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Infection and Immunity, March 2009, p. 1053-1060, Vol. 77, No. 3
0019-9567/09/$08.00+0 doi:10.1128/IAI.00967-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Critical Roles of Inflammation and Apoptosis in Improved Survival in a Model of Hyperoxia-Induced Acute Lung Injury in Pneumocystis murina-Infected Mice
James M. Beck,1,2*
Angela M. Preston,1
Steven E. Wilcoxen,1
Susan B. Morris,1
Anne Sturrock,3 and
Robert Paine III1,2,3
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School,1 Department of Veterans Affairs Medical Center, Ann Arbor, Michigan 48105,2 Division of Respiratory, Critical Care and Occupational Pulmonary Medicine, University of Utah School of Medicine, and Department of Veterans Affairs Medical Center, Salt Lake City, Utah 841323
Received 1 August 2008/ Returned for modification 11 September 2008/ Accepted 20 December 2008
Pneumocystis infections increase host susceptibility to additional insults that would be tolerated in the absence of infection, such as hyperoxia. In an in vivo model using CD4-depleted mice, we previously demonstrated that Pneumocystis murina pneumonia causes significant mortality following an otherwise nonlethal hyperoxic insult. Infected mice demonstrated increased pulmonary inflammation and alveolar epithelial cell apoptosis compared to controls. To test the mechanisms underlying these observations, we examined expression of components of the Fas-Fas ligand pathway in P. murina-infected mice exposed to hyperoxia. Hyperoxia alone increased expression of Fas on the surface of type II alveolar epithelial cells; conversely, infection with P. murina led to increased lung expression of Fas ligand. We hypothesized that inhibition of inflammatory responses or direct inhibition of alveolar epithelial cell apoptosis would improve survival in P. murina-infected mice exposed to hyperoxia. Mice were depleted of CD4+ T cells and infected with P. murina and then were exposed to >95% oxygen for 4 days, followed by return to normoxia. Experimental groups received vehicle, dexamethasone, or granulocyte-macrophage colony-stimulating factor (GM-CSF). Compared with the vehicle-treated group, treatment with dexamethasone reduced Fas ligand expression and significantly improved survival. Similarly, treatment with GM-CSF, an agent we have shown protects alveolar epithelial cells against apoptosis, decreased Fas ligand expression and also improved survival. Our results suggest that the dual stresses of P. murina infection and hyperoxia induce lung injury via activation of the Fas-Fas ligand pathway and that corticosteroids and GM-CSF reduce mortality in P. murina-infected mice exposed to hyperoxic stress by inhibition of inflammation and apoptosis.
* Corresponding author. Mailing address: Pulmonary Medicine (111G), Department of Veterans Affairs Medical Center, 2215 Fuller Road, Ann Arbor, MI 48105. Phone: (734) 845-3457. Fax: (734) 845-3257. E-mail: jamebeck{at}umich.edu
Published ahead of print on 5 January 2009.
Infection and Immunity, March 2009, p. 1053-1060, Vol. 77, No. 3
0019-9567/09/$08.00+0 doi:10.1128/IAI.00967-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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