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This Article Full Text Full Text (PDF) All Versions of this Article: 295/1/L114    most recent 00309.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Ballinger, M. N. Articles by Moore, B. B. Search for Related Content PubMed PubMed Citation Articles by Ballinger, M. N. Articles by Moore, B. B.

Paradoxical role of alveolar macrophage-derived granulocyte-macrophage colony-stimulating factor in pulmonary host defense post-bone marrow transplantation

¹The Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, ²The Graduate Program in Immunology, and ³The Department of Veterans Affairs Medical Center, University of Michigan, Ann Arbor, Michigan

Submitted 2 August 2007 ; accepted in final form 26 April 2008

Impaired host defense post-bone marrow transplant (BMT) is related to overproduction of prostaglandin E₂ (PGE₂) by alveolar macrophages (AMs). We show AMs post-BMT overproduce granulocyte-macrophage colony-stimulating factor (GM-CSF), whereas GM-CSF in lung homogenates is impaired both at baseline and in response to infection post-BMT. Homeostatic regulation of GM-CSF may occur by hematopoietic/structural cell cross talk. To determine whether AM overproduction of GM-CSF influenced immunosuppression post-BMT, we compared mice that received BMT from wild-type donors (control BMT) or mice that received BMT from GM-CSF–/– donors (GM-CSF–/– BMT) with untransplanted mice. GM-CSF–/– BMT mice were less susceptible to pneumonia with Pseudomonas aeruginosa compared with control BMT mice and showed antibacterial responses equal to or better than untransplanted mice. GM-CSF–/– BMT AMs displayed normal phagocytosis and a trend toward enhanced bacterial killing. Surprisingly, AMs from GM-CSF–/– BMT mice overproduced PGE₂, but expression of the inhibitory EP₂ receptor was diminished. As a consequence of decreased EP₂ receptor expression, we found diminished accumulation of cAMP in response to PGE₂ stimulation in GM-CSF–/– BMT AMs compared with control BMT AMs. In addition, GM-CSF–/– BMT AMs retained cysteinyl leukotriene production and normal TNF- response compared with AMs from control BMT mice. GM-CSF–/– BMT neutrophils also showed improved bacterial killing. Although genetic ablation of GM-CSF in hematopoietic cells post-BMT improved host defense, transplantation of wild-type bone marrow into GM-CSF–/– recipients demonstrated that parenchymal cell-derived GM-CSF is necessary for effective innate immune responses post-BMT. These results highlight the complex regulation of GM-CSF and innate immunity post-BMT.

lung; Pseudomonas aeruginosa; eicosanoid; neutrophil