Altered bleomycin-induced lung fibrosis in osteopontin-deficient mice

TLDR

Osteopontin is a multifunctional matricellular protein highly expressed during inflammation and repair, with deficiency linked to abnormal collagen fibrillogenesis in heart and skin, and it is abundantly expressed in human and mouse lung fibrosis where macrophages and T cells are major sources but expression persists after inflammation subsides, implying alternative sources. The study aims to identify osteopontin expression in lung epithelial and inflammatory cells in human usual interstitial pneumonitis and murine bleomycin‑induced lung fibrosis. Immunohistochemical analysis was performed on lung tissues from human UIP patients and bleomycin‑treated mice to detect osteopontin in epithelial and inflammatory cells. Osteopontin‑null mice exhibited bleomycin‑induced lung fibrosis with dilated distal air spaces, reduced type I collagen, lower active TGF‑β1 and MMP‑2 levels, while type III collagen and total collagenase activity remained unchanged, indicating osteopontin’s role in fibrogenic signaling and suggesting epithelial cells as a key source.

Abstract

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-beta(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.