Article ; Online: Female resistance to pneumonia identifies lung macrophage nitric oxide synthase-3 as a therapeutic target.
2014 Volume 3
Abstract: ... for estrogen-mediated activation of lung macrophage nitric oxide synthase-3 (NOS3). Epidemiologic data show ... lung inflammation, and better survival. In vitro, lung macrophages from female mice and humans show ... the natural experiment of gender differences in resistance to infections. Female and estrogen-treated male ...
| 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. |
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| MeSH term(s) | Adolescent ; Adult ; Aged ; Aged, 80 and over ; Animals ; Benzodioxoles/pharmacology ; Benzodioxoles/therapeutic use ; Case-Control Studies ; Estrogens/pharmacology ; Female ; Hospitalization ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use ; Immunity, Innate/drug effects ; Indans/pharmacology ; Indans/therapeutic use ; Macrophage Activation/drug effects ; Macrophages, Alveolar/drug effects ; Macrophages, Alveolar/enzymology ; Male ; Mice, Inbred C57BL ; Microbial Viability/drug effects ; Middle Aged ; Molecular Targeted Therapy ; Nitric Oxide Synthase Type III/metabolism ; Odds Ratio ; Phagocytosis/drug effects ; Pneumonia, Pneumococcal/enzymology ; Pneumonia, Pneumococcal/immunology ; Pneumonia, Pneumococcal/pathology ; Pneumonia, Pneumococcal/therapy ; Young Adult |
| Chemical Substances | 2,2-difluorobenzo(1,3)dioxole-5-carboxylic acid indan-2-ylamide ; Benzodioxoles ; Estrogens ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; Indans ; Nitric Oxide Synthase Type III (EC 1.14.13.39) |
| Language | English |
| Publishing date | 2014-10-15 |
| Publishing country | England |
| Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 2687154-3 |
| ISSN | 2050-084X ; 2050-084X |
| ISSN (online) | 2050-084X |
| ISSN | 2050-084X |
| DOI | 10.7554/eLife.03711 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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