Chronic rhinosinusitis negatively impacts patients’ quality of life, and olfactory dysfunction is considered one of its cardinal symptoms. In the first session of the 2024 American Rhinologic Society meeting at the COSM, held on May 15–16, 2024 in Chicago, Jennifer Mulligan, PhD from the University of Florida presented data indicating that intranasal calcitriol administration may have therapeutic potential in chronic rhinosinusitis, since intranasally administered calcitriol reduced inflammation and restored olfactory impairment in an animal model of smoke-induced sinusitis.
It has been shown that vitamin D levels are decreased in patients with chronic rhinosinusitis, and that there is an inverse correlation between vitamin D levels and the degree of chronic rhinosinusitis. Moreover, vitamin D has demonstrated anti-inflammatory effects and the ability to promote anti-microbial immune responses without over-activating the immune system. As a result, vitamin D has emerged as an attractive therapeutic candidate for airway disorders.
However, no previous studies have been able to demonstrate alleviation of symptoms of chronic rhinosinusitis with vitamin D supplementation. Notably, vitamin D3 is produced in the skin upon sunlight exposure, metabolized to its main circulating form 25(OH)D3 in the liver, and subsequently transformed to its most active form 1,25(OH)2D3 in the kidney and other tissues. In patients with chronic inflammatory diseases, the metabolism of vitamin D3 may be impaired, for example because of interfering medications, such as steroids.
To avoid the risk of interferences in vitamin D3 metabolism, Dr. Mulligan and her team decided to use calcitriol, which is a clinical analog of the most active form of vitamin D3 (1,25(OH)2D3). They set out to explore whether intranasal administration of calcitriol can reduce sinonasal inflammation in an animal model of smoke-induced sinusitis and can alleviate disease severity. Ultimately, they wanted to gain insight into the therapeutic potential of vitamin D for chronic rhinosinusitis.
To establish an animal model of smoke-induced sinusitis, 8-week-old Balb/c male mice were exposed to cigarette smoke for 5 hours/day during 5 days/week over 9 months. Subsequently, cigarette smoke exposure was ceased, and the mice were treated with intranasal calcitriol or vehicle 3 times/week throughout the course of 4 weeks. The T-maze odorant avoidance sniff behavior test was used to assess olfactory function, whereas CT scans were employed to assess disease severity, and RNAseq analysis of sinonasal tissues was utilized to identify molecular pathways implicated in the effects of smoke exposure.
In mice with smoke-induced sinusitis, the combination of calcitriol and smoke cessation resulted in significantly greater reduction of sinus opacification observed in a CT scan (18%) than smoke cessation and vehicle (5%), indicating more pronounced decrease of disease severity with calcitriol treatment. In addition, calcitriol reduced neutrophil counts and chemokine concentrations in nasal lavage fluid, alleviating inflammation.
Next, Dr. Mulligan and her team examined the molecular mechanisms involved in the effects of smoke exposure and identified odorant binding as the pathway most profoundly affected by smoking using RNAseq KEGG reactome analysis. Accordingly, they tested the effect of calcitriol on olfactory function with an odorant avoidance test and found that intranasal administration of calcitriol alleviated olfactory epithelial injury and metaplasia and reversed the olfactory loss caused by cigarette smoke exposure and aging.
Finally, Dr. Mulligan summarized the findings of the study, emphasizing that intranasally administered calcitriol reduced neutrophilic inflammation and disease severity in mice with smoke-induced sinusitis. In addition, calcitriol alleviated the symptoms of olfactory loss caused by cigarette smoke exposure and aging and enhanced the presence of olfactory epithelium. Together, the findings support the potential of intranasally delivered calcitriol as a therapeutic candidate for chronic rhinosinusitis and chronic rhinosinusitis-induced olfactory loss.