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Background: The role of Akt in nasal immunity is unstudied. Akt phosphorylates and activates endothelial nitric oxide synthase (eNOS) expressed in epithelial ciliated cells. Nitric oxide (NO) production by ciliated cells can have antibacterial and antiviral effects. Increasing nasal NO may be a useful antipathogen strategy in chronic rhinosinusitis (CRS). We previously showed that small‐molecule Akt activator SC79 induces nasal cell NO production and suppresses IL‐8 via the transcription factor Nrf‐2. We hypothesized that SC79 NO production may additionally have antibacterial effects. Methods: NO production was measured using fluorescent dye DAF‐FM. We tested effects of SC79 during co‐culture of Pseudomonas aeruginosa with primary nasal epithelial cells, using CFU counting and live–dead staining to quantify bacterial killing. Pharmacology determined the mechanism of SC79‐induced NO production and tested dependence on Akt. Results: SC79 induced dose‐dependent, Akt‐dependent NO production in nasal epithelial cells. The NO production required eNOS and Akt. The NO released into the airway surface liquid killed P. aeruginosa. No toxicity (LDH release) or inflammatory effects (IL8 transcription) were observed over 24 h. Conclusions: Together, these data suggest multiple immune pathways are stimulated by SC79, with antipathogen effects. This in vitro pilot study suggests that a small‐molecule Akt activator may have clinical utility in CRS or respiratory other infection settings, warranting future in vivo studies. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusion The inability of topical medications to reach sinus cavities is a potential reason for lack of efficacy in chronic rhinosinusitis (CRS). One purpose of endoscopic sinus surgery (ESS) is to enable delivery of medications into the sinus cavities. The exhalation delivery system with fluticasone (EDS‐FLU; XHANCE) creates unique biomechanics that enable deposition of intranasal corticosteroid into sinuses and sinus drainage pathways but may have differing efficacy in operated versus unoperated sinuses. Two 24‐week randomized trials (ReOpen1/2) evaluated EDS‐FLU versus EDS‐placebo in patients with CRS, stratified by surgical status.Surgery‐naive (n = 332) and prior‐surgery (n = 215) patient groups were analyzed as pooled data from ReOpen1/2. Outcome measures (least‐squares mean change from baseline) included combined symptom score (CSS) and congestion score at weeks 4, 8, and 12 and average of percentages of opacified volume (APOV) of ethmoid/maxillary sinuses on CT and Sinonasal Outcome Test 22 (SNOT‐22) total score at week 24.Baseline scores suggested moderate–severe disease: mean CSS = 5.8; APOV = 67.2%. EDS‐FLU produced significant improvement versus placebo (p < 0.05): CSS (surgery‐naive, −0.68 vs. −1.42; prior ESS, −0.70 vs. −1.87); congestion (surgery‐naive, −0.24 vs. −0.59; prior ESS, −0.24 vs. −0.69); and SNOT‐22 (surgery‐naive, −7.56 vs. −18.30; prior ESS, −10.72 vs. −18.74). Similar results were observed for APOV (p < 0.05). No statistically significant difference was observed between surgery subgroups with either EDS‐FLU dose.EDS‐FLU improved symptoms, sinus opacification, and quality of life in patients with CRS with or without prior ESS, suggesting a role for EDS‐FLU in both populations. [ABSTRACT FROM AUTHOR]