Role of matrix metalloprotease-9 in hyperoxic injury in developing lung.
Matrix metalloprotease-9 (MMP-9) is increased in lung injury following hyperoxia exposure in neonatal mice, in association with impaired alveolar development. We studied the role of MMP-9 in the mechanism of hyperoxia-induced functional and histological changes in neonatal mouse lung. Reduced alveolarization with remodeling of ECM is a major morbidity component of oxidant injury in developing lung. MMP-9 mediates oxidant injury in developing lung causing altered lung remodeling. Five-day-old neonatal wild-type (WT) and MMP-9 (-/-) mice were exposed to hyperoxia for 8 days. The lungs were inflation fixed, and sections were examined for morphometry. The mean linear intercept and alveolar counts were evaluated. Immunohistochemistry for MMP-9 and elastin was performed. MMP-2, MMP-9, type I collagen, and tropoelastin were measured by Western blot analysis. Lung quasistatic compliance was studied in anaesthetized mice. MMP-2 and MMP-9 were significantly increased in lungs of WT mice exposed to hyperoxia compared with controls. Immunohistochemistry showed an increase in MMP-9 in mesenchyme and alveolar epithelium of hyperoxic lungs. The lungs of hyperoxia-exposed WT mice had less gas exchange surface area and were less compliant compared with room air-exposed WT and hyperoxia-exposed MMP-9 (-/-) mice. Type I collagen and tropoelastin were increased in hyperoxia-exposed WT with aberrant elastin staining. These changes were ameliorated in hyperoxia-exposed MMP-9 (-/-) mice. MMP-9 plays an important role in the structural changes consequent to oxygen-induced lung injury. Blocking MMP-9 activity may lead to novel therapeutic approaches in preventing bronchopulmonary dysplasia.
Chetty
Anne
A
Dept. of Pediatrics, Tufts Medical Center, Boston, MA 02111, USA. achetty@tuftsmedicalcenter.org
Cao
Gong-Jie
GJ
Severgnini
Mariano
M
Simon
Amy
A
Warburton
Rod
R
Nielsen
Heber C
HC
D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight; D004549:Elastin / Q000378:metabolism; D018496:Hyperoxia / Q000235:genetics / Q000503:physiopathology*; D008168:Lung / Q000254:growth & development / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D011650:Pulmonary Alveoli / Q000201:enzymology / Q000473:pathology; D012128:Respiratory Distress Syndrome / Q000201:enzymology*; D012129:Respiratory Function Tests
D004549:Elastin; D020780:Matrix Metalloproteinase 9