Role of matrix metalloproteinase-2 in newborn mouse lungs under hypoxic conditions.
Hypoxia impairs normal neonatal pulmonary artery remodeling and alveolar development. Matrix metalloproteinase-2 (MMP-2), which regulates collagen breakdown, is important during development. Our objective was to test the hypothesis that hypoxia attenuates the normal postnatal increase in MMP-2 and evaluate alveolar development and pulmonary arterial remodeling in Mmp2 mice. C57BL/6 wild-type (WT), Mmp2, Mmp2, and MMP-inhibited (with doxycycline) mice were exposed to hypoxia (12% O2) or air from birth to 2 wk of age. Pulmonary arterial remodeling, alveolar development, and vascular collagen and elastin were evaluated. MMP-2 was estimated by quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay, immunohistochemistry, and zymography. We observed that 1) in WT mice, hypoxia led to thicker-walled pulmonary arteries and impaired alveolarization, accompanied by decreased MMP-2 and increased tissue inhibitor of metalloproteinases-2 (TIMP-2); 2) Mmp2 mice in air had thicker-walled arteries, impaired alveolarization, and increased perivascular collagen and elastin compared with WT; 3) hypoxia further inhibited alveolarization but did not alter arterial thickening in Mmp2 mice. Mmp2 and MMP-inhibited mice also had thicker-walled arteries than WT in air, but alveolarization was not different. We conclude that hypoxia reduces the postnatal MMP-2 increase in the lung, which may contribute to abnormal pulmonary arterial remodeling and impaired alveolarization.
Department of Pediatrics, Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL 35233, USA. ambal@uab.edu
Namasivayam
N
Ambalavanan
Teodora
T
Nicola
Peng
P
Li
Arlene
A
Bulger
Joanne
J
Murphy-Ullrich
Suzanne
S
Oparil
Yiu-Fai
YF
Chen
D000818:Animals; D000831:Animals, Newborn; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D004318:Doxycycline / Q000494:pharmacology; D004549:Elastin / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D000860:Hypoxia / Q000201:enzymology* / Q000473:pathology; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development / Q000473:pathology; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011480:Protease Inhibitors / Q000494:pharmacology; D011650:Pulmonary Alveoli / Q000201:enzymology / Q000254:growth & development; D011651:Pulmonary Artery / Q000201:enzymology / Q000254:growth & development; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism
D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D012333:RNA, Messenger; D019716:Tissue Inhibitor of Metalloproteinase-2; D003094:Collagen; D004549:Elastin; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D004318:Doxycycline