Type-2 Cannabinoid Receptors Maintain Epithelial Barrier in Aspirin-Exacerbated Respiratory Disease

Transcription of type-2 cannabinoid receptors (CB2) is increased in Aspirin-exacerbated respiratory disease (AERD) nasal polyp epithelium. However, physiologic function is yet to be determined. The endogenous cannabinoid system is an innate signaling network with control of eicosanoid production and the potential to influence epithelial barrier. We therefore hypothesize that CB2 is over-expressed in AERD as a compensatory source to maintain epithelial barrier. Consecutive patients undergoing sinus surgery for AERD were included. Epithelium from collected polyps were isolated and expanded prior to differentiation at air-liquid interface. Pharmacologic experiments were completed in triplicate with trans-epithelial resistance (TER) as the primary outcome. Compounds include 2-arachidonoylglycerol (2-AG), a nonspecific cannabinoid receptor agonist, and SMM-189, a specific CB2 antagonist/inverse agonist. Group differences over time were evaluated using repeated measures ANOVA. Bonferroni correction was performed for multiple comparisons. Four AERD subjects were included. At 24 hours, the 2-AG group demonstrated the highest TER and the SMM-189 group demonstrated the lowest (mean 2,389 vs. 1,255ohm/cm2). Analysis revealed both significant effects of either compound versus vehicle control (p<0.005) and between the two evaluated compounds (p<0.001). Statistically significant differences were identified between all group comparisons (p<0.05). The endogenous cannabinoid system is an emerging immunomodulatory network that may be involved in AERD via the control of epithelial barrier. This study offers the first evidence of CB2 function in AERD and provides potential insight into future therapeutic options for this recalcitrant disease. Additional study is warranted to further validate these findings.