Blocking follistatin-like 1 attenuates bleomycin-induced pulmonary fibrosis in mice.
Bottom Line: Pulmonary fibrosis is an epithelial-mesenchymal disorder in which TGF-β1 plays a central role in pathogenesis.Here we show that follistatin-like 1 (FSTL1) differentially regulates TGF-β and bone morphogenetic protein signaling, leading to epithelial injury and fibroblast activation.These data suggest that Fstl1 may serve as a novel therapeutic target for treatment of progressive lung fibrosis.
Affiliation: State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071, China Cam-Su Genomic Resource Center, Soochow University, Suzhou 215123, China.Show MeSH
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Mentions: To investigate the biological significance of the inducible expression of Fstl1 during fibrogenesis, we examined the fibrotic response to bleomycin-induced lung injury in Fstl1-deficient mice. Because homozygous Fstl1−/− mice die of respiratory failure shortly after birth (Geng et al., 2011), heterozygous Fstl1+/− mice were used to study the fibrotic response to bleomycin injury. Fstl1+/− mice made significant less FSTL1 protein in the lung tissue (∼59% decrease), and bleomycin-induced increase of FSTL1 protein was dramatically reduced in Fstl1+/− lungs (∼57% decrease; Fig. 2 A). Fstl1+/− mice were significantly less susceptible to bleomycin-induced lung injury and showed an increase in survival relative to WT littermates (Fig. 2 B). Importantly, Fstl1+/− mice exhibited reduced lung fibrosis. Collagen accumulation was significantly reduced in lung tissue of Fstl1+/− mice, as determined by hydroxyproline content (Fig. 2 C) and Masson’s trichrome staining (Fig. 2 D). Quantification of fibrotic lung sections by a blinded pathologist illustrated the attenuated fibrosis in Fstl1+/− mice (Fig. 2 E). The attenuated fibrosis in Fstl1+/− mice was further supported by decreased mRNA and protein levels for type I collagen and fibronectin (Fig. 2, F–I). These in vivo data indicate that Fstl1 is induced in response to lung injury and causally involved in driving pulmonary fibrogenesis as a profibrotic factor.
Affiliation: State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071, China Cam-Su Genomic Resource Center, Soochow University, Suzhou 215123, China.