Inflammatory cells as a source of airspace extracellular superoxide dismutase after pulmonary injury.
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. EC-SOD sticks to the matrix by a proteolytically sensitive heparin-binding domain; therefore, we hypothesized that interstitial inflammation and matrix remodeling contribute 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 staining strongly for EC-SOD. EC-SOD accumulated in airspaces at 24 h 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 with wild types. We conclude that the source of accumulating EC-SOD in airspaces in interstitial lung disease is inflammatory cells and not the lung and that interstitial processes such as those found in pulmonary fibrosis are required to remove EC-SOD from lung matrix.
Tan
Roderick J
RJ
Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Lee
Janet S
JS
Manni
Michelle L
ML
Fattman
Cheryl L
CL
Tobolewski
Jacob M
JM
Zheng
Mingquan
M
Kolls
Jay K
JK
Martin
Thomas R
TR
Oury
Tim D
TD
D000818:Animals; D001761:Bleomycin / Q000633:toxicity; D001992:Bronchoalveolar Lavage Fluid; D004195:Disease Models, Animal; D004927:Escherichia coli Infections / Q000201:enzymology; D005110:Extracellular Space; D006801:Humans; D008168:Lung / Q000201:enzymology* / Q000473:pathology; D017563:Lung Diseases, Interstitial / Q000201:enzymology / Q000473:pathology; D055370:Lung Injury; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D011014:Pneumonia / Q000201:enzymology* / Q000473:pathology*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*
D001761:Bleomycin; D013482:Superoxide Dismutase; D020780:Matrix Metalloproteinase 9