|Budget Amount *help
¥2,900,000 (Direct Cost : ¥2,900,000)
Fiscal Year 2004 : ¥1,200,000 (Direct Cost : ¥1,200,000)
Fiscal Year 2003 : ¥1,700,000 (Direct Cost : ¥1,700,000)
BACKGROUND : Pulmonary fibrosis is an interstitial disorder of the lung parenchyma, of which mechanism is poorly understood. Prostanoids are known to participate in the process of fibrogenesis and produced by various cells in the lung, such as macrophages, epithelial cells, endothelial cells, smooth muscle cells, and fibroblasts, which are involved in the pathogenesis of pulmonary fibrosis. We hypothesized that intratracheal gene transfer of a synthase of anti-fibrotic (prostaglandin I2 [PGI2]) or pro-fibrotic (thromboxane [TX]A2) prostaglandins (PGs) alters severity of lung fibrosis. METHODS : A 1.6-BamHI fragment containing human PGIS gene or a 1.8-kb BamHI fragment containing human TXAS gene was ligated into pCI-neo expression vector, and designated pCI-PGIS and pCI-TXAS, respectively. We injected HVJ-liposome complex including 20 mcg of pCI-PGIS or pCI-TXAS into tracheas of C57BL/6 mice at age of 6-8 weeks. The animals were administered with 60 mcg of bloemycin intratracheally 24 hours after gene transfer, observed daily, and sacrificed for histological study of right lungs and hydroxyproline assay of left lungs. RESULTS : The gene transfer of PGIS increased body weight (157%, day 21, vs null-vector control ; p<0.05), decreased hydroxyproline content in the lung (75%, day 14, vs null-vector control ; p<0.05) and decreased cell infiltration in the lung, whereas TXAS gene transfer tended to present opposite effects. CONCLUSION : These results suggest that a balance of antifibrotic and profibrotic PGs might be a determinant of severity of lung fibrosis. The anti-fibrotic or pro-fibrotic PGs might be molecular targets for new therapies to treat pulmonary fibrosis.