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Follistatin like-1 aggravates silica-induced mouse lung injury.

ABSTRACT: Occupational inhalation of dust, such as crystalline silica, for prolonged periods in the workplace leads to fibrotic lung diseases worldwide. The mechanisms underlying the diseases are unknown, so that no effective treatment exists for these conditions. We found elevated levels of follistatin like 1 (FSTL1) in serum from patients with silicosis and in lungs from silica-induced mouse model. The induced Fstl1 regulated inflammation response via activation of nod-like receptor family, pyrin domain containing 3v (NLRP3) inflammasome-mediated IL-1? production from macrophages. Meanwhile, Fstl1 promoted fibrosis via positive regulation of TGF-?1 signaling. Haploinsufficiency of Fstl1 or blockage of FSTL1 with a neutralizing antibody was protective from silica-induced lung injury in mice in vivo. Our data suggest that Fstl1 plays an important role in lung fibrosis, and may serve as a novel therapeutic target for treatment of silicosis.

SUBMITTER: Fang Y

PROVIDER: S-EPMC5428474 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Follistatin like-1 aggravates silica-induced mouse lung injury.

Fang Yinshan Y Zhang Si S Li Xiaohe X Jiang Fangxin F Ye Qiao Q Ning Wen W

Scientific reports 20170324 1

Occupational inhalation of dust, such as crystalline silica, for prolonged periods in the workplace leads to fibrotic lung diseases worldwide. The mechanisms underlying the diseases are unknown, so that no effective treatment exists for these conditions. We found elevated levels of follistatin like 1 (FSTL1) in serum from patients with silicosis and in lungs from silica-induced mouse model. The induced Fstl1 regulated inflammation response via activation of nod-like receptor family, pyrin domain ...[more]

PMID: 28341862

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Project description:BackgroundSilicosis, a progressive inflammatory lung disease attributed mainly to occupational exposure to silica dust, shows loss of lung function even after cessation of exposure. In addition to conventional evaluation methods such as chest X-ray, computed tomography, and spirometry, we identified heme oxygenase (HO)-1, an inducible antioxidant, as a potential biomarker to identify at-risk patients. We found that HO-1 was critical in attenuating the disease progression of silicosis; however, the key signaling pathway has not yet been elucidated. Here, we report the critical pathway after silica exposure, focusing on the role of silica-derived reactive oxygen species (ROS) signaling and its attenuation, which is mediated by HO-1 induction, in vivo and in vitro.MethodsNormal bronchial epithelial cells and a macrophage cell line, as well as a murine silicosis model generated by intratracheal administration of 2.5 mg of crystalline silica, were used in this study. The pathways activated in response to silica exposure, including the mitogen-activated protein kinase (MAPK) signaling pathway, were examined and compared with or without super-induction of HO-1.ResultsThe murine silicosis model was first assessed for the evaluation of activated pathways after silica exposure, focusing on ROS-MAPK activation. In the murine model, increased expression of HO-1 in the lungs was observed after silica-instillation. Moreover, silica-medicated activation of extracellular signal-regulated kinase (ERK) in the lungs was attenuated in response to silica-induced HO-1 upregulation. Activation of other MAPKs, such as p38 and c-Jun N-terminal kinase pathways, after silica exposure was not significantly different irrespective of HO-1 induction. Further in vitro studies showed that 1) silica-induced HO-1 was significantly attenuated by inhibiting ERK activation, and 2) carbon monoxide and bilirubin as final byproducts of HO-1 could inhibit ERK activation. Taken together, silica-induced HO-1 upregulation was mediated by ERK activation, and HO-1 further regulates ERK activation via its final byproducts, carbon monoxide and bilirubin.ConclusionsThis is the first study to demonstrate the regulatory role of HO-1 in silicosis. This finding could contribute to the development of a treatment strategy of monitoring HO-1 levels as a marker of therapeutic intervention.

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Follistatin like-1 aggravates silica-induced mouse lung injury.

Publications

Follistatin like-1 aggravates silica-induced mouse lung injury.

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