1. Human Biology and Medicine
  2. Immunology and Inflammation
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Female resistance to pneumonia identifies lung macrophage nitric oxide Synthase-3 as a therapeutic target

  1. Zhiping Yang
  2. Yuh-Chin T Huang
  3. Henry Koziel
  4. Rini de Crom
  5. Hartmut Ruetten
  6. Paulus Wohlfart
  7. Reimar W Thomsen
  8. Johnny Kahlert
  9. Henrik Toft Sørensen
  10. Szczepan Jozefowski
  11. Amy Colby
  12. Lester Kobzik  Is a corresponding author
  1. Harvard School of Public Health, United States
  2. US Environmental Protection Agency, United States
  3. Beth Israel Deaconness Medical Center, United States
  4. Erasmus University Medical Center, Netherlands
  5. Sanofi Research and Development, Germany
  6. Aarhus University Hospital, Denmark
  7. Jagiellonian University Medical College, Poland
Research Article
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Cite this article as: eLife 2014;3:e03711 doi: 10.7554/eLife.03711

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.

Article and author information

Author details

  1. Zhiping Yang

    Harvard School of Public Health, Boston, United States
    Competing interests
    No competing interests declared.
  2. Yuh-Chin T Huang

    US Environmental Protection Agency, Chapel Hill, United States
    Competing interests
    No competing interests declared.
  3. Henry Koziel

    Beth Israel Deaconness Medical Center, Boston, United States
    Competing interests
    No competing interests declared.
  4. Rini de Crom

    Erasmus University Medical Center, Rotterdam, Netherlands
    Competing interests
    No competing interests declared.
  5. Hartmut Ruetten

    Sanofi Research and Development, Frankfurt, Germany
    Competing interests
    Hartmut Ruetten, Named as inventor on patents (US 7,179,839; 8,309,608, held by Sanofi, Inc.) describing AVE3085 as a useful compound for cardiovascular indications.
  6. Paulus Wohlfart

    Sanofi Research and Development, Frankfurt, Germany
    Competing interests
    Paulus Wohlfart, Named as inventor on patents (US 7,179,839; 8,309,608, held by Sanofi, Inc.) describing AVE3085 as a useful compound for cardiovascular indications.
  7. Reimar W Thomsen

    Aarhus University Hospital, Aarhus, Denmark
    Competing interests
    No competing interests declared.
  8. Johnny Kahlert

    Aarhus University Hospital, Aarhus, Denmark
    Competing interests
    No competing interests declared.
  9. Henrik Toft Sørensen

    Aarhus University Hospital, Aarhus, Denmark
    Competing interests
    No competing interests declared.
  10. Szczepan Jozefowski

    Jagiellonian University Medical College, Kraków, Poland
    Competing interests
    No competing interests declared.
  11. Amy Colby

    Harvard School of Public Health, Boston, United States
    Competing interests
    No competing interests declared.
  12. Lester Kobzik

    Harvard School of Public Health, Boston, United States
    For correspondence
    lkobzik@hsph.harvard.edu
    Competing interests
    No competing interests declared.

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.

Reviewing Editor

  1. Nicholas J White, Mahidol University, Thailand

Publication history

  1. Received: June 17, 2014
  2. Accepted: October 12, 2014
  3. Accepted Manuscript published: October 15, 2014 (version 1)
  4. Version of Record published: November 3, 2014 (version 2)

Copyright

© 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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