A role for matrix metalloproteinase 9 in IFNγ-mediated injury in developing lungs: Relevance to bronchopulmonary dysplasia

Anantha Harijith, Rayman Choo-Wing, Sule Cataltepe, Ryuji Yasumatsu, Zubair H. Aghai, Joakim Janèr, Sture Andersson, Robert J. Homer, Vineet Bhandari

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

We noted a marked increase in IFNγ mRNA in newborn (NB) murine lungs after exposure to hyperoxia. We sought to evaluate the role of IFNg in lung injury in newborns. Using a unique triple-transgenic (TTG), IFNγ- overexpressing, lung-targeted, externally regulatable NB murine model, we describe a lung phenotype of impaired alveolarization, resembling human bronchopulmonary dysplasia (BPD). IFNγ-mediated abnormal lung architecture was associated with increased cell death and the upregulation of cell death pathway mediators caspases 3, 6, 8, and 9, and angiopoietin 2. Moreover, an increase was evident in cathepsins B, H, K, L, and S, and in matrix metalloproteinases (MMPs) 2, 9, 12, and 14. The IFNγ-mediated abnormal lung architecture was found to be MMP9-dependent, as indicated by the rescue of the IFNγ-induced pulmonary phenotype and survival during hyperoxia with a concomitant partial deficiency of MMP9. This result was concomitant with a decrease in caspases 3, 6, 8, and 9 and angiopoietin 2, but an increase in the expression of angiopoietin 1. In addition,NB IFNγ TTG mice exhibited significantly decreased survival during hyperoxia, compared with littermate controls. Furthermore, as evidence of clinical relevance, we show increased concentrations of the downstreamtargets of IFNγ chemokine (C-X-C motif) ligands (CXCL10 and CXCL11) in baboon and human lungs with BPD. IFNγ and its downstream targets may contribute significantly to the final common pathway of hyperoxia-induced injury in the developing lung and in human BPD.

Original languageEnglish
Pages (from-to)621-630
Number of pages10
JournalAmerican journal of respiratory cell and molecular biology
Volume44
Issue number5
DOIs
Publication statusPublished - May 1 2011

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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