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.
Ambalavanan
Namasivayam
N
Department of Pediatrics, Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL 35233, USA. ambal@uab.edu
Nicola
Teodora
T
Li
Peng
P
Bulger
Arlene
A
Murphy-Ullrich
Joanne
J
Oparil
Suzanne
S
Chen
Yiu-Fai
YF
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