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BBC3 in macrophages promoted pulmonary fibrosis development through inducing autophagy during silicosis.

ABSTRACT: Following inhalation into the lungs, silica particles are engulfed by alveolar macrophages, which triggers endogenous or exogenous apoptosis signaling pathways. As an inducer of apoptosis, the role of BBC3/PUMA (BCL2-binding component 3) in macrophages during silicosis remains unknown. Here, we exposed U937 cell-derived macrophages (UDMs) to SiO₂ in vitro to explore the function of BBC3 in SiO₂-induced disease. We found that SiO₂ induced increased BBC3 expression, as well as macrophage activation and apoptosis. Knockdown of Bbc3 with specific siRNA significantly mitigated the SiO₂-induced effects. In addition, our results clearly showed increased levels of autophagy in macrophages exposed to SiO₂. However, inhibition of BBC3 decreased the occurrence of autophagy. Furthermore, we observed that the blockade of autophagy with 3-MA, an autophagy inhibitor, inhibited SiO₂-induced macrophage activation and apoptosis. In contrast, rapamycin, an autophagy inducer, further enhanced the effects induced by SiO₂. The conditioned medium from macrophages exposed to SiO₂ promoted the proliferation and migration of fibroblasts, and the inhibition of BBC3/autophagy reduced the effects of the conditioned medium on fibroblasts. In the mouse model of silicosis, Bbc3 knockout mice clearly exhibited decreased levels of autophagy and fibrosis progression. These results suggest that downregulation of BBC3 expression may become a novel therapeutic strategy for the treatment of silicosis.

SUBMITTER: Liu H

PROVIDER: S-EPMC5386570 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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BBC3 in macrophages promoted pulmonary fibrosis development through inducing autophagy during silicosis.

Liu Haijun H Cheng Yusi Y Yang Jian J Wang Wei W Fang Shencun S Zhang Wei W Han Bing B Zhou Zewei Z Yao Honghong H Chao Jie J Liao Hong H

Cell death & disease 20170309 3

Following inhalation into the lungs, silica particles are engulfed by alveolar macrophages, which triggers endogenous or exogenous apoptosis signaling pathways. As an inducer of apoptosis, the role of BBC3/PUMA (BCL2-binding component 3) in macrophages during silicosis remains unknown. Here, we exposed U937 cell-derived macrophages (UDMs) to SiO2 in vitro to explore the function of BBC3 in SiO2-induced disease. We found that SiO2 induced increased BBC3 expression ...[more]

PMID: 28277537

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Project description:As an interstitial fibrosis disease characterized by diffuse alveolitis and structural alveolar disorders, idiopathic pulmonary fibrosis (IPF) has high lethality but lacks limited therapeutic drugs. A hospital preparation used for the treatment of viral pneumonia, Qingfei Tongluo mixture (QFTL), is rumored to have protective effects against inflammatory and respiratory disease. This study aims to confirm whether it has a therapeutic effect on bleomycin-induced IPF in rats and to elucidate its mechanism of action. Male SD rats were randomly divided into the following groups: control, model, CQ + QFTL (84 mg/kg chloroquine (CQ) + 3.64 g/kg QFTL), QFTL-L, M, H (3.64, 7.28, and 14.56 g/kg, respectively) and pirfenidone (PFD 420 mg/kg). After induction modeling and drug intervention, blood samples and lung tissue were collected for further detection. Body weight and lung coefficient were examined, combined with hematoxylin and eosin (H&E) and Masson staining to observe lung tissue lesions. The enzyme-linked immunosorbent assay (ELISA) and the hydroxyproline (HYP) assay kit were used to detect changes in proinflammatory factors (transforming growth factor-β (TGF-β), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β)) and HYP. Immunohistochemistry and Western blotting were performed to observe changes in proteins related to pulmonary fibrosis (α-smooth muscle actin (α-SMA) and matrix metalloproteinase 12 (MMP12)) and autophagy (P62 and mechanistic target of rapamycin (mTOR)). Treatment with QFTL significantly improved the adverse effects of bleomycin on body weight, lung coefficient, and pathological changes. Then, QFTL reduced bleomycin-induced increases in proinflammatory mediators and HYP. The expression changes of pulmonary fibrosis and autophagy marker proteins are attenuated by QFTL. Furthermore, the autophagy inhibitor CQ significantly reversed the downward trend in HYP levels and α-SMA protein expression, which QFTL improved in BLM-induced pulmonary fibrosis rats. In conclusion, QFTL could effectively attenuate bleomycin-induced inflammation and pulmonary fibrosis through mTOR-dependent autophagy in rats. Therefore, QFTL has the potential to be an alternative treatment for IPF in clinical practice.

Dataset Information

BBC3 in macrophages promoted pulmonary fibrosis development through inducing autophagy during silicosis.

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BBC3 in macrophages promoted pulmonary fibrosis development through inducing autophagy during silicosis.

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