Chetty A, Cao G-J, Severgnini M, Simon A, Warburton R, Nielsen HC. Role of matrix metalloprotease-9 in hyperoxic injury in developing lung. Am J Physiol Lung Cell Mol Physiol 295: L584 -L592, 2008. First published July 25, 2008 doi:10.1152/ajplung.00441.2007.-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 (Ϫ/Ϫ) 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 hyperoxiaexposed WT mice had less gas exchange surface area and were less compliant compared with room air-exposed WT and hyperoxiaexposed MMP-9 (Ϫ/Ϫ) 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 (Ϫ/Ϫ) 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. morphometry; elastin; bronchopulmonary dysplasia THE PATHOPHYSIOLOGICAL FEATURES of the newer forms of bronchopulmonary dysplasia (BPD) are characterized by increased airway responsiveness to direct stimuli, with evidence of minimal alveolarization, variable alveolar wall cellularity and fibrosis, and alveolar-capillary dysplasia (14). Alveolarization begins in the distal saccules of the lung in parallel with development of the alveolar capillary bed in infants born at 24 -28 wk of gestation (28). The major manifestation of hyperoxic lung injury in neonates is an interference with normal lung development, particularly alveolar development. In the new BPD, fewer and larger alveoli are present. Hyperoxiaexposed preterm baboons showed a complete arrest of alveolar septation with fewer and larger alveoli. Even though the normal signal for septation of the saccules is unknown, hyperoxia has been shown to delay alveolar development (14).Interactions between epithelial and mesodermal cells during lung development and repair from injury lead to characteristic morphological and functional changes in the n...