Female resistance to pneumonia identifies lung macrophage nitric oxide synthase-3 as a therapeutic target

View/ Open
Author
Yang, Zhiping
Huang, Yuh-Chin T
Koziel, Henry
de Crom, Rini
Ruetten, Hartmut
Wohlfart, Paulus
Thomsen, Reimar W
Kahlert, Johnny A
Sørensen, Henrik Toft
Jozefowski, Szczepan
Colby, Amy
Note: Order does not necessarily reflect citation order of authors.
Published Version
https://doi.org/10.7554/eLife.03711Metadata
Show full item recordCitation
Yang, Z., Y. T. Huang, H. Koziel, R. de Crom, H. Ruetten, P. Wohlfart, R. W. Thomsen, et al. 2014. “Female resistance to pneumonia identifies lung macrophage nitric oxide synthase-3 as a therapeutic target.” eLife 3 (1): e03711. doi:10.7554/eLife.03711. http://dx.doi.org/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. DOI: http://dx.doi.org/10.7554/eLife.03711.001Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4215537/pdf/Terms of Use
This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAACitable link to this page
http://nrs.harvard.edu/urn-3:HUL.InstRepos:13454661
Collections
- HMS Scholarly Articles [15665]
- SPH Scholarly Articles [4830]
Contact administrator regarding this item (to report mistakes or request changes)