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Organ fibrosis, including idiopathic pulmonary fibrosis (IPF), is associated with significant morbidity and mortality. Since currently available therapies have limited effect, there is need to better understand the mechanisms by which organ fibrosis occurs. We have recently reported that TGF-β, a key cytokine which promotes fibrogenesis, induces the expression of the enzymes of the de novo serine and glycine synthesis pathway in human lung fibroblasts and that phosphoglycerate dehydrogenase (PHGDH, the first and rate limiting enzyme of the pathway) is required to promote collagen protein synthesis downstream of TGF-β. In this study, we investigated whether inhibition of de novo serine and glycine synthesis attenuates lung fibrosis in vivo. We found that TGF-β induces mRNA and protein expression of PHGDH in murine fibroblasts. Similarly, intratracheal administration of bleomycin resulted in increased expression of PHGDH in mouse lungs, localized to fibrotic regions. Using a newly developed small molecule inhibitor of PHGDH (NCT-503), we tested whether pharmacologic inhibition of PHGDH could inhibit fibrogenesis both in vitro and in vivo. Treatment of murine and human lung fibroblasts with NCT-503 decreased TGF-β-induced collagen protein synthesis. Mice treated with the PHGDH inhibitor beginning 7 days after intratracheal instillation of bleomycin had attenuation of lung fibrosis. These results indicate that the de novo serine synthesis pathway is necessary for TGF-β-induced collagen synthesis and bleomycin-induced pulmonary fibrosis. PHGDH and other enzymes in the de novo serine synthesis pathway may be a therapeutic target for treatment of fibrotic diseases, including IPF.
This article was published in the following journal.
Name: American journal of respiratory cell and molecular biology
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