title: p53/PUMA expression in human pulmonary fibroblasts mediates cell activation and migration in silicosis.
abstract: Phagocytosis of SiO2 into the lung causes an inflammatory cascade that results in fibroblast proliferation and migration, followed by fibrosis. Clinical evidence has indicated that the activation of alveolar macrophages by SiO2 produces rapid and sustained inflammation characterized by the generation of monocyte chemotactic protein 1, which, in turn, induces fibrosis. However, the details of events downstream of monocyte chemotactic protein 1 activity in pulmonary fibroblasts remain unclear. Here, to elucidate the role of p53 in fibrosis induced by silica, both the upstream molecular mechanisms and the functional effects on cell proliferation and migration were investigated. Experiments using primary cultured adult human pulmonary fibroblasts led to the following results: 1) SiO2 treatment resulted in a rapid and sustained increase in p53 and PUMA protein levels; 2) the MAPK and PI3K pathways were involved in the SiO2-induced alteration of p53 and PUMA expression; and 3) RNA interference targeting p53 and PUMA prevented the SiO2-induced increases in fibroblast activation and migration. Our study elucidated a link between SiO2-induced p53/PUMA expression in fibroblasts and cell migration, thereby providing novel insight into the potential use of p53/PUMA in the development of novel therapeutic strategies for silicosis treatment.
authors.affiliation: Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China.|Department of Physiology, Medical School of Southeast University, Nanjing, Jiangsu 210009, China.|Nine Department of Respiratory Medicine, Nanjing Chest Hospital, Nanjing, Jiangsu 210029, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Physiology, Medical School of Southeast University, Nanjing, Jiangsu 210009, China.|Neurobiology Laboratory, New Drug Screening Centre, China Pharmaceutical University, Nanjing, Jiangsu 210009, China.
authors.forename: Haijun
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Physiology, Medical School of Southeast University, Nanjing, Jiangsu 210009, China.
authors.forename: Xiaoniu
authors.initials: X
authors.lastname: Dai
authors.affiliation: Nine Department of Respiratory Medicine, Nanjing Chest Hospital, Nanjing, Jiangsu 210029, China.
authors.forename: Shencun
authors.initials: S
authors.lastname: Fang
authors.affiliation: Department of Physiology, Medical School of Southeast University, Nanjing, Jiangsu 210009, China.
authors.forename: Xingang
authors.initials: X
authors.lastname: Wang
authors.affiliation: Nine Department of Respiratory Medicine, Nanjing Chest Hospital, Nanjing, Jiangsu 210029, China.
authors.forename: Yingming
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Medical School of Southeast University, Nanjing, Jiangsu 210009, China.
authors.forename: Honghong
authors.initials: H
authors.lastname: Yao
authors.affiliation: Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Xilong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Physiology, Medical School of Southeast University, Nanjing, Jiangsu 210009, China.|Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing, 210096, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Chao
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D003094:Collagen / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism*; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D012822:Silicon Dioxide / Q000009:adverse effects; D012829:Silicosis / Q000175:diagnosis / Q000209:etiology* / Q000378:metabolism; D014057:Tomography, X-Ray Computed; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D012822:Silicon Dioxide; D003094:Collagen; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases