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Role of matrix metalloprotease-9 in hyperoxic injury in developing lung

Anne Chetty1, Gong-Jie Cao, Mariano Severgnini

  • 1Dept. of Pediatrics, Tufts Medical Center, Boston, MA 02111, USA. achetty@tuftsmedicalcenter.org

American Journal of Physiology. Lung Cellular and Molecular Physiology
|July 29, 2008
PubMed

Insights

Matrix metalloprotease-9 (MMP-9) exacerbates lung injury in neonatal mice exposed to hyperoxia, impairing alveolar development. Blocking MMP-9 may offer new therapeutic strategies for preventing bronchopulmonary dysplasia.

Area of Science:

  • Neonatal lung development and injury
  • Matrix metalloproteinases in lung disease
  • Oxygen-induced lung damage mechanisms

Background:

  • Neonatal lung injury from hyperoxia is linked to impaired alveolar development and extracellular matrix (ECM) remodeling.
  • Matrix metalloprotease-9 (MMP-9) is implicated in the pathogenesis of oxidant injury in the developing lung.
  • Understanding MMP-9's role is crucial for developing therapeutic interventions for conditions like bronchopulmonary dysplasia.

Purpose of the Study:

  • To investigate the specific role of MMP-9 in the functional and histological alterations of neonatal mouse lungs following hyperoxia exposure.
  • To determine if MMP-9 mediates the adverse effects of hyperoxia on alveolar development and ECM remodeling.
  • To evaluate the therapeutic potential of inhibiting MMP-9 in oxygen-induced lung injury.

Main Methods:

  • Neonatal wild-type (WT) and MMP-9 knockout (MMP-9-/-) mice were exposed to hyperoxia or room air.
  • Lung morphometry, including mean linear intercept and alveolar counts, was assessed.
  • Immunohistochemistry for MMP-9 and elastin, Western blot analysis for MMP-2, MMP-9, collagen, and tropoelastin, and lung compliance measurements were performed.

Main Results:

  • Hyperoxia significantly increased MMP-2 and MMP-9 levels in WT mouse lungs, with MMP-9 localized in mesenchyme and alveolar epithelium.
  • Hyperoxia-exposed WT mice exhibited reduced gas exchange surface area and decreased lung compliance compared to controls and MMP-9-/- mice.
  • Increased type I collagen and tropoelastin with aberrant elastin staining were observed in hyperoxic WT lungs, with amelioration in MMP-9-/- mice.

Conclusions:

  • MMP-9 plays a critical role in the structural and functional lung damage induced by hyperoxia in neonatal mice.
  • The absence of MMP-9 significantly mitigates the adverse effects of hyperoxia on lung development and remodeling.
  • Targeting MMP-9 presents a promising therapeutic strategy for preventing or treating bronchopulmonary dysplasia.

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