Hyperoxia decreases matrix metalloproteinase-9 and increases tissue inhibitor of matrix metalloproteinase-1 protein in the newborn rat lung: Association with arrested alveolarization
Hyperoxia decreases matrix metalloproteinase-9 and increases tissue inhibitor of matrix metalloproteinase-1 protein in the newborn rat lung: Association with arrested alveolarization
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DOI：
10.1203/01.pdr.0000130658.45564.1f
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发表时间：
2004-07-01
影响因子：
3.6
通讯作者：
Olson, DM
中科院分区：
文献类型：
--
作者：
Hosford, GE;Fang, X;Olson, DM
基质金属蛋白酶（MMP）可能是正常肺发育的效应因子，特别是分支形态发生、血管生成和细胞外基质降解。由于新生大鼠幼仔从第4天到第14天的高氧暴露（> 95%O-2）导致肺泡化停滞并模拟新生儿慢性肺病，我们测试了高氧是否改变MMP-2和MMP-9的mRNA、蛋白和酶活性，以及MMP内源性组织抑制剂TIMP-1的mRNA和蛋白表达。在第6天和第14天之间，没有观察到由于高氧暴露导致的MMP-2 mRNA或前酶（72 kD）蛋白水平的变化，尽管活性（68 kD）酶的总蛋白质质量和酶谱活性降低（p < 0.05，ANOVA）。然而，高氧显着降低MMP-9 mRNA和MMP-9蛋白的水平，并减少整体MMP-9酶原活性。TIMP-1 mRNA直到第14天才被高氧升高，但蛋白水平从第9天到第14天被高氧显著升高（p < 0.001）。为了估计MMP抑制阻止肺泡化的潜力，给予多西环素（20 mg/kg，每天两次，通过管饲法），一种泛MMP蛋白水解抑制剂，阻止了肺肺泡化。我们的结论是，高氧降低MMP-9的mRNA，蛋白质和活性，并提高TIMP-1蛋白，这些变化有可能有助于正常肺发育的逮捕。
Matrix metalloproteinases (MMP) are likely effectors of normal lung development, especially branching morphogenesis, angiogenesis, and extracellular matrix degradation. Because hyperoxia exposure (>95% O-2) from d 4 to 14 in newborn rat pups leads to arrest of alveolarization and mimics newborn chronic lung disease, we tested whether hyperoxia altered MMP-2 and -9 mRNA, protein, and enzymatic activity, and the mRNA and protein expression of the endogenous tissue inhibitor of MMP, TIMP-1. No changes due to hyperoxia exposure were observed in MMP-2 mRNA or pro-enzyme (72 kD) protein levels between d 6 and 14, although the overall protein mass and zymographic activity of the active (68 kD) enzyme were diminished (p < 0.05, ANOVA). However, hyperoxia significantly decreased levels of MMP-9 mRNA and pro-MMP-9 protein and diminished overall MMP-9 pro-enzyme activity. TIMP-1 mRNA was not elevated by hyperoxia until d 14, but protein levels were significantly (p < 0.001) elevated by hyperoxia from d 9 to 14. To estimate the potential of MMP inhibition to arrest alveolarization, administration of doxycycline (20 mg/kg, twice daily by gavage), a pan-MMP proteolysis inhibitor, arrested lung alveolarization. We conclude that hyperoxia decreases MMP-9 mRNA, protein, and activity and elevates TIMP-1 protein, and these changes have the potential to contribute to the arrest of normal lung development.