Increased lung matrix metalloproteinase-9 levels in extremely premature baboons with bronchopulmonary dysplasia.
Matrix metalloproteinases (MMPs) regulate the formation of normal lung architecture. Extremely premature infants exposed to hyperoxia and mechanical ventilation often develop lung inflammation and injury. We hypothesized that an imbalance between MMPs and their tissue inhibitors plays a key role. Our hypothesis was tested to: 1) examine the ontogeny of lung MMPs and tissue inhibitors of metalloproteinases (TIMPs); and 2) determine the effects of hyperoxia and mechanical ventilation on lung MMPs and TIMPs in premature newborn baboons developing chronic lung disease/bronchopulmonary dysplasia (CLD/BPD). Lung specimens were obtained from five groups of gestational controls (GCs) sacrificed at 125, 140, 160, 175, and 185 (term) days of gestation, one fetal baboon model of CLD/BPD delivered at 125 days, and two at 140 days of gestation. Paraffin-embedded lung tissue sections were examined for pathological changes, and frozen lung specimens were analyzed for MMPs-1, -2, -8, and -9; TIMPs-1 and -2; and messenger RNA expression of type I collagen. In GCs, MMP-1 and -9 were elevated in the last trimester, whereas MMP-2 and -8 levels were decreased. Significant changes in lung architecture were noted in the BPD models. MMP-1 was increased in the 125-day model, but decreased in both 140-day models. MMP-8 and collagen mRNA levels were decreased, while MMP-9 and MMP-9 to TIMP-1 ratios were increased in all BPD models. We conclude that an imbalance between MMP-9 and TIMP-1 leading to excessive MMP-9 activity contributes to lung inflammation and edema in CLD/BPD.
Tambunting
Francis
F
Division of Neonatal-Perinatal Medicine, Department of Pediatrics, University of California, Irvine Medical Center, Orange, California 92868, USA.
Beharry
Kay D
KD
Hartleroad
Jeffrey
J
Waltzman
Joshua
J
Stavitsky
Yuri
Y
Modanlou
Houchang D
HD
D000818:Animals; D000831:Animals, Newborn; D001997:Bronchopulmonary Dysplasia / Q000201:enzymology* / Q000503:physiopathology* / Q000662:veterinary; D002908:Chronic Disease; D004195:Disease Models, Animal; D004487:Edema / Q000503:physiopathology; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D007249:Inflammation / Q000503:physiopathology; D008168:Lung / Q000201:enzymology* / Q000473:pathology; D008171:Lung Diseases / Q000201:enzymology / Q000503:physiopathology / Q000662:veterinary; D020780:Matrix Metalloproteinase 9 / Q000032:analysis* / Q000096:biosynthesis* / Q000494:pharmacology; D010215:Papio; D012333:RNA, Messenger / Q000032:analysis; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000032:analysis* / Q000096:biosynthesis* / Q000494:pharmacology
D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D020780:Matrix Metalloproteinase 9