Altered bleomycin-induced lung fibrosis in osteopontin-deficient mice

• Published in: American journal of physiology. Lung cellular and molecular physiology 2004-06, Vol.286 (6), p.L1311-L1318
• Main Authors: Berman, Jeffrey S, Serlin, David, Li, Xinfang, Whitley, Geoffrey, Hayes, John, Rishikof, David C, Ricupero, Dennis A, Liaw, Lucy, Goetschkes, Margaret, O'Regan, Anthony W
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics, Antineoplastic; Bleomycin; Collagen Type I - genetics; Female; Gene Expression; Male; Matrix Metalloproteinase 2 - genetics; Mice; Mice, Mutant Strains; Osteopontin; Pneumonia - chemically induced; Pneumonia - pathology; Pneumonia - physiopathology; Pulmonary Fibrosis - chemically induced; Pulmonary Fibrosis - pathology; Pulmonary Fibrosis - physiopathology; Sialoglycoproteins - genetics; Signal Transduction - physiology; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta1
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00394.2003

1 The Pulmonary Center, Boston University School of Medicine, Boston 02118; 2 The Pulmonary Department, Boston Veterans Administration Medical Center, Boston 02132; 3 Department of Pathology, Boston University School of Medicine, Boston 02118; 5 Pathology Services, Incorporated, Cambridge, Massachusetts 02139; and 4 Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, Maine 04074 Submitted 18 November 2003 ; accepted in final form 12 February 2004 Osteopontin is a multifunctional matricellular protein abundantly expressed during inflammation and repair. Osteopontin deficiency is associated with abnormal wound repair characterized by aberrant collagen fibrillogenesis in the heart and skin. Recent gene microarray studies found that osteopontin is abundantly expressed in both human and mouse lung fibrosis. Macrophages and T cells are known to be major sources of osteopontin. During lung fibrosis, however, osteopontin expression continues to increase when inflammation has receded, suggesting alternative sources of ostepontin during this response. In this study, we demonstrate immunoreactivity for osteopontin in lung epithelial and inflammatory cells in human usual interstitial pneumonitis and murine bleomycin-induced lung fibrosis. After treatment with bleomycin, osteopontin-null mice develop lung fibrosis characterized by dilated distal air spaces and reduced type I collagen expression compared with wild-type controls. There is also a significant decrease in levels of active transforming growth factor- 1 and matrix metalloproteinase-2 in osteopontin null mice. Type III collagen expression and total collagenase activity are similar in both groups. These results demonstrate that osteopontin expression is associated with important fibrogenic signals in the lung and that the epithelium may be an important source of osteopontin during lung fibrosis. pulmonary fibrosis; type I collagen; matrix metalloproteinase-2; transforming growth factor- Address for reprint requests and other correspondence: A. O'Regan, Pulmonary Center, R-304, Boston Univ. School of Medicine, 715 Albany St., Boston, MA 02118 (E-mail: aoregan{at}lung.bumc.bu.edu ).