Intranasal Calcitriol Accelerates Improvement of Sinonasal Inflammation and Olfactory Impairment in Mice After Cessation of Chronic Cigarette‐Smoke Exposure

Smoking has been shown to be associated with circulating deficiencies in 25(OH)D3 and reduced sinonasal tissue levels of the active form of vitamin D, 1,25(OH)2D3. Given vitamin D's ability to reduce inflammation, we sought to examine if intranasal (IN) delivery of calcitriol [clinical analog of 1,25(OH)2D3] could reduce inflammation and improve disease severity in a murine model of chronic cigarette smoke-induced sinonasal inflammation (CS-SI). Mice were exposed to CS 5 h/day, 5 days/week for 9 months, and then began IN calcitriol three times per week for 4 weeks. Micro-CT was used to assess disease severity. Sinonasal tissues were collected for RNA-seq analysis. Olfactory function was assessed using a T-maze odorant avoidance sniff behavior test. Nasal lavage fluid (NALF) was used for cytology and cytokines analysis. Quantification of disease severity by micro-CT showed IN calcitriol reduced opacification by 18%, as compared to smoke cessation alone, in which only a 5% reduction was noted. H&E analysis of NAFL demonstrated heightened neutrophil infiltration and neutrophil-associated chemokines in CS-SI mice, which was reduced with IN calcitriol treatment. RNA-seq pathway analysis demonstrated that smoking was associated with odorant binding changes and that calcitriol treatment reduced neutrophil migration and inflammation. Lastly, IN calcitriol reversed olfactory loss caused in CS-SI. IN delivery of calcitriol accelerates inflammatory resolution in the nose and olfactory mucosa after prolonged CS exposure. Furthermore, treatment was associated with improved olfactory function in mice CS-SI, as such local delivery of calcitriol may serve as a novel treatment for modulating sinonasal inflammation.