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Matrix Metalloproteinase-9 Deficiency Worsens Lung Injury in a Model of Bronchopulmonary Dysplasia

¹ Department of Pediatrics, University of Gothenburg, Gothenburg, Sweden

Correspondence and requests for reprints should be addressed to Heikki Lukkarinen, M.D., Ph.D., Department of Pediatrics, University of Gothenburg, Medicinaregatan 1G, Medical Chemistry Rm. 4367, SWE-41390 Gothenburg, Sweden. E-mail: heikki.lukkarinen{at}utu.fi

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-1β (IL-1β) 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-1β–induced lung injury in the newborn, we compared the effects of IL-1β on fetal and postnatal lung inflammation and development in transgenic mice with regulatable pulmonary overexpression of human mature IL-1β with wild-type (IL-1β/MMP-9^+/+) or null (IL-1β/MMP-9^–/–) MMP-9 loci. IL-1β increased the expression of MMP-9 mRNA and amount of MMP-9 protein in the lungs of MMP-9^+/+ mice. IL-1β/MMP-9^–/– mice had fewer neutrophils but more macrophages in the lungs than did IL-1β/MMP-9^+/+ mice. MMP-9 deficiency increased pulmonary cell death and macrophage clearance of dying cells in IL-1β–expressing mice. IL-1β/MMP-9^–/– mice had more severe alveolar hypoplasia than IL-1β/MMP-9^+/+ mice, implying that IL-1β–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.

Key Words: alveolar development • apoptosis • inflammation • interleukin-1β

CLINICAL RELEVANCE The present study shows that matrix metalloproteinase (MMP)-9 deficiency worsens alveolar hypoplasia in a transgenic model of bronchopulmonary dysplasia (BPD). Thus, instead of playing a pathogenetic role in the development of BPD as previously suggested, MMP-9 activity in the newborn lung may be a host-defense mechanism that protects the lung against inflammatory injury.

 

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