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Prostaglandin F receptor signaling facilitates bleomycin-induced pulmonary fibrosis independently of transforming growth factor-β

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterized by fibroblast proliferation and excess deposition of collagen and other extracellular matrix (ECM) proteins, which lead to distorted lung architecture and function1. Given that anti-inflammatory or immunosuppressive therapy currently used for IPF does not improve disease progression therapies targeted to blocking the mechanisms of fibrogenesis are needed1. Although transforming growth factor-β (TGF-β) functions are crucial in fibrosis2,3, antagonizing this pathway in bleomycin-induced pulmonary fibrosis, an animal model of IPF, does not prevent fibrosis completely4,5,6,7, indicating an additional pathway also has a key role in fibrogenesis. Given that the loss of cytosolic phospholipase A2 (cPLA2) suppresses bleomycin-induced pulmonary fibrosis8, we examined the roles of prostaglandins using mice lacking each prostoaglandin receptor9,10,11,12,13,14,15. Here we show that loss of prostaglandin F (PGF) receptor (FP) selectively attenuates pulmonary fibrosis while maintaining similar levels of alveolar inflammation and TGF-β stimulation as compared to wild-type (WT) mice, and that FP deficiency and inhibition of TGF-β signaling additively decrease fibrosis. Furthermore, PGF is abundant in bronchoalveolar lavage fluid (BALF) of subjects with IPF and stimulates proliferation and collagen production of lung fibroblasts via FP, independently of TGF-β. These findings show that PGF-FP signaling facilitates pulmonary fibrosis independently of TGF-β and suggests this signaling pathway as a therapeutic target for IPF.

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Figure 1: Bleomycin-induced pulmonary fibrosis in Ptgfr−/− mice.
Figure 2: TGF-β1–independent action of FP signaling in pulmonary fibrosis.
Figure 3: Effects of PGF on proliferation and collagen production of lung fibroblasts.

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Acknowledgements

We thank M. Trojanowska (Medical University of South Carolina) and H. Ihn (Kumamoto University) for the −3500COL1A2/CAT construct, and Ono Pharmaceutical Company for ONO-AE3-208. We also thank Y. Kobashi for BALF analysis, T. Fujiwara for animal care and T. Arai for assistance. This work was supported in part by a Grant-in-Aid for Scientific Research (18002015) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, a grant of the Program for Promotion of Fundamental Studies in Health Science from the National Institute of Biomedical Innovation of Japan and a grant from Ono Research Foundation.

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Contributions

Experimental design and discussion: T.O., T.M. and S.N.; performance of experiments and data analysis and interpretation: T.O. (for bleomycin experiments, cell culture and microarray analysis), T.M. (for promoter assays), C.Y. (for RT-PCR), K.N. (for microarray analysis and western blotting), S.K. (for X-gal staining), D.S. (for cell proliferation assays and flow cytometry), Y.K. and T.S. (for liquid chromatography–tandem mass spectrometry analysis), K.T. and Y.T. (for BALF from human subjects), K.C. and M.M. (for analysis of lung function); manuscript preparation: T.O., T.M. and S.N.

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Correspondence to Shuh Narumiya.

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Supplementary Methods, Supplementary Tables 1–4 and Supplementary Figures 1–5 (PDF 3387 kb)

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Oga, T., Matsuoka, T., Yao, C. et al. Prostaglandin F receptor signaling facilitates bleomycin-induced pulmonary fibrosis independently of transforming growth factor-β. Nat Med 15, 1426–1430 (2009). https://doi.org/10.1038/nm.2066

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