Abstract |
Innate immunity plays an important role in pulmonary host defense against Pneumocystis carinii, an important pathogen in individuals with impaired cell-mediated immunity. We investigated the role of GM-CSF in host defense in a model of P. carinii pneumonia induced by intratracheal inoculation of CD4-depleted mice. Lung GM-CSF levels increased progressively during the infection and were significantly greater than those in uninfected controls 3, 4, and 5 wk after inoculation. When GM-CSF gene-targeted mice (GM-/-) depleted of CD4+ cells were inoculated with P. carinii, the intensities of infection and inflammation were increased significantly compared with those in CD4-depleted wild-type mice. In contrast, transgenic expression of GM-CSF directed solely in the lungs of GM-/- mice (using the surfactant protein C promoter) dramatically decreased the intensity of infection and inflammation 4 wk after inoculation. The concentrations of surfactant proteins A and D were greater in both uninfected and infected GM-/- mice compared with those in wild-type controls, suggesting that this component of the innate response was preserved in the GM-/- mice. However, alveolar macrophages (AM) from GM-/- mice demonstrated impaired phagocytosis of purified murine P. carinii organisms in vitro compared with AM from wild-type mice. Similarly, AM production of TNF-alpha in response to P. carinii in vitro was totally absent in AM from GM-/- mice, while GM-CSF-replete mice produced abundant TNF in this setting. Thus, GM-CSF plays a critical role in the inflammatory response to P. carinii in the setting of impaired cell-mediated immunity through effects on AM activation.
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Authors | R Paine 3rd, A M Preston, S Wilcoxen, H Jin, B B Siu, S B Morris, J A Reed, G Ross, J A Whitsett, J M Beck |
Journal | Journal of immunology (Baltimore, Md. : 1950)
(J Immunol)
Vol. 164
Issue 5
Pg. 2602-9
(Mar 01 2000)
ISSN: 0022-1767 [Print] United States |
PMID | 10679099
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Proteolipids
- Pulmonary Surfactants
- Tumor Necrosis Factor-alpha
- Granulocyte-Macrophage Colony-Stimulating Factor
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Topics |
- Animals
- Cells, Cultured
- Genetic Predisposition to Disease
- Granulocyte-Macrophage Colony-Stimulating Factor
(biosynthesis, deficiency, genetics, physiology)
- Immunity, Innate
(genetics)
- Lung
(immunology, metabolism, microbiology, pathology)
- Macrophages, Alveolar
(immunology, metabolism, microbiology)
- Mice
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Mice, Nude
- Mice, Transgenic
- Phagocytosis
(genetics, immunology)
- Pneumocystis
(immunology)
- Pneumonia, Pneumocystis
(genetics, immunology, metabolism, pathology)
- Proteolipids
(genetics)
- Pulmonary Surfactants
(genetics, metabolism)
- Tumor Necrosis Factor-alpha
(metabolism)
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