Vitamin D as a modulator of inflammation in CRS-related olfactory loss - ABSTRACT: Chronic rhinosinusitis (CRS) is the leading cause of olfactory dysfunction in the general population. Olfactory dysfunction most commonly occurs in patients with CRS with nasal polyposis (CRSwNP), with up to 80% of patients exhibiting olfactory loss. One anti-inflammatory agent that may have beneficial effects in the treatment of CRSwNP is vitamin D3 (VD3). We and others have reported, that patients with CRSwNP are deficient in 25(OH)D3. Recently we have also observed that 25(OH)D3 deficiency was associated both subjective and objective olfactory loss. Conversely, using a murine model of cigarette smoke (CS)-induced CRS, we observed that IN delivery of 1,25(OH)2D3 was able to improve olfactory function. Therefore, we hypothesize that VD3 metabolites could serve as novel broad spectrum anti-inflammatory capable of reversing CRS-related olfactory loss. While human observational studies have suggested that in the superior turbinate an elevated presence of granulocytes, such as eosinophils and neutrophils, are associated with olfactory dysfunction in CRSwNP, mechanistic studies confirming this observation are lacking. Previously we have shown in mice, that dietary deficiency in VD3 caused significant increases in eosinophils and neutrophils. Therefore, will also test the hypothesis that VD3’s ability to reduce inflammation and improve olfactory outcomes, is through its modulation of granulocyte functions. We will test these novel hypotheses through the execution of the following aims. AIM 1 will dissect role of VD3 metabolites in the regulation of inflammation associated with CRSwNP-olfactory loss. In Aim 1A we will dissect the interplay between olfactory loss, VD3 metabolites, and sinonasal inflammation in patients with CRSwNP. AIM 1B we will dissect mechanisms by which VD3 metabolites can modulate endogenous and irritant-induced inflammation using human sinonasal nasal epithelial cells. Collectively, AIM 2 we will determine the role of VD3 metabolites in modulating granulocyte-induced olfactory loss in vivo. AIM 2A will determine the impact of granulocyte depletion on improving olfaction functions in vivo. We will utilize two murine models of CRS: aspergillus fumigates-extract induced model to generate eosinophilic disease, and a CS-induced mouse model to create neutrophilic disease. We will pair these models with eosinophil or neutrophil depletion protocols to determine whether removal promotes reversal of established disease and restores olfactory loss. AIM 2B will determine the ability of IN VD3 metabolites to improve olfactory loss and disease severity, reduce inflammatory cell infiltrate, and allow for regeneration of olfactory neurons and epithelium. If successful, these studies could provide evidence for the use of IN VD3 as a treatment for CRSwNP-related olfactory loss.
