title: Increased lethality and defective pulmonary clearance of Streptococcus pneumoniae in microsomal prostaglandin E synthase-1-knockout mice.
abstract: The production of prostaglandin E2 (PGE2) increases dramatically during pneumococcal pneumonia, and this lipid mediator impairs alveolar macrophage (AM)-mediated innate immune responses. Microsomal prostaglandin E synthase-1 (mPGES-1) is a key enzyme involved in the synthesis of PGE2, and its expression is enhanced during bacterial infections. Genetic deletion of mPGES-1 in mice results in diminished PGE2 production and elevated levels of other prostaglandins after infection. Since PGE2 plays an important immunoregulatory role during bacterial pneumonia we assessed the impact of mPGES-1 deletion in the host defense against pneumococcal pneumonia in vivo and in AMs in vitro. Wild-type (WT) and mPGES-1 knockout (KO) mice were challenged with Streptococcus pneumoniae via the intratracheal route. Compared with WT animals, we observed reduced survival and increased lung and spleen bacterial burdens in mPGES-1 KO mice 24 and 48 h after S. pneumoniae infection. While we found modest differences between WT and mPGES-1 KO mice in pulmonary cytokines, AMs from mPGES-1 KO mice exhibited defective killing of ingested bacteria in vitro that was associated with diminished inducible nitric oxide synthase expression and reduced nitric oxide (NO) synthesis. Treatment of AMs from mPGES-1 KO mice with an NO donor restored bacterial killing in vitro. These results suggest that mPGES-1 plays a critical role in bacterial pneumonia and that genetic ablation of this enzyme results in diminished pulmonary host defense in vivo and in vitro. These results suggest that specific inhibition of PGE2 synthesis by targeting mPGES-1 may weaken host defense against bacterial infections.
authors.affiliation: Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Michigan;
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Dolan
authors.affiliation: Department of Pediatrics and Communicable Disease and Microbiology and Immunology, School of Medicine, University of Michigan, Ann Arbor, Michigan;
authors.forename: Jason B
authors.initials: JB
authors.lastname: Weinberg
authors.affiliation: Department of Environmental Health Sciences, School of Public Health, University of Michigan, Ann Arbor, Michigan;
authors.forename: Edmund
authors.initials: E
authors.lastname: O'Brien
authors.affiliation: Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Michigan;
authors.forename: Anya
authors.initials: A
authors.lastname: Abashian
authors.affiliation: Department of Pediatrics and Communicable Disease and Microbiology and Immunology, School of Medicine, University of Michigan, Ann Arbor, Michigan;
authors.forename: Megan C
authors.initials: MC
authors.lastname: Procario
authors.affiliation: Division of Infectious Diseases, Vanderbilt University School of Medicine, Nashville, Tennessee;
authors.forename: David M
authors.initials: DM
authors.lastname: Aronoff
authors.affiliation: Division of Rheumatology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee;
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Crofford
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, School of Medicine, University of Michigan, Ann Arbor, Michigan; Graduate Program in Immunology, University of Michigan, Ann Arbor, Michigan; and.
authors.forename: Marc
authors.initials: M
authors.lastname: Peters-Golden
authors.affiliation: Department of Environmental Health Sciences, School of Public Health, University of Michigan, Ann Arbor, Michigan;
authors.forename: Lindsay
authors.initials: L
authors.lastname: Ward
authors.affiliation: Graduate Program in Immunology, University of Michigan, Ann Arbor, Michigan; and Department of Nutritional Sciences, School of Public Health, University of Michigan, Ann Arbor, Michigan pmancuso@umich.edu.
authors.forename: Peter
authors.identifier: 0000-0002-2559-7320
authors.initials: P
authors.lastname: Mancuso
mesh_terms: D000818:Animals; D051545:Cyclooxygenase 1 / Q000235:genetics*; D016207:Cytokines / Q000096:biosynthesis / Q000097:blood; D015232:Dinoprostone / Q000096:biosynthesis; D005260:Female; D007113:Immunity, Innate; D008168:Lung / Q000201:enzymology / Q000276:immunology / Q000382:microbiology; D016676:Macrophages, Alveolar / Q000201:enzymology / Q000276:immunology; D008565:Membrane Proteins / Q000235:genetics*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008861:Microsomes / Q000201:enzymology; D009569:Nitric Oxide / Q000096:biosynthesis; D011018:Pneumonia, Pneumococcal / Q000201:enzymology* / Q000276:immunology; D013296:Streptococcus pneumoniae / Q000276:immunology*
chemical_list: D016207:Cytokines; D008565:Membrane Proteins; D009569:Nitric Oxide; D051545:Cyclooxygenase 1; C496512:Ptgs1 protein, mouse; D015232:Dinoprostone
keywords: Streptococcus pneumoniae; bacterial pneumonia; host defense; lung; microsomal prostaglandin E synthase; prostaglandins