DIFFERENTIAL EXPRESSION OF EXTRACELLULAR-MATRIX REMODELING GENES IN AMURINE MODEL OF BLEOMYCIN-INDUCED PULMONARY FIBROSIS

Exposure to the chemotherapeutic drug bleomycin leads to pulmonary fib rosis in humans and has been widely used in animal models of the disea se. Using C57BL/6 bleomycin-sensitive mice, pulmonary fibrosis was ind uced by multiple intraperitoneal injections of the drug. An increase i n the relative amounts of steady-state alpha 1(I) procollagen, alpha 1 (III) procollagen, and fibronectin mRNA as well as histopathological e vidence of fibrosis was observed. The effect of bleomycin on the expre ssion of the enzymes responsible for extracellular matrix degradation, the matrix metalloproteinases (MMPs), and their inhibitors (TIMPs), w as selective and showed temporal differences during the development of fibrosis. Of the MMPs tested, bleomycin treatment resulted in the up- regulation of gelatinase A and macrophage metalloelastase gene express ion in whole-lung homogenates, whereas gelatinase B, stromelysin-l, an d interstitial collagenase gene expression was not significantly chang ed. Timp2 and Timp3, the murine homologues of the respective TIMP gene s, were constitutively expressed, whereas Timp1 was markedly up-regula ted during fibrosis. The strong correlation between enhanced extracell ular matrix gene expression, differential MMP and TIMP gene expression , and histopathological evidence of fibrosis suggest that dysregulated matrix remodeling is likely to contribute to the pathology of bleomyc in-induced pulmonary fibrosis.