Role of osteopontin in the pathogenesis of bleomycin-induced pulmonary fibrosis.
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.
Department of Respiratory Medicine, Atopy (Allergy) Research Center, Tokyo, Japan.
F
F
Takahashi
K
K
Takahashi
T
T
Okazaki
K
K
Maeda
H
H
Ienaga
M
M
Maeda
S
S
Kon
T
T
Uede
Y
Y
Fukuchi
D000818:Animals; D001761:Bleomycin / Q000633:toxicity*; D002448:Cell Adhesion / Q000502:physiology; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology; D016207:Cytokines / Q000502:physiology; D004195:Disease Models, Animal; D006909:Hydroxyproline / Q000032:analysis; D007249:Inflammation; D008168:Lung / Q000473:pathology / Q000502:physiology / Q000503:physiopathology; D016676:Macrophages, Alveolar / Q000473:pathology / Q000502:physiology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D053495:Osteopontin; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D012333:RNA, Messenger / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012795:Sialoglycoproteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D013997:Time Factors; D014158:Transcription, Genetic
D016207:Cytokines; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D012795:Sialoglycoproteins; C506896:Spp1 protein, mouse; D053495:Osteopontin; D001761:Bleomycin; D006909:Hydroxyproline