Takahashi F, Takahashi K, Okazaki T, Maeda K, Ienaga H, Maeda M, Kon S, Uede T, Fukuchi Y
Department of Respiratory Medicine, Atopy (Allergy) Research Center, Tokyo, Japan.
Am J Respir Cell Mol Biol. 2001 Mar;24(3):264-71. doi: 10.1165/ajrcmb.24.3.4293.
Pulmonary fibrosis is initiated by migration, adhesion, and proliferation of fibroblasts. Osteopontin (OPN) is one of the cytokines produced by activated macrophages and mediates various functions, including cell attachment and migration, by interacting with alphav integrin. In this study, we have investigated the role of OPN in the pathogenesis of pulmonary fibrosis. We developed a mouse model for pulmonary fibrosis by intratracheal instillation of bleomycin (BLM). OPN was strongly expressed in alveolar macrophages accumulating in the fibrotic area of the lung. OPN messenger RNA (mRNA) in the lung was notably induced by BLM instillation, and the development of the fibrotic process was associated with an increase in the expression of OPN mRNA and protein. In vitro, recombinant OPN enhanced migration, adhesion, and platelet-derived growth factor (PDGF)-mediated DNA synthesis of murine fibroblast cell line NIH3T3. These effects of OPN on fibroblasts were significantly suppressed by addition of antimouse alphav integrin monoclonal antibody (RMV-7). Furthermore, treatment of mice with RMV-7 repressed the extent of pulmonary fibrosis in this model. Conclusively, these data suggest that OPN produced by alveolar macrophages functions as a fibrogenic cytokine that promotes migration, adhesion, and proliferation of fibroblasts in the development of BLM-induced pulmonary fibrosis.
肺纤维化由成纤维细胞的迁移、黏附和增殖引发。骨桥蛋白（OPN）是活化巨噬细胞产生的细胞因子之一，通过与αv整合素相互作用介导多种功能，包括细胞黏附和迁移。在本研究中，我们探究了OPN在肺纤维化发病机制中的作用。我们通过气管内滴注博来霉素（BLM）建立了肺纤维化小鼠模型。OPN在聚集于肺纤维化区域的肺泡巨噬细胞中强烈表达。肺内的OPN信使核糖核酸（mRNA）在滴注BLM后显著诱导产生，并且纤维化进程的发展与OPN mRNA和蛋白表达的增加相关。在体外，重组OPN增强了小鼠成纤维细胞系NIH3T3的迁移、黏附和血小板衍生生长因子（PDGF）介导的DNA合成。添加抗小鼠αv整合素单克隆抗体（RMV-7）可显著抑制OPN对成纤维细胞的这些作用。此外，用RMV-7治疗小鼠可抑制该模型中肺纤维化的程度。总之，这些数据表明，肺泡巨噬细胞产生的OPN作为一种促纤维化细胞因子，在BLM诱导的肺纤维化发展过程中促进成纤维细胞的迁移、黏附和增殖。
