Female resistance to pneumonia identifies lung macrophage nitric oxide Synthase-3 as a therapeutic target
- Harvard School of Public Health, United States
- US Environmental Protection Agency, United States
- Beth Israel Deaconness Medical Center, United States
- Erasmus University Medical Center, Netherlands
- Sanofi Research and Development, Germany
- Aarhus University Hospital, Denmark
- Jagiellonian University Medical College, Poland
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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Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (Harvard Medical Area IACUC) protocol (#03287).
Human subjects: We studied incidence of hospitalized pneumonia associated with use of estrogen and statins in a population-based case-control study based on medical databases in Denmark. Cases of pneumonia were identified as all women who received a first-time principal hospital diagnosis of pneumonia in the former North Jutland and Aarhus Counties, Northern Denmark (1.2 million inhabitants) between 1997 and 2012. Using the Danish Civil Registration System, each case subject was matched with five population control subjects with same age, female gender, and residence in Northern Denmark on the pneumonia index date. The study was approved by the Danish Data Protection Agency (record number: 2013-41-1924). Danish registry data are generally available for research purposes, and, according to Danish law, use of the data does not require informed consent.
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© 2014, Yang et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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