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

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.03711.001

Lymphatic endothelial cells are a replicative niche for Mycobacterium tuberculosis

“…eNOS is upregulated in the acute phase of experimental bacterial meningitis (47). In macrophages, eNOS contributes to the killing of Streptococcus pneumoniae (48). Supporting an important role for this enzyme in tuberculosis, eNOS is expressed and functional in the granulomas of macaques, and other isoforms different from iNOS contribute to NO production in infected tissues (49).…”

Plasma gelsolin improves lung host defense against pneumonia by enhancing macrophage NOS3 function

“…Primary pneumococcal pneumonia was modeled as previously reported (1,28). Pneumonia was induced by intranasal instillation of ϳ10 5 colony-forming units (CFU) of Streptococcus pneumoniae type 3 into mice under anesthesia with ketamine (120 mg/kg ip) plus xylazine (16 mg/kg ip); actual CFU administered were quantitated by CFU assay and used subsequently to calculate percent clearance.…”

“…Pneumonia was induced by intranasal instillation of ϳ10 5 colony-forming units (CFU) of Streptococcus pneumoniae type 3 into mice under anesthesia with ketamine (120 mg/kg ip) plus xylazine (16 mg/kg ip); actual CFU administered were quantitated by CFU assay and used subsequently to calculate percent clearance. For analysis at 4 or 24 h of lung inflammation and bacterial clearance, bronchoalveolar lavage was performed and analyzed as previously described (1,28). In experiments to assess survival from primary pneumonia, mice were instilled intranasally with a single 25-l suspension containing a higher dose of S. pneumoniae (ϳ3 ϫ 10 5 CFU), and survival was followed for periods as reported in RESULTS.…”

“…6303 and 19138, respectively, American Type Culture Collection, Rockville, MD) and Francisella tularensis LVS strain were cultured overnight on 5% sheep blood-supplemented agar petri dishes (catalog no. 90001-282, VWR, West Chester, PA) and prepared and quantified elsewhere (1,28).…”

“…We found that pGSN enhances the ability of lung macrophages to kill bacteria in vitro, in large part through a nitric oxide (NO) synthase type III (NOS3)-dependent mechanism (28). We also used a model of primary pneumococcal infection that approximates the frequent challenge to lung defenses of small numbers by bacteria and then studied a model of postviral susceptibility to bacterial pneumonia.…”