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.
Highlights
Bacterial pneumonia remains a major cause of morbidity and mortality (Mizgerd, 2006; Shrestha et al, 2013)
We found that AVE3085 treatment improved bacterial killing by macrophages in vitro (Figure 5E) and that mice treated with AVE3085 either by oral or subcutaneous administration showed substantially increased clearance of pneumococci in vivo, an effect not observed in Nos3−/− mice (Figure 5F)
We conclude that estrogen mediates greater host resistance to pneumonia in female mice via effects on the constitutively expressed nitric oxide synthase-3 (NOS3) in lung macrophages
Summary
Bacterial pneumonia remains a major cause of morbidity and mortality (Mizgerd, 2006; Shrestha et al, 2013). One approach to the problem might be to enhance innate immunity to infection. Normal host defenses are already quite robust, albeit imperfect, as they keep the incidence of pneumonia much lower than possible given the normal nocturnal aspiration of nasopharyngeal bacteria, example Streptococcus pneumoniae (Gleeson et al, 1997; Dockrell et al, 2012; Donkor, 2013). The resident alveolar macrophage (AM) functions as a ‘first responder’ phagocyte, ingesting and killing inhaled bacteria (Green and Kass, 1964; Fels and Cohn, 1985; Hussell and Bell, 2014). The importance of this function of AMs is indicated by greater susceptibility to infection and
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