Matrix metalloproteinase-9 deficiency worsens lung injury in a model of bronchopulmonary dysplasia.
Increased activity of matrix metalloproteinase (MMP)-9 is associated with the development of bronchopulmonary dysplasia (BPD) in newborn infants, but the role of MMP-9 in the pathophysiology of BPD is unclear. We have shown that perinatal expression of interleukin-1 beta (IL-1 beta) in the lung is sufficient to cause a BPD-like illness in infant mice. To study the hypothesis that MMP-9 is an important downstream mediator in IL-1 beta-induced lung injury in the newborn, we compared the effects of IL-1 beta on fetal and postnatal lung inflammation and development in transgenic mice with regulatable pulmonary overexpression of human mature IL-1 beta with wild-type (IL-1 beta/MMP-9(+/+)) or null (IL-1 beta/MMP-9(-/-)) MMP-9 loci. IL-1 beta increased the expression of MMP-9 mRNA and amount of MMP-9 protein in the lungs of MMP-9(+/+) mice. IL-1 beta/MMP-9(-/-) mice had fewer neutrophils but more macrophages in the lungs than did IL-1 beta/MMP-9(+/+) mice. MMP-9 deficiency increased pulmonary cell death and macrophage clearance of dying cells in IL-1 beta-expressing mice. IL-1 beta/MMP-9(-/-) mice had more severe alveolar hypoplasia than IL-1 beta/MMP-9(+/+) mice, implying that IL-1 beta-induced lung disease was worsened in the absence of MMP-9. These results suggest that MMP-9 activity in the inflamed neonatal lung protects the lung against injury.
Lukkarinen
Heikki
H
Department of Pediatrics, University of Gothenburg, Medicinaregatan 1G, Gothenburg, Sweden. heikki.lukkarinen@utu.fi
Hogmalm
Anna
A
Lappalainen
Urpo
U
Bry
Kristina
K
D000367:Age Factors; D000375:Aging / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000831:Animals, Newborn; D001997:Bronchopulmonary Dysplasia / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D016923:Cell Death; D018932:Chemokine CCL2 / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism; D004195:Disease Models, Animal; D005865:Gestational Age; D006801:Humans; D007231:Infant, Newborn; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000196:embryology / Q000201:enzymology* / Q000254:growth & development / Q000473:pathology; D008264:Macrophages / Q000201:enzymology; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020556:Neutrophil Infiltration; D011014:Pneumonia / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism
C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D018925:Chemokines; D053583:Interleukin-1beta; D012333:RNA, Messenger; C074302:keratinocyte-derived chemokines; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse