Published ahead of print on October 13, 2005, doi:10.1165/rcmb.2005-0212OC Am. J. Respir. Cell Mol. Biol., Volume 34, Number 2, February 2006, 226-232 A more recent version of this article appeared on February 1, 2006
Submitted on June 7, 2005 Inflammatory Cells as a Source of Airspace Extracellular Superoxide Dismutase after Pulmonary InjuryRoderick J Tan1,1 Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA, 2 Department of Medicine, Divsion of Pulmonary Allergy and Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA; VA Puget Sound Health Care System and Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, WA, USA, 3 Department of Pediatrics, University of Pittsburgh Medical Center, Pittsburgh, PA, USA, 4 VA Puget Sound Health Care System and Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, WA, USA * To whom correspondence should be addressed. E-mail: tdoury{at}pitt.edu.
Extracellular superoxide dismutase (EC-SOD) is an antioxidant abundant in the lung. Previous studies demonstrated depletion of lung parenchymal EC-SOD in mouse models of interstitial lung disease coinciding with an accumulation of EC-SOD in airspaces. As EC-SOD sticks to the matrix by a proteolytically sensitive heparin-binding domain, we hypothesized that interstitial inflammation and matrix remodeling contributed to proteolytic redistribution of EC-SOD from lung parenchyma into the airspaces. To determine if inflammation limited to airspaces leads to EC-SOD redistribution, we examined a bacterial pneumonia model. This model led to increases in airspace polymorphonuclear leukocytes (PMN) staining strongly for EC-SOD. EC-SOD accumulated in airspaces at 24h without depletion of EC-SOD from lung parenchyma. This led us to hypothesize that airspace EC-SOD was released from inflammatory cells and was not a redistribution of matrix EC-SOD. To test this hypothesis, transgenic mice with lung-specific expression of human EC-SOD were treated with asbestos or bleomycin to initiate an interstitial lung injury. In these studies, EC-SOD accumulating in airspaces was entirely the mouse isoform, demonstrating an extrapulmonary source (inflammatory cells) for this EC-SOD. We also demonstrate that EC-SOD knockout mice possess greater lung inflammation in response to bleomycin and bacteria when compared to wild types. We conclude that 1) the source of accumulating EC-SOD in airspaces in interstitial lung disease are inflammatory cells and not the lung, and 2) interstitial processes such as those found in pulmonary fibrosis are required to remove EC-SOD from lung matrix.
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