title: 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 SiO2in vitro to explore the function of BBC3 in SiO2-induced disease. We found that SiO2induced 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 SiO2promoted 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.
authors.affiliation: Neurobiology Laboratory, New Drug Screening Centre, China Pharmaceutical University, Nanjing, China.|Department of Physiology, School of Medicine, Southeast University, Nanjing, China.
authors.forename: Haijun
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Physiology, School of Medicine, Southeast University, Nanjing, China.
authors.forename: Yusi
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Physiology, School of Medicine, Southeast University, Nanjing, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
authors.affiliation: Nine Department of Respiratory Medicine, Nanjing Chest Hospital, Nanjing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Nine Department of Respiratory Medicine, Nanjing Chest Hospital, Nanjing, China.
authors.forename: Shencun
authors.initials: S
authors.lastname: Fang
authors.affiliation: Department of Physiology, School of Medicine, Southeast University, Nanjing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, School of Medicine, Southeast University, Nanjing, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Han
authors.affiliation: Department of Physiology, School of Medicine, Southeast University, Nanjing, China.|Department of Pharmacology, School of Medicine, Southeast University, Nanjing, China.
authors.forename: Zewei
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Department of Pharmacology, School of Medicine, Southeast University, Nanjing, China.|Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing, China.
authors.forename: Honghong
authors.initials: H
authors.lastname: Yao
authors.affiliation: Department of Physiology, School of Medicine, Southeast University, Nanjing, China.|Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing, China.|Department of Respiration, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Chao
authors.affiliation: Neurobiology Laboratory, New Drug Screening Centre, China Pharmaceutical University, Nanjing, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Liao
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D011658:Pulmonary Fibrosis / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D012822:Silicon Dioxide / Q000633:toxicity; D012829:Silicosis / Q000150:complications / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D020123:Sirolimus / Q000008:administration & dosage; D020298:U937 Cells
chemical_list: D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D011518:Proto-Oncogene Proteins; D012822:Silicon Dioxide; D020123:Sirolimus