title: Enhanced lung injury and delayed clearance of Pneumocystis carinii in surfactant protein A-deficient mice: attenuation of cytokine responses and reactive oxygen-nitrogen species.
abstract: 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.
authors.affiliation: Pulmonary and Critical Care Division, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Elena N
authors.initials: EN
authors.lastname: Atochina
authors.forename: James M
authors.initials: JM
authors.lastname: Beck
authors.forename: Angela M
authors.initials: AM
authors.lastname: Preston
authors.forename: Angela
authors.initials: A
authors.lastname: Haczku
authors.forename: Yaniv
authors.initials: Y
authors.lastname: Tomer
authors.forename: Seth T
authors.initials: ST
authors.lastname: Scanlon
authors.forename: Trevor
authors.initials: T
authors.lastname: Fusaro
authors.forename: John
authors.initials: J
authors.lastname: Casey
authors.forename: Samuel
authors.initials: S
authors.lastname: Hawgood
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Gow
authors.forename: Michael F
authors.initials: MF
authors.lastname: Beers
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D016207:Cytokines / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D008168:Lung / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism; D016720:Pneumocystis Infections / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D045363:Pneumocystis carinii / Q000502:physiology*; D037662:Pulmonary Surfactant-Associated Protein A / Q000172:deficiency* / Q000235:genetics; D037663:Pulmonary Surfactant-Associated Protein D / Q000378:metabolism; D026361:Reactive Nitrogen Species / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D016207:Cytokines; D037662:Pulmonary Surfactant-Associated Protein A; D037663:Pulmonary Surfactant-Associated Protein D; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine