title: Regulation of silicosis formation by lysophosphatidic acid and its receptors.
abstract: Silicosis is a serious occupational disease characterized by lung fibrosis that is caused by long-term inhalation of silica-containing fine particles. Lysophosphatidic acid (LPA) and LPA1/3 plays a role in lung fibrosis. Until recently, there has been little research investigating the role of LPA and LPA receptors (LPAR) in silica-induced development of pulmonary fibrosis. In this study, we evaluated the hypothesis that LPA and LPA1/3 may play a role in silicosis pathogenesis using rat silicosis models induced by intratracheal instillation of silica, and randomly divided into control, silica, and VPC-12249 groups. LPA serum and bronchoalveolar lavage fluid (BALF) levels were quantified by ELISA. α-smooth muscle actin (α-SMA), type I and III collagen protein expression was quantified by western blotting (WB), and type I and III collagen mRNAs detected by reverse transcriptase-polymerase chain reaction (RT-PCR). Lung hydroxyproline (HYP) levels were detected using alkaline hydrolysis, with hematoxylin and eosin (H&E) and picrosirius red staining used for pathological examination. In vitro experiments showed that LPA stimulated fibroblasts proliferated in a time and dose-dependent manner and promoted expression of α-SMA, and type I and III collagen. Moreover, LPA serum and BALF levels increased in silica-instilled rats. In vivo and in vitro experiments revealed that α-SMA expression and collagen deposition reduced significantly after VPC-12249 treatment, and histopathological results show VPC-12249 alleviates silicosis progression. In conclusion, our findings suggest that LPA promotes the proliferation, transformation, and collagen synthesis of fibroblasts, and that LPA-LPA1/3 are involved in the development of silicosis and may serve as novel therapeutic targets for treatment.
authors.affiliation: Occupational Disease Department, Peking University Third Hospital, Beijing, China.
authors.forename: Cuicui
authors.initials: C
authors.lastname: Cong
authors.forename: Lijun
authors.initials: L
authors.lastname: Mao
authors.forename: Yanlin
authors.initials: Y
authors.lastname: Zhang
authors.forename: Zanmei
authors.initials: Z
authors.lastname: Zhao
authors.forename: Xixian
authors.initials: X
authors.lastname: Xu
authors.forename: Jinyuan
authors.initials: J
authors.lastname: Zhao
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D024042:Collagen Type I / Q000378:metabolism; D024061:Collagen Type III / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008246:Lysophospholipids / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D049368:Receptors, Lysophosphatidic Acid / Q000378:metabolism*; D012822:Silicon Dioxide / Q000494:pharmacology; D012829:Silicosis / Q000378:metabolism* / Q000473:pathology
chemical_list: D000199:Actins; D024042:Collagen Type I; D024061:Collagen Type III; D008246:Lysophospholipids; D049368:Receptors, Lysophosphatidic Acid; D012822:Silicon Dioxide; C032881:lysophosphatidic acid
keywords: collagen; lysophosphatidic acid; pulmonary fibrosis; silicosis