title: Resveratrol has salutary effects on mucociliary transport and inflammation in sinonasal epithelium.
abstract: OBJECTIVE
  Therapeutic agents that enhance mucociliary transport (via stimulation of transepithelial Cl- secretion) and inhibit inflammation could provide considerable advantages over conventional treatments for chronic rhinosinusitis (CRS). The objectives of the present study were to investigate whether the polyphenolic compound resveratrol promotes transepithelial Cl- transport and inhibits KC/IL-8 secretion in sinonasal epithelium.
  
  
  METHODS
  In vitro and in vivo study.
  
  
  METHODS
  Transepithelial Cl- transport was investigated in primary murine nasal septal (MNSE) and human sinonasal epithelial (HSNE) cultures. In vivo activity was also measured using the murine nasal potential difference assay. CFTR R-domain phosphorylation and cAMP levels were examined as a test of cAMP/PKA-dependent activation. In vitro LPS-induced KC/IL-8 secretion was quantified and compared to a panel of intranasal steroids.
  
  
  RESULTS
  Resveratrol(100 μM) significantly increased CFTR-mediated Cl- transport (change in short-circuit current, ΔI(SC) ) in both MNSE (13.51 ± 0.77 vs. 4.4 ± 0.66 [control]; P < .05) and HSNE (12.28 ± 1.08 vs. 0.69 ± 0.32 [control]; P < .05). Cl- secretion across in vivo murine nasal epithelium was also enhanced (-4 ± 1.8 vs. -0.8 ± 1.7mV [control], P < .05). There was no increase in cellular cAMP or CFTR R-domain phosphorylation detected. Resveratrol also significantly inhibited KC/IL-8 secretion in a dose-dependent fashion (pg/mL) in MNSE (181 ± 39[100 μM) vs. 94 ± 16 [200 μM] vs. 16 ± 22 [500 μM] vs. 1195 ± 355 [LPS control]; P < .001). The compound robustly abrogated KC/IL-8 secretion when compared to ciclesonide (765 ± 139), triamcinolone (561 ± 124), and budesonide (742 ± 428), but had similar activity to fluticasone proprionate (65 ± 47). Similar effects were demonstrated in HSNE (975 ± 244 [100 μM] vs. 1825 ± 144 [LPS control]; P < .001) with inhibition comparable to fluticasone proprionate (785 ± 277).
  
  
  CONCLUSIONS
  These in vitro and in vivo findings indicate resveratrol is a potent Cl- secretagogue and anti-inflammatory agent. Future clinical trials for CRS are warranted.
authors.affiliation: Department of Surgery/Division of Otolaryngology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
authors.forename: Nathan S
authors.initials: NS
authors.lastname: Alexander
authors.forename: Neal
authors.initials: N
authors.lastname: Hatch
authors.forename: Shaoyan
authors.initials: S
authors.lastname: Zhang
authors.forename: Daniel
authors.initials: D
authors.lastname: Skinner
authors.forename: James
authors.initials: J
authors.lastname: Fortenberry
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Sorscher
authors.forename: Bradford A
authors.initials: BA
authors.lastname: Woodworth
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D018118:Chloride Channels / Q000187:drug effects*; D000242:Cyclic AMP / Q000032:analysis; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000187:drug effects* / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D004848:Epithelium / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009079:Mucociliary Clearance / Q000187:drug effects*; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D018118:Chloride Channels; D016209:Interleukin-8; D013267:Stilbenes; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000242:Cyclic AMP; D000077185:Resveratrol