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* Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine,
Graduate Program in Immunology,
Division of Infectious Diseases, and
Bone and Marrow Transplantation Program, University of Michigan, Ann Arbor, MI 48109
The success of bone marrow transplantation (BMT) as a therapy for malignant and inherited disorders is limited by infectious complications. We previously demonstrated syngeneic BMT mice are more susceptible to Pseudomonas aeruginosa pneumonia due to defects in the ability of donor-derived alveolar macrophages (AMs), but not polymorphonuclear leukocytes (PMNs), to phagocytose bacteria. We now demonstrate that both donor-derived AMs and PMNs display bacterial killing defects post-BMT. PGE2 is a lipid mediator with potent immunosuppressive effects against antimicrobial functions. We hypothesize that enhanced PGE2 production post-BMT impairs host defense. We demonstrate that lung homogenates from BMT mice contain 2.8-fold more PGE2 than control mice, and alveolar epithelial cells (2.7-fold), AMs (125-fold), and PMNs (10-fold) from BMT animals all overproduce PGE2. AMs also produce increased prostacyclin (PGI2) post-BMT. Interestingly, the E prostanoid (EP) receptors EP2 and EP4 are elevated on donor-derived phagocytes post-BMT. Blocking PGE2 synthesis with indomethacin overcame the phagocytic and killing defects of BMT AMs and the killing defects of BMT PMNs in vitro. The effect of indomethacin on AM phagocytosis could be mimicked by an EP2 antagonist, AH-6809, and exogenous addition of PGE2 reversed the beneficial effects of indomethacin in vitro. Importantly, in vivo treatment with indomethacin reduced PGE2 levels in lung homogenates and restored in vivo bacterial clearance from the lung and blood in BMT mice. Genetic reduction of cyclooxygenase-2 in BMT mice also had similar effects. These data clearly demonstrate that overproduction of PGE2 post-BMT is a critical factor determining impaired host defense against pathogens.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants HL071586 (to B.B.M.), P50HL56402 (to B.B.M., G.B.T., and M.P.-G.), HL078727 (to D.M.A.), and RG8909N (to D.M.A.), and a Career Investigator Award (to B.B.M.) from the American Lung Association of Michigan.
2 Address correspondence and reprint requests to Dr. Bethany B. Moore, Internal Medicine/Pulmonary and Critical Care Medicine, 4062 Biomedical Science Research Building, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200. E-mail address: Bmoore{at}umich.edu
3 Abbreviations used in this paper: BMT, bone marrow transplantation; BM, bone marrow; AM, alveolar macrophage; PMN, polymorphonuclear leukocyte; AA, arachidonic acid; COX, cyclooxygenase; 5-LO, 5-lipoxygenase; FLAP, 5-LO activating protein; LT, leukotriene; EP, E prostanoid; BALF, bronchoalveolar lavage fluid; PLF, peritoneal lavage fluid; AEC, alveolar epithelial cell; EIA, enzyme immunoassay; WT, wild type; i.t., intratracheal.
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