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,
* Division of Infectious Diseases and
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health Systems, Ann Arbor, MI 48109;
Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil; and
Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University, Nashville, TN 37232
PGI2 (prostacyclin) is a lipid mediator with vasodilatory and antithrombotic effects used in the treatment of vasoconstrictive/ischemic diseases including pulmonary artery hypertension. However, emerging research supports a role for PGs, including PGI2, in the regulation of both innate and acquired immunity. As PGI2 is unstable, we sought to define the effects of various PGI2 analogs on resident alveolar macrophage (AM) and peritoneal macrophage (PM) innate immune functions. The effects of iloprost, carbaprostacyclin, and treprostinil on the regulation of phagocytosis, bacterial killing, and inflammatory mediator production were determined in both macrophage populations from rats. Iloprost failed to suppress AM functions to the same degree that it did in PMs, a characteristic shared by carbaprostacyclin. This difference reflected greater expression of the G
s protein-coupled I prostanoid receptor and greater cAMP generation in PMs than AMs. Treprostinil inhibited phagocytosis, bacterial killing, and cytokine generation in AMs to a much greater degree than the other PGI2 analogs and more closely resembled the effects of PGE2. Studies with the E prostanoid (EP) 2 receptor antagonist AH-6809 and EP2-null macrophages indicated that this was due in part to the previously unknown ability of treprostinil to stimulate the EP2 receptor. The present investigation for the first time identifies differences in immunoregulatory properties of clinically administered PGI2 analogs. These studies are the first to explore the capacity of PGI2 to regulate bacterial killing and phagocytosis in macrophages, and our findings may hold important consequences regarding the risk of infection for patients receiving such agents.
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 the National Institutes of Health Grants AI054660, HL069949, HL078727, HL071586, and HL058897; the American Lung Association Grant RG-8909-N; and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Capes-Brazil).
2 D.M.A. and C.M.P. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. David M. Aronoff, University of Michigan Health System, 5220-D Medical Sciences Research Building III, 1150 West Medical Center Drive, Ann Arbor, MI 48109-0640. E-mail address: daronoff{at}umich.edu
4 Abbreviations used in this paper: IP, G protein-coupled I prostanoid receptor; AM, alveolar macrophage; EP, G protein-coupled E prostanoid receptor; IBMX, 3-isobu-tyl-1-methylxantine; KO, knockout; PAH, pulmonary arterial hypertension; PGI2, prostacyclin/epoprostenol; PPAR
, peroxisome proliferator-activated receptor .
This article has been cited by other articles:
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  C. H. Serezani, J. Chung, M. N. Ballinger, B. B. Moore, D. M. Aronoff, and M. Peters-Golden Prostaglandin E2 Suppresses Bacterial Killing in Alveolar Macrophages by Inhibiting NADPH Oxidase Am. J. Respir. Cell Mol. Biol., November 1, 2007; 37(5): 562 - 570. [Abstract] [Full Text] [PDF]
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