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Role of Granulocyte Macrophage Colony-Stimulating Factor during Gram-Negative Lung Infection with Pseudomonas aeruginosa

Immunology Graduate Program, Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine and Division of Infectious Diseases, University of Michigan; the Department of Veterans Affairs Medical Center, Ann Arbor, Michigan; and the Department of Immunology, Institute of Biomedical Science IV, University of São Paulo, São Paulo, Brazil

Correspondence and requests for reprints should be addressed to Bethany B. Moore, Ph.D., The University of Michigan, Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, 6301 MSRB III, 1150 W. Medical Center Dr., Ann Arbor, MI 48109-0642. E-mail: Bmoore{at}umich.edu

Granulocyte macrophage colony-stimulating factor (GM-CSF) stimulates survival, proliferation, differentiation, and function of myeloid cells. Recently, GM-CSF has been shown to be important for normal pulmonary homeostasis. We report that GM-CSF is induced in lung leukocytes during infection with Gram-negative bacteria. Therefore, we postulated that deficiencies in GM-CSF would increase susceptibility to Gram-negative infection in vivo. After an intratracheal inoculum with Pseudomonas aeruginosa, GM-CSF–/– mice show decreased survival compared with wild-type mice. GM-CSF–/– mice show increased lung, spleen, and blood bacterial CFU. GM-CSF–/– mice are defective in the production of cysteinyl leukotrienes, prostaglandin E₂, macrophage inflammatory protein, and keratinocyte-derived chemokine in lung leukocytes postinfection. Despite these defects, inflammatory cell recruitment is not diminished at 6 or 24 h postinfection, and the functional activity of polymorphonuclear leukocytes from the lung and peritoneum against P. aeruginosa is enhanced in GM-CSF–/– mice. In contrast, alveolar macrophage (AM) phagocytosis, killing, and H₂O₂ production are defective in GM-CSF–/– mice. Although the absence of GM-CSF has profound effects on AMs, peritoneal macrophages seem to have normal bactericidal activities in GM-CSF–/– mice. Defects in AM function may be related to diminished levels of IFN- and TNF- postinfection. Thus, GM-CSF–/– mice are more susceptible to lung infection with P. aeruginosa as a result of impaired AM function.

Key Words: innate immunity • macrophage • neutrophil • bacterial infection

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