Limits...
Blocking follistatin-like 1 attenuates bleomycin-induced pulmonary fibrosis in mice.

Dong Y, Geng Y, Li L, Li X, Yan X, Fang Y, Li X, Dong S, Liu X, Li X, Yang X, Zheng X, Xie T, Liang J, Dai H, Liu X, Yin Z, Noble PW, Jiang D, Ning W - J. Exp. Med. (2015)

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.

View Article: PubMed Central - HTML - PubMed

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

Related in: MedlinePlus

Similar inflammatory response in Fstl1+/− mice.Fstl1+/− and their WT littermates were subjected to 2.5 U/kg bleomycin-induced lung injury for 7 d. (A) BALF cells were collected from lung tissues, and percentage of differential BALF cell numbers was determined (n = 9 per group). (B) FACS analysis of inflammatory cells in lung tissues with specific antibodies to CD3, CD8, CD4, B cell marker (B220), and the NK cell marker (NK1.1). Percentages of CD8+, CD4+, B220+, and NK1.1+ cells were plotted. FACS analysis of macrophages using specific antibodies to macrophage cell markers (CD11c and Gr-1), alveolar macrophage cell marker (CD11b), and interstitial macrophage cell marker (IA-b; n = 6 per group) is shown. (C) ELISA analysis of IFN-γ, IL-13, IL-6, IL-1β, IL-17A, and TNF expressions in BALF and lung tissues (n = 6 per group). (A–C) The experiments were performed three times. Error bars indicate mean ± SEM.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4322044&req=5

fig3: Similar inflammatory response in Fstl1+/− mice.Fstl1+/− and their WT littermates were subjected to 2.5 U/kg bleomycin-induced lung injury for 7 d. (A) BALF cells were collected from lung tissues, and percentage of differential BALF cell numbers was determined (n = 9 per group). (B) FACS analysis of inflammatory cells in lung tissues with specific antibodies to CD3, CD8, CD4, B cell marker (B220), and the NK cell marker (NK1.1). Percentages of CD8+, CD4+, B220+, and NK1.1+ cells were plotted. FACS analysis of macrophages using specific antibodies to macrophage cell markers (CD11c and Gr-1), alveolar macrophage cell marker (CD11b), and interstitial macrophage cell marker (IA-b; n = 6 per group) is shown. (C) ELISA analysis of IFN-γ, IL-13, IL-6, IL-1β, IL-17A, and TNF expressions in BALF and lung tissues (n = 6 per group). (A–C) The experiments were performed three times. Error bars indicate mean ± SEM.

Mentions: Persistent inflammation often drives fibrotic progression in the bleomycin injury model, although the contribution of inflammation to fibrogenesis is controversial (Wynn, 2008). Previous studies have implicated a role of FSTL1 in inflammatory response in rheumatoid arthritis (Clutter et al., 2009) and in heart allograft rejection (Le Luduec et al., 2008). We analyzed the inflammatory response of Fstl1+/− mice 7 d after bleomycin treatment. Notably, compared with WT mice, the increase of inflammatory cells was comparable in Fstl1+/− mice (Fig. 3 A). Consistently, FACS analysis showed no major differences in immune cell subset infiltration, such as CD4+, CD8+, NKT, NK, and B cells, as well as alveolar and interstitial macrophages and neutrophils, in lung tissues between the mouse strains (Fig. 3 B). A Th1/Th2 imbalance has been suggested to play a role in fibrogenesis (Wynn, 2008). We measured cytokines IFN-γ (Th1), IL-13 (Th2), IL-6, IL-1β, IL-17A, and TNF, whose dysregulation has been reported in lung tissue of IPF patients (Agostini and Gurrieri, 2006; Wynn, 2011) and in animal models (Saito et al., 2008; Wynn, 2008). As shown in Fig. 3 C, similar concentrations of cytokines were measured by ELISA in the bronchoalveolar lavage (BAL) fluid (BALF) and homogenized lung tissue from Fstl1+/− and WT littermates. These data suggest that deletion of Fstl1 attenuates bleomycin-induced lung fibrosis without affecting the inflammatory response in response to lung injury.


Blocking follistatin-like 1 attenuates bleomycin-induced pulmonary fibrosis in mice.

Dong Y, Geng Y, Li L, Li X, Yan X, Fang Y, Li X, Dong S, Liu X, Li X, Yang X, Zheng X, Xie T, Liang J, Dai H, Liu X, Yin Z, Noble PW, Jiang D, Ning W - J. Exp. Med. (2015)

Similar inflammatory response in Fstl1+/− mice.Fstl1+/− and their WT littermates were subjected to 2.5 U/kg bleomycin-induced lung injury for 7 d. (A) BALF cells were collected from lung tissues, and percentage of differential BALF cell numbers was determined (n = 9 per group). (B) FACS analysis of inflammatory cells in lung tissues with specific antibodies to CD3, CD8, CD4, B cell marker (B220), and the NK cell marker (NK1.1). Percentages of CD8+, CD4+, B220+, and NK1.1+ cells were plotted. FACS analysis of macrophages using specific antibodies to macrophage cell markers (CD11c and Gr-1), alveolar macrophage cell marker (CD11b), and interstitial macrophage cell marker (IA-b; n = 6 per group) is shown. (C) ELISA analysis of IFN-γ, IL-13, IL-6, IL-1β, IL-17A, and TNF expressions in BALF and lung tissues (n = 6 per group). (A–C) The experiments were performed three times. Error bars indicate mean ± SEM.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4322044&req=5

fig3: Similar inflammatory response in Fstl1+/− mice.Fstl1+/− and their WT littermates were subjected to 2.5 U/kg bleomycin-induced lung injury for 7 d. (A) BALF cells were collected from lung tissues, and percentage of differential BALF cell numbers was determined (n = 9 per group). (B) FACS analysis of inflammatory cells in lung tissues with specific antibodies to CD3, CD8, CD4, B cell marker (B220), and the NK cell marker (NK1.1). Percentages of CD8+, CD4+, B220+, and NK1.1+ cells were plotted. FACS analysis of macrophages using specific antibodies to macrophage cell markers (CD11c and Gr-1), alveolar macrophage cell marker (CD11b), and interstitial macrophage cell marker (IA-b; n = 6 per group) is shown. (C) ELISA analysis of IFN-γ, IL-13, IL-6, IL-1β, IL-17A, and TNF expressions in BALF and lung tissues (n = 6 per group). (A–C) The experiments were performed three times. Error bars indicate mean ± SEM.
Mentions: Persistent inflammation often drives fibrotic progression in the bleomycin injury model, although the contribution of inflammation to fibrogenesis is controversial (Wynn, 2008). Previous studies have implicated a role of FSTL1 in inflammatory response in rheumatoid arthritis (Clutter et al., 2009) and in heart allograft rejection (Le Luduec et al., 2008). We analyzed the inflammatory response of Fstl1+/− mice 7 d after bleomycin treatment. Notably, compared with WT mice, the increase of inflammatory cells was comparable in Fstl1+/− mice (Fig. 3 A). Consistently, FACS analysis showed no major differences in immune cell subset infiltration, such as CD4+, CD8+, NKT, NK, and B cells, as well as alveolar and interstitial macrophages and neutrophils, in lung tissues between the mouse strains (Fig. 3 B). A Th1/Th2 imbalance has been suggested to play a role in fibrogenesis (Wynn, 2008). We measured cytokines IFN-γ (Th1), IL-13 (Th2), IL-6, IL-1β, IL-17A, and TNF, whose dysregulation has been reported in lung tissue of IPF patients (Agostini and Gurrieri, 2006; Wynn, 2011) and in animal models (Saito et al., 2008; Wynn, 2008). As shown in Fig. 3 C, similar concentrations of cytokines were measured by ELISA in the bronchoalveolar lavage (BAL) fluid (BALF) and homogenized lung tissue from Fstl1+/− and WT littermates. These data suggest that deletion of Fstl1 attenuates bleomycin-induced lung fibrosis without affecting the inflammatory response in response to lung injury.

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.

View Article: PubMed Central - HTML - PubMed

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
Related in: MedlinePlus