibrosis in the model. These results suggest that pamrevlumab could be an option for the treatment of pulmonary fibrosis.Competing Interest StatementT. Yanagihara was funded by the Uehara Memorial Foundation Research Fellowship and Mitacs Canada, and the research institute of St Joseph Hospital, Hamilton, ON, Canada (Post-doctoral Fellowship Award). K. Ask reports grants and personal fees from Boehringer Ingelheim, grants from Canadian Pulmonary Fibrosis Foundation, Synairgen, Alkermes, GlaxoSmitheKline, Pharmaxis, Unity, Avalyn, Canadian Institutes of Health Research, Ceapro, Pieris, outside the submitted work. M. Kolb reports grants from the Canadian Institute for Health Research and grants/ personal fees from Roche, Boehringer Ingelheim, Prometic, Respivert, Alkermes, and Pharmaxis and personal fees from Genoa. K.E. Lipson is an employee and shareholder of FibroGen, Inc. J. Tikkanen reports personal fees from CSL Behring, outside the submitted work. S.G. Chong, M. Gholiof, Q. Zhou, C. Scallan, C. Upagupta, and S. Keshavjee report no conflict of interest.View Full Text

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Yanagihara, T., Chong, S. G., Gholiof, M., Lipson, K. E., Zhou, Q., Scallan, C., Upagupta, C., Tikkanen, J., Keshavjee, S., Ask, K., Kolb, M. R.. 2020-07-04. Connective-Tissue Growth Factor (CTGF/CCN2) Contributes to TGF-β1-Induced Lung Fibrosis. https://doi.org/10.1101/2020.07.04.187492

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