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: Evidence suggests that lung fibrosis is a dysregulated epithelial-mesenchymal disorder, in which epithelial injury is an initiating event (Selman and Pardo, 2002). Haplodeletion of Fstl1 showed a significant reduction of lung architectural damage 7 d after bleomycin injury (Fig. 5 A). Injured AECs likely undergo many cellular and molecular changes and may create a profibrotic environment in an effort to activate fibroblasts. Injured AECs may lose epithelial markers and gain mesenchymal markers at the same time (King et al., 2011; Kage and Borok, 2012). We isolated AECs from WT mice 7 d after bleomycin treatment. We found decreased mRNA expression of epithelial markers, such as Sftpc, E-cadherin (Cdh1), Occludin (Ocln), and ZO-1, and increased mRNA expression of mesenchymal markers, such as α-SMA, vimentin (Vim), and Fsp1 (Fig. 5, B and C). FACS analysis (Fig. 5 D) also showed increased numbers of E-cad+Fsp1+ AECs in response to bleomycin injury, supporting the notion that injured AECs are activated and may express mesenchymal genes. We performed double immunostaining for α-SMA and pro-SPC on WT lung sections and identified costaining of pro-SPC+α-SMA+ AECs on days 7 and 14 after bleomycin treatment (Fig. 5 E), confirming that epithelial cells with a mesenchymal phenotype serve as a marker of epithelial injury. Notably, Fstl1 haplodeficiency inhibited bleomycin-induced expression of mesenchymal markers and restored the expression of epithelial markers in Fstl1+/− AECs (Fig. 5, B and C). In addition, the bleomycin-increased numbers of mesenchymal markers expressing AECs were significantly decreased in Fstl1+/− epithelial cells (Fig. 5, D and E), indicating that Fstl1 deficiency in Fstl1+/− mice is protective against bleomycin-induced epithelial injury.
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.