title: Epithelial neoplasia coincides with exacerbated injury and fibrotic response in the lungs of Gprc5a-knockout mice following silica exposure.
abstract: Exposure to crystalline silica is suggested to increase the risk for a variety of lung diseases, including fibrosis and lung cancer. However, epidemiological evidences for the exposure-risk relationship are ambiguous and conflicting, and experimental study from a reliable animal model to explore the relationship is lacking. We reasoned that a mouse model that is sensitive to both lung injury and tumorigenesis would be appropriate to evaluate the exposure-risk relationship. Previously, we showed that, Gprc5a-/- mice are susceptible to both lung tumorigenesis and endotoxin-induced acute lung injury. In this study, we investigated the biological consequences in Gprc5a-/- mouse model following silica exposure. Intra-tracheal administration of fine silica particles in Gprc5a-/- mice resulted in more severe lung injury and pulmonary inflammation than in wild-type mice. Moreover, an enhanced fibrogenic response, including EMT-like characteristics, was induced in the lungs of Gprc5a-/- mice compared to those from wild-type ones. Importantly, increased hyperplasia or neoplasia coincided with silica-induced tissue injury and fibrogenic response in lungs from Gprc5a-/- mice. Consistently, expression of MMP9, TGFβ1 and EGFR was significantly increased in lungs from silica-treated Gprc5a-/- mice compared to those untreated or wild-type ones. These results suggest that, the process of tissue repair coincides with tissue damages; whereas persistent tissue damages leads to abnormal repair or neoplasia. Thus, silica-induced pulmonary inflammation and injury contribute to increased neoplasia development in lungs from Gprc5a-/- mouse model.
authors.affiliation: Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.|Department of Pulmonary Medicine, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Wang
authors.affiliation: Key Laboratory of Cell Differentiation and Apoptosis of Chinese Minister of Education, Department of Pathophysiology, Shanghai, China.|Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Dongliang
authors.initials: D
authors.lastname: Xu
authors.affiliation: Key Laboratory of Cell Differentiation and Apoptosis of Chinese Minister of Education, Department of Pathophysiology, Shanghai, China.|Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yueling
authors.initials: Y
authors.lastname: Liao
authors.affiliation: Key Laboratory of Cell Differentiation and Apoptosis of Chinese Minister of Education, Department of Pathophysiology, Shanghai, China.|Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Shuangshuang
authors.initials: S
authors.lastname: Zhong
authors.affiliation: Key Laboratory of Cell Differentiation and Apoptosis of Chinese Minister of Education, Department of Pathophysiology, Shanghai, China.|Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Hongyong
authors.initials: H
authors.lastname: Song
authors.affiliation: Translation Medicine Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Beibei
authors.initials: B
authors.lastname: Sun
authors.affiliation: Department of Molecular and Cellular Biochemistry, Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, USA.
authors.forename: Binhua P
authors.initials: BP
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Cell Differentiation and Apoptosis of Chinese Minister of Education, Department of Pathophysiology, Shanghai, China.|Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Translation Medicine Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Jiong
authors.initials: J
authors.lastname: Deng
authors.affiliation: Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.|Translation Medicine Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Baohui
authors.initials: B
authors.lastname: Han
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics / Q000473:pathology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D004848:Epithelium / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D015972:Gene Expression Regulation, Neoplastic; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D011014:Pneumonia / Q000139:chemically induced / Q000235:genetics; D011654:Pulmonary Edema / Q000139:chemically induced / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012822:Silicon Dioxide / Q000633:toxicity*
chemical_list: D016207:Cytokines; C554251:GPRC5A protein, mouse; D043562:Receptors, G-Protein-Coupled; D012822:Silicon Dioxide
keywords: Gprc5a; SiO2; fibrosis; lung cancer; neoplasia