title: Female resistance to pneumonia identifies lung macrophage nitric oxide synthase-3 as a therapeutic target.
abstract: To identify new approaches to enhance innate immunity to bacterial pneumonia, we investigated the natural experiment of gender differences in resistance to infections. Female and estrogen-treated male mice show greater resistance to pneumococcal pneumonia, seen as greater bacterial clearance, diminished lung inflammation, and better survival. In vitro, lung macrophages from female mice and humans show better killing of ingested bacteria. Inhibitors and genetically altered mice identify a critical role for estrogen-mediated activation of lung macrophage nitric oxide synthase-3 (NOS3). Epidemiologic data show decreased hospitalization for pneumonia in women receiving estrogen or statins (known to activate NOS3). Pharmacologic targeting of NOS3 with statins or another small-molecule compound (AVE3085) enhanced macrophage bacterial killing, improved bacterial clearance, and increased host survival in both primary and secondary (post-influenza) pneumonia. The data identify a novel mechanism for host defense via NOS3 and suggest a potential therapeutic strategy to reduce secondary bacterial pneumonia after influenza.
authors.affiliation: Department of Environmental Health, Harvard School of Public Health, Boston, United States.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Human Studies Division, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Chapel Hill, United States.
authors.forename: Yuh-Chin T
authors.initials: YC
authors.lastname: Huang
authors.affiliation: Division of Pulmonary, Critical Care and Sleep Medicine, Beth Israel Deaconness Medical Center, Boston, United States.
authors.forename: Henry
authors.initials: H
authors.lastname: Koziel
authors.affiliation: Department of Cell Biology and Genetics, Erasmus University Medical Center, Rotterdam, Netherlands.
authors.forename: Rini
authors.initials: R
authors.lastname: de Crom
authors.affiliation: Diabetes Division, Sanofi Research and Development, Frankfurt, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Ruetten
authors.affiliation: Diabetes Division, Sanofi Research and Development, Frankfurt, Germany.
authors.forename: Paulus
authors.initials: P
authors.lastname: Wohlfart
authors.affiliation: Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Reimar W
authors.initials: RW
authors.lastname: Thomsen
authors.affiliation: Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Johnny A
authors.initials: JA
authors.lastname: Kahlert
authors.affiliation: Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Henrik Toft
authors.initials: HT
authors.lastname: Sørensen
authors.affiliation: Department of Immunology, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Szczepan
authors.initials: S
authors.lastname: Jozefowski
authors.affiliation: Department of Environmental Health, Harvard School of Public Health, Boston, United States.
authors.forename: Amy
authors.initials: A
authors.lastname: Colby
authors.affiliation: Department of Environmental Health, Harvard School of Public Health, Boston, United States.
authors.forename: Lester
authors.initials: L
authors.lastname: Kobzik
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D052117:Benzodioxoles / Q000494:pharmacology / Q000627:therapeutic use; D016022:Case-Control Studies; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D006760:Hospitalization; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D007113:Immunity, Innate / Q000187:drug effects; D007189:Indans / Q000494:pharmacology / Q000627:therapeutic use; D008262:Macrophage Activation / Q000187:drug effects; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008810:Mice, Inbred C57BL; D050296:Microbial Viability / Q000187:drug effects; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D016017:Odds Ratio; D010587:Phagocytosis / Q000187:drug effects; D011018:Pneumonia, Pneumococcal / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D055815:Young Adult
chemical_list: C528910:2,2-difluorobenzo(1,3)dioxole-5-carboxylic acid indan-2-ylamide; D052117:Benzodioxoles; D004967:Estrogens; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007189:Indans; D052250:Nitric Oxide Synthase Type III
keywords: bacteria; gender; human; human biology; immunology; innate immunity; macrophages; medicine; mouse; nitric oxide; pneumonia