ORIGINAL ARTICLE
Intranasal Calcitriol Accelerates Improvement of Sinonasal Inflammation and Olfactory Impairment in Mice After Cessation of Chronic Cigarette-Smoke Exposure
Logan Langerude,
Alex McQuiston,
Carl Atkinson,
Jennifer K. Mulligan,
Logan Langerude
Department of Surgery, Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
Search for more papers by this authorAlex McQuiston
Department of Surgery, Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
Search for more papers by this authorCarl Atkinson
Department of Surgery, Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
Search for more papers by this authorCorresponding Author
Jennifer K. Mulligan
Division of Division of Rhinology & Skull Base Surgery Department of Otolaryngology, University of Florida, Gainesville, Florida, USA
Correspondence: Jennifer K. Mulligan ([email protected])
Search for more papers by this authorLogan Langerude,
Alex McQuiston,
Carl Atkinson,
Jennifer K. Mulligan,
Logan Langerude
Department of Surgery, Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
Search for more papers by this authorAlex McQuiston
Department of Surgery, Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
Search for more papers by this authorCarl Atkinson
Department of Surgery, Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
Search for more papers by this authorCorresponding Author
Jennifer K. Mulligan
Division of Division of Rhinology & Skull Base Surgery Department of Otolaryngology, University of Florida, Gainesville, Florida, USA
Correspondence: Jennifer K. Mulligan ([email protected])
Search for more papers by this authorFirst published: 15 January 2025
Funding: Research reported in this publication was supported by the National Institutes of Health Awards R01AI134698 (J.K.M.), R01AI144364 (J.K.M. and C.A.), and R01HL140470 (C.A.).
ABSTRACT
Rationale
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).
Methods
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.
Results
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.
Conclusions
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.
Conflicts of Interest
J.K.M. is senior advisor for 3D Matrix Medical Technologies. None of the other listed authors have any potential conflicts to disclose related to the research presented herein.
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