Inflammatory cells as a source of airspace extracellular superoxide dismutase after pulmonary injury

Our plain-English summary of Inflammatory cells as a source of airspace extracellular superoxide dismutase after pulmonary injury, by R.J. Tan, J.S. Lee, M.L. Manni, et al (American Journal of Respiratory Cell and Molecular Biology, 2006).

The study

• Authors: R.J. Tan, J.S. Lee, M.L. Manni, C.L. Fattman, J.M. Tobolewski, M. Zheng, J.K. Kolls, T.R. Martin, T.D. Oury
• Journal: American Journal of Respiratory Cell and Molecular Biology
• Published: 2006;34(2):226-32
• Cited by: 34 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

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.

In plain English

This was a laboratory study in mice about extracellular superoxide dismutase (EC-SOD), an antioxidant enzyme found in the lung. The authors asked where the EC-SOD that builds up in the lung's airspaces after injury comes from. First, they gave wild-type mice inhaled E. coli bacteria, which caused pneumonia mainly in the airspaces. At 24 hours, neutrophils in lung fluid had risen by a factor of about 1,000, and EC-SOD had built up in the airspaces. EC-SOD in the lung tissue itself was not depleted, and inflammatory cells in the airspaces stained strongly for it. Next, mice engineered to make human EC-SOD in their lungs were given 0.1 mg crocidolite asbestos or bleomycin to cause interstitial lung injury. Only the mouse form of EC-SOD appeared in their lung fluid. Mice lacking EC-SOD had significantly more neutrophils than normal mice after bleomycin, and a trend toward more after killed bacteria. The authors concluded that inflammatory cells are a source of airspace EC-SOD. They said they could not rule out that only the mouse form was being moved into the airspaces.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Animal experiment (laboratory study in mice: a bacterial pneumonia model, transgenic mice, and knockout mice)
• Who was studied: Laboratory mice: wild-type C57BL/6 mice, transgenic mice making human EC-SOD in the lung under the surfactant protein C promoter, and EC-SOD knockout mice. They were bred at the VA Puget Sound Health Care System (Seattle) and the University of Pittsburgh Medical Center. Group sizes are not clearly given for most experiments.
• Exposure: Inhaled live E. coli (serotype K1). Intratracheal crocidolite asbestos (0.1 mg, with lung fluid collected at 14 days). Intratracheal bleomycin (0.04 units). Heat-killed Klebsiella pneumoniae (1 times 10 to the 5th bacteria per mouse) in knockout and wild-type mice. Asbestos and bleomycin were used as ways to cause interstitial lung injury.
• Main results:
  • In wild-type mice given inhaled E. coli, bacteria in the lungs averaged 3,567 cfu/ml at 0 h and fell to 700 CFU/ml at 24 h.
  • In E. coli-exposed mice at 24 h, macrophages in lung fluid rose by a factor of 3 and neutrophils (PMNs) by a factor of 1,000.
  • In E. coli-exposed mice, EC-SOD accumulated in the airspaces at 24 h. Most of it was the cut-down form lacking the heparin-binding domain. EC-SOD activity in lung fluid was 11.7 U/ml (plus or minus 3.07) at 24 h, with no detectable activity at 0 and 6 h.
  • In E. coli-exposed mice, EC-SOD in lung tissue was not depleted at 24 h. Tissue staining showed no significant difference between 0-h and 24-h lungs.
  • In E. coli-exposed mice, neutrophils and macrophages in the airspaces stained strongly for EC-SOD at 24 h.
  • In transgenic mice making human EC-SOD in the lung, only mouse EC-SOD (not human EC-SOD) accumulated in lung fluid 14 days after asbestos or 3 days after bleomycin.
  • Twenty-four hours after bleomycin, EC-SOD knockout mice had significantly more neutrophils in lung fluid than wild-type mice. After heat-killed K. pneumoniae, knockout mice showed only a trend toward more neutrophils.
• The authors' conclusion: The authors concluded that inflammatory cells are a source of airspace EC-SOD during lung inflammatory responses. They also concluded that this antioxidant is regulated differently in interstitial lung disease than in bacterial pneumonia.
• Limitations the authors state:
  • The authors could not rule out the less likely possibility that only mouse EC-SOD, but not human EC-SOD, is redistributed to the airspace.
  • The authors could not rule out a role for macrophages as the source.
  • The authors stated it is not known whether the increased EC-SOD in lung fluid is a protective response.

Topics

Medical terms in this study, explained in our Lexicon: Superoxide, Interstitial Lung Disease, Interstitial, Inflammation, Parenchyma, Pulmonary Fibrosis.

Related studies

• Leukocyte-derived extracellular superoxide dismutase does not contribute to airspace EC-SOD after interstitial pulmonary injury — M.L. Manni, M.W. Epperly, et al. (2012)
• Extracellular superoxide dismutase inhibits inflammation by preventing oxidative fragmentation of hyaluronan — F. Gao, J.R. Koenitzer, et al. (2008)
• Increased sensitivity to asbestos-induced lung injury in mice lacking extracellular superoxide dismutase — C.L. Fattman, R.J. Tan, et al. (2006)
• Extracellular superoxide dismutase protects against matrix degradation of heparan sulfate in the lung — C.R. Kliment, J.M. Tobolewski, et al. (2008)
• Extracellular superoxide dismutase in pulmonary fibrosis — F. Gao, V.L. Kinnula, et al. (2008)
• Mitochondrial Cu,Zn-superoxide dismutase mediates pulmonary fibrosis by augmenting H2O2 generation — C. He, S. Murthy, et al. (2011)

Browse more research in American Journal of Respiratory Cell and Molecular Biology, or return to medical research.