Description of Research: David M. Aronoff

MEDICAL RESEARCH: LUNG IMMUNOLOGY

Our laboratory is interested in the regulation of the innate immune system in the lung. A primary focus of our work involves the alveolar macrophage, which functions as a key sentinel of host defense against invading microorganisms. A fundamental question we are trying to answer is the importance of eicosanoids (lipid mediators derived from the cell membrane constituent arachidonic acid) in modulating alveolar macrophage antimicrobial functions. Specific areas of investigation include:

• Regulation of Alveolar Macrophage Phagocytosis and Bacterial Killing by Prostaglandin E2

Our work has shown that prostaglandin E2 (PGE2), an inflammatory mediator produced in aboundance at sites of inflammation/infection, suppresses the phagocytosis and killing of immunoglobulin G-opsonized bacteria by alveolar macrophages. These suppressive effects follow increases in intracellular cAMP provoked by PGE2. The mechanism(s) whereby cAMP elevation inhibits phagocytosis and bacterial killing are subjects of major interest.

• The Role of Prostaglandin E2 in Modulating Lung Innate Immunity During Acute Bacterial Pneumonia

Our in vitro work and studies of other investigators suggest that PGE2 might play an important role as an immunosuppressant in vivo that enhances susceptibility to bacterial pneumonia, particularly when its production is exaggerated. To address this question we are genetically or pharmacologically altering PGE2 production/signaling in mice and infecting their lower respiratory tracts with Streptococcus pneumoniae.

Recent Publications

Aronoff DM, Canetti C, Serezani CH, Luo M, and Peters-Golden M. Cutting Edge: Macrophage inhibition by cAMP: differential roles of protein kinase A and exchange protein directly activated by cAMP-1. J Immunol. 2005; 174 (2): 595-99.

White ES, Atrasz RG, Dickie EG, Aronoff DM, Stambolic V, Mak TW, Moore BB, Peters-Golden M. Prostaglandin E2 inhibits fibroblast migration by EP2 receptor-mediated increase in PTEN activity. Am J Respir Cell Mol Bio. 2005; 32 (2): 135-41.

Serezani CHC, Aronoff DM, Jancar S, Mancuso P, Peters-Golden M. Leukotrienes enhance the bactericidal activity of alveolar macrophages against Klebsiella pneumoniae through the activation of NADPH oxidase. Blood 106(3):1067-1075, 2005.

Romanovsky AA, Almeida MC, Aronoff DM, Ivanov AI, Konsman JP, Steiner AA, Turek VF. Fever and hypothermia in systemic inflammation: Recent discoveries and revisions. Front Biosci 10: 2193-2216, 2005.

Serezani CHC, Aronoff DM, Jancar S, Peters-Golden M. Leukotriene B-4 mediates p47phox phosphorylation and membrane translocation in polyunsaturated fatty acid-stimulated neutrophils. J Leukocyte Biol 78:976-984, 2005.

Luo M, Jones, SM, Flamand N, Aronoff DM, Peters-Golden M, Brock TG. Phosphorylation by protein kinase a inhibits nuclear import of 5-lipoxygenase. J Biol Chem 280: 40609-40616, 2005.

Canetti C, Aronoff DM, Choe M, Flamand N, Wettlaufer S, Toews GB, Chen GH, Peters-Golden M. Differential regulation by leukotrienes and calcium of Fc gamma receptor-induced phagocytosis and Syk activation in dendritic cells versus macrophages. J Leukocyte Biol 79 (6): 1234-1241, 2006.

Aronoff DM, Oates JA, Boutaud O. New insights into the mechanism of action of acetaminophen: Its clinical pharmacologic characteristics reflect its inhibition of the two prostaglandin H-2 synthases. Clin Pharmacol Ther 79: 9-19, 2006.

Young MH, Engleberg NC, Mulla ZD, Aronoff DM. Therapies for necrotising fasciitis. Expert Opin Biol Ther 6 (2): 155-165, 2006.

Aronoff DM, Mulla ZD. Nonsteroidal anti inflammatory drugs and group A streptococcal infection. Emerg Infect Dis 12 (8): 1291-1291, 2006.

Malani AN, Aronoff DM, Bradley SF, Kauffman CA. Cardiobacterium hominis endocarditis: two cases and a review of the literature. Eur J Clin Micorbiol Infect Dis 25 (9): 587-595, 2006.

Ballinger MN, Aronoff DM, McMillan TR, Cooke KR, Olkiewicz K, Toews GB, Peters-Golden M, Moore BB. Critical role of prostaglandin E-2 overproduction in impaired pulmonary host response following bone marrow transplantation. J Immunol 177 (8): 5499-5508, 2006.

Aronoff DM, Carstens JK, Chen GH, Toews GB, Peters-Golden M. Differences between macrophages and dendritic cells in the cyclic AMP-dependent regulation of lipopolysaccharide-induced cytokine and chemokine synthesis. J Interferon Cytokine Res 26 (11): 827-833, 2006.

Aronoff DM; Peres CM, Serezani CH, Ballinger MN, Carstens JK, Coleman N, Moore BB, Peebles RS, Faccioli LH, Peters-Golden M. Synthetic prostacyclin analogs differentially regulate macrophage function via distinct analog-receptor binding specificities. J Immunol 178 (3): 1628-1634, 2007.

Huang, S; Wettlaufer, SH; Hogaboam, C; Aronoff, DM; Peters-Golden, M. Prostaglandin E-2 inhibits collagen expression and proliferation in patient-derived normal lung fibroblasts via E prostanoid 2 receptor and cAMP signaling. Am J Physiol 292 (2): L405-L413, 2007.

Aronoff, DM. Losing by a nose: Diagnostic and therapeutic challenges of the trigeminal trophic syndrome. South Med J 100 (1): 3, 2007.

Hsu A, Aronoff DM, Phipps J, Goel D, Mancuso P. Leptin improves pulmonary bacterial clearance and survival in ob ob mice during pneumococcal pneumonia. Clin Exper Immunol 150 (2): 332-339, 2007

Mulla ZD, Gibbs SG, Aronoff DM. Correlates of length of stay, cost of care, and mortality among patients hospitalized for necrotizing fasciitis. Epidemiol Infect 135 (5): 868-876, 2007.

Peres CM, Aronoff DM, Serezani CH, Flamand N, Faccioli LH, Peters-Golden M. Specific leukotriene receptors couple to distinct G proteins to effect stimulation of alveolar macrophage host defense functions. J Immunol 179 (8): 5454-5461, 2007.

Aronoff DM, Mulla ZD. Comments regarding "pain and a purple lesion". Am J Med 120 (11): E15-E15, 2007.

Frantz FG, Rosada RS, Turato WM, Peres CM, Coelho-Castelo AAM, Ramos SG, Aronoff DM, Silva CL, Faccioli LH. The immune response to toxocariasis does not modify susceptibility to Mycobacterium tuberculosis infection in BALB/c mice. Am J Trop Med Hyg 77 (4): 691-698, 2007.

Serezani CH, Chung JH, Ballinger MN, Moore BB, Aronoff DM, Peters-Golden M. Prostaglandin E-2 suppresses bacterial killing in alveolar macrophages by inhibiting NADPH oxidase. Am J Respir Cell Molec Biol 37 (5): 562-570, 2007.

Canetti C, Serezani CH, Atrasz RG, White ES, Aronoff DM, Peters-Golden M. Activation of phosphatase and tensin homolog on chromosome 10 mediates the inhibition of Fc gamma R phagocytosis by prostaglandin E-2 in alveolar macrophages. J Immunol 179 (12): 8350-8356, 2007.

Brock TG, Serezani CH, Carstens JK, Peters-Golden M, Aronoff DM. Effects of prostaglandin E-2 on the subcellular localization of Epac-1 and Rap1 proteins during Fc gamma-receptor-mediated phagocytosis in alveolar macrophages. Experiment Cell Res 314 (2): 255-263, 2008.