OBJECTIVEArrested lung development and lung fibrosis are characteristic pathological changes in chronic lung disease (CLD). Therefore, the role of extracellular matrix (ECM) remodeling in lung fibrosis has been emphasized recently. Plasmin system is also an important factor to modulate ECM degradation and matrix metalloproteinase (MMP) system. In this study, the authors established an animal model of CLD induced by inhaling high concentration oxygen (hyperoxia) to investigate the changes and functions of urokinase-plasminogen activator (u-PA) and plasminogen activator inhibitor-1 (PAI-1) in CLD.

METHODSFull-term newborn rats were continuously exposed to oxygen (0.90 - 0.95 O(2)) or room air within 12 h after birth. On day 1, 3, 7, 14, 21 in hyperoxia groups and air controls, lung pathology in newborn rats were observed. The changes of u-PA and PAI-1 protein and mRNA expression were measured by Western blotting and RT-PCR.

RESULTS(1) The pathological findings of the lung tissue: on day 3, there was a few inflammatory cells exuded out, bleeding, edema, and interstitial cells increased in hyperoxia group. On day 7 and thereafter, the terminal air space size of the oxygen-exposed rat became large, there was inflammatory response and more interstitial cells, interstitium was thicker, and collagen deposited. (2) u-PA expression: On day 3, the u-PA protein expression increased in hyperoxia group compared with controls (115.52 +/- 7.10 vs. 96.51 +/- 6.33), P < 0.01. On day 7 to day 21, u-PA protein expression (97.66 +/- 7.98, 99.91 +/- 7.60, 103.23 +/- 6.24) was lower than in the control groups (112.43 +/- 6.01, 123.25 +/- 8.35, 103.23 +/- 6.24), P < 0.05, < 0.01 and < 0.01, respectively. u-PA mRNA increased on d 3 in hyperoxia group compared with controls (1.18 +/- 0.07 vs. 0.99 +/- 0.05), P < 0.01. On d 7 to 21, mRNA expression (1.01 +/- 0.06, 1.10 +/- 0.12, 1.27 +/- 0.06) was lower than that in the controls (1.15 +/- 0.08, 1.51 +/- 0.32, 1.60 +/- 0.24) too, P < 0.01. (3) PAI-1 expression: From d 7 to 21 of oxygen exposure, PAI-1 protein expression (147.83 +/- 12.27, 149.07 +/- 11.17, 161.42 +/- 13.08) increased compared with the controls (116.18 +/- 10.67, 113.73 +/- 15.58, 126.60 +/- 8.59), P < 0.01, < 0.05 and < 0.01, respectively. mRNA expression (1.49 +/- 0.28, 1.46 +/- 0.31, 1.51 +/- 0.33) increased compared with the control group (0.94 +/- 0.01, 0.94 +/- 0.03, 0.98 +/- 0.03), P < 0.05, < 0.01 and < 0.05, respectively.

CONCLUSIONSIn the early stage of hyperoxic exposure, the balance of u-PA/PAI-1 mRNA and protein increased, plasmin and degradation activity increased, which may increase the degradation of ECM in lung base membrane. During the middle and late stage, the expression of u-PA/PAI-1 mRNA and protein decreased, plasmin and degradation activity were lower, in parallel to thicker interstitium, suggesting that the imbalance of u-PA/PAI-1 may also play a role in lung fibrosis in CLD induced by hyperoxia.