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This Article Full Text Full Text (PDF) All Versions of this Article: 289/6/L931    most recent 00037.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Berk, J. L. Articles by Goldstein, R. H. Search for Related Content PubMed PubMed Citation Articles by Berk, J. L. Articles by Goldstein, R. H.

Hypoxia suppresses elastin repair by rat lung fibroblasts

¹The Pulmonary Center, Departments of ²Medicine and ³Biochemistry, ⁴Boston University School of Medicine; and ⁵The Veterans Affairs Boston Health Care System, Boston, Massachusetts

Submitted 20 January 2005 ; accepted in final form 20 July 2005

Macrophage and neutrophil proteinases damage lung elastin, disrupting alveolar epithelium and filling alveoli with inflammatory exudate. Alveolar collapse and regional hypoxia occur. Whether low oxygen tension alters fibroblast-mediated lung repair is unknown. To determine the effect of chronic hypoxia on repair of enzyme-induced elastin disruption, primary rat lung fibroblasts produced elastin matrix for 5 wk before treatment with porcine pancreatic elastase (PPE). After exposure to PPE or saline, cultures recovered for 2 wk in normoxia (21% O₂) or hypoxia (3% O₂). Hypoxia suppressed regeneration of hot alkali-resistant elastin, achieving only 49% of the repair achieved in normoxic cultures. Vascular smooth muscle cells and lung fibroblasts repair elastin by two pathways: de novo synthesis and salvage repair. Although both pathways were affected, hypoxia predominantly inhibited de novo synthesis, decreasing formation of new elastin matrix by 63% while inhibiting salvage repair by only 36%. Prolonged hypoxia alone downregulated steady-state levels of elastin mRNA by 45%, whereas PPE had no significant effect on elastin gene expression. Electron microscopy documented preservation of intracellular organelles and intact nuclei. Together, these data suggest that regional hypoxia limits lung elastin repair following protease injury at least in part by inhibiting elastin gene expression.

tropoelastin; elastase; lung injury; elastic fiber; extracellular matrix