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Infection and Immunity, October 2004, p. 6002-6011, Vol. 72, No. 10
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.10.6002-6011.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Enhanced Lung Injury and Delayed Clearance of Pneumocystis carinii in Surfactant Protein A-Deficient Mice: Attenuation of Cytokine Responses and Reactive Oxygen-Nitrogen Species

Elena N. Atochina,1 James M. Beck,2 Angela M. Preston,2 Angela Haczku,1 Yaniv Tomer,1 Seth T. Scanlon,1 Trevor Fusaro,3 John Casey,3 Samuel Hawgood,4 Andrew J. Gow,3 and Michael F. Beers1*

Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pennsylvania School of Medicine,1 Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania,3 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School and Veterans Affairs Medical Center, Ann Arbor, Michigan,2 Division of Neonatology, University of California at San Francisco, San Francisco, California4

Received 28 April 2004/ Returned for modification 2 June 2004/ Accepted 13 July 2004

Surfactant protein A (SP-A), a member of the collectin family, selectively binds to Pneumocystis carinii and mediates interactions between pathogen and host alveolar macrophages in vitro. To test the hypothesis that mice lacking SP-A have delayed clearance of Pneumocystis organisms and enhanced lung injury, wild-type C57BL/6 (WT) and SP-A-deficient mice (SP-A–/–) with or without selective CD4+-T-cell depletion were intratracheally inoculated with Pneumocystis organisms. Four weeks later, CD4-depleted SP-A-deficient mice had developed a more severe Pneumocystis infection than CD4-depleted WT (P. carinii pneumonia [PCP] scores of 3 versus 2, respectively). Whereas all non-CD4-depleted WT mice were free of PCP, intact SP-A–/– mice also had evidence of increased organism burden. Pneumocystis infection in SP-A-deficient mice was associated histologically with enhanced peribronchial and/or perivascular cellularity (score of 4 versus 2, SP-A–/– versus C57BL/6 mice, respectively) and a corresponding increase in bronchoalveolar lavage (BAL) cell counts. Increases in SP-D content, gamma interferon, interleukin-4, interleukin-5, and tumor necrosis factor alpha in BAL fluid occurred but were attenuated in PCP-infected SP-A–/– mice compared to WT mice. There were increases in total BAL NO levels in both infected groups, but nitrite levels were higher in SP-A–/– mice, indicating a reduction in production of higher oxides of nitrogen that was also reflected in lower levels of 3-nitrotyrosine staining in the SP-A–/– group. We conclude that despite increases in inflammatory cells, SP-A-deficient mice infected with P. carinii exhibit an enhanced susceptibility to the organism and attenuated production of proinflammatory cytokines and reactive oxygen-nitrogen species. These data support the concept that SP-A is a local effector molecule in the lung host defense against P. carinii in vivo.

* Corresponding author. Mailing address: Pulmonary and Critical Care Division, University of Pennsylvania School of Medicine, 807 BRB II/III Bldg., 421 Curie Blvd., Philadelphia, PA 19104. Phone: (215) 898-9106. Fax: (215) 573-4469. E-mail: mfbeers{at}mail.med.upenn.edu.

Editor: F. C. Fang

Infection and Immunity, October 2004, p. 6002-6011, Vol. 72, No. 10
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.10.6002-6011.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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