Female resistance to pneumonia identifies lung macrophage nitric oxide synthase-3 as a therapeutic target
Zhiping Yang,
Yuh-Chin T Huang,
Henry Koziel,
Rini de Crom,
Hartmut Ruetten,
Paulus Wohlfart,
Reimar W Thomsen,
Johnny A Kahlert,
Henrik Toft Sørensen,
Szczepan Jozefowski,
Amy Colby,
Lester Kobzik
Affiliations
Zhiping Yang
Department of Environmental Health, Harvard School of Public Health, Boston, United States
Yuh-Chin T Huang
Human Studies Division, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Chapel Hill, United States
Henry Koziel
Division of Pulmonary, Critical Care and Sleep Medicine, Beth Israel Deaconness Medical Center, Boston, United States
Rini de Crom
Department of Cell Biology and Genetics, Erasmus University Medical Center, Rotterdam, Netherlands
Hartmut Ruetten
Diabetes Division, Sanofi Research and Development, Frankfurt, Germany
Paulus Wohlfart
Diabetes Division, Sanofi Research and Development, Frankfurt, Germany
Reimar W Thomsen
Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark
Johnny A Kahlert
Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark
Henrik Toft Sørensen
Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark
Szczepan Jozefowski
Department of Immunology, Jagiellonian University Medical College, Kraków, Poland
Amy Colby
Department of Environmental Health, Harvard School of Public Health, Boston, United States
Lester Kobzik
Department of Environmental Health, Harvard School of Public Health, Boston, United States; Department of Pathology, Brigham and Women's Hospital, Boston, United States
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.
