Hyperoxia decreases matrix metalloproteinase-9 and increases tissue inhibitor of matrix metalloproteinase-1 protein in the newborn rat lung: association with arrested alveolarization.
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.
Hosford
Gayle E
GE
Departmen of Physiology, Perinatal Research Centre, The University of Alberta, Edmonton, Alberta, Canada.
Fang
Xin
X
Olson
David M
DM
D000818:Animals; D000831:Animals, Newborn; D004318:Doxycycline / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000502:physiology; D018496:Hyperoxia / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D011650:Pulmonary Alveoli / Q000254:growth & development* / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism*
D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D004318:Doxycycline