cholecalciferol and Sinusitis

The immunopathogenesis of chronic rhinosinusitis (CRS) is largely unknown, but it is thought that different inflammatory profiles are responsible for the different CRS subtypes. 25-Hydroxyvitamin-D (25-VD3) has been shown to alter inflammatory mediators in other disease processes and 25-VD3 deficiency is associated with CRS with nasal polyps (CRSwNP), but it is unknown if 25-VD3 levels impact local inflammation in CRS. This study investigated the correlation between plasma 25-VD3 and sinonasal mucus monocyte chemoattractant protein-1 (MCP-1), regulated upon activation normal T cell expressed and secreted (RANTES), and basic fibroblast growth factor (bFGF) levels in patients with CRS.. Study subjects undergoing endoscopic sinus surgery (ESS) for CRS were prospectively enrolled from January 2012 to August 2014. Control subjects included patients undergoing ESS for noninflammatory pathology. Blood and sinonasal mucus were collected at the time of ESS. Plasma 25-VD3 was measured by enzyme-linked immunosorbent assay (ELISA) and mucus levels of MCP-1, RANTES, and bFGF by cytometric bead array (CBA).. A total of 57 patients were enrolled and categorized as CRS without nasal polyps (CRSsNP) (n = 31), CRSwNP (n = 14), and controls (n = 12). No significant correlation was found between MCP-1 and 25-VD3. There was a significant negative correlation between 25-VD3 and RANTES (r = -0.612; p = 0.026) and bFGF (r = -0.578; p = 0.039) in CRSwNP patients; however, there was no significant correlation in CRSsNP patients.. This data suggests that 25-VD3 may play a role in regulation of RANTES and bFGF expression in CRSwNP. This may occur through regulation of NP fibroblasts or other immune cells. Further investigation is warranted to better elucidate the role of RANTES, bFGF, and 25-VD3 in CRSwNP.

Topics: Chemokine CCL2; Chemokine CCL5; Cholecalciferol; Chronic Disease; Endoscopy; Female; Fibroblast Growth Factor 2; Fibroblasts; Humans; Male; Middle Aged; Mucus; Nasal Polyps; Rhinitis; Sinusitis; Vitamin D; Vitamins

Eosinophilic chronic rhinosinusitis (ECRS) is a chronic inflammatory disease, characterized by eosinophilic infiltration, T-helper type 2 (Th2-type) response, and olfactory dysfunction. A master regulator of Th2-type inflammation, thymic stromal lymphopoietin (TSLP), is important for basophil activation. TSLP-elicited basophils are a key factor in the pathogenesis of ECRS.. In order to elucidate the mechanisms of ECRS in humans, we aimed to establish a murine model of ECRS based on TSLP production in response to the topical application of MC903 (a vitamin D3 analog) and the subsequent TSLP-induced basophil activation. Histological analyses were performed to assess immune cell infiltration into the nasal mucosa and to explore the impact of eosinophilic inflammation on the olfactory epithelium. The status of Th2-type inflammation was evaluated by quantitative real-time PCR and enzyme-linked immunosorbent assay (ELISA).. Eosinophils, basophils, and M2 macrophages increased significantly in the nasal mucosa of the mice treated with MC903 and ovalbumin (OVA), compared to those treated with OVA alone or the controls. Quantitative real-time PCR and ELISA revealed elevated expression of interleukin (IL)-4, IL-5, IL-13, TSLP, the chemokine CCL11, and CCL24 in the nasal mucosa of the ECRS mice. In parallel, thinned olfactory epithelium and decreased mature olfactory sensory neurons were observed in the ECRS mice.. Our model of ECRS displayed Th2-type inflammation in the sinonasal region, including both eosinophil infiltration and basophil infiltration. Additionally, olfactory epithelium turned out to be affected by eosinophilic inflammation. These features are consistent with the characteristics of the human ECRS.

Topics: Animals; Cholecalciferol; Chronic Disease; Cytokines; Disease Models, Animal; Eosinophilia; Eosinophils; Mice; Nasal Polyps; Rhinitis; Sinusitis

Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) have been shown to be vitamin D3 (VD3) deficient, which is associated with more severe disease and increased polyp size. To gain mechanistic insights into these observational studies, we examined the impact of VD3 deficiency on inflammation and VD3 metabolism in an Aspergillus fumigatus (Af) mouse model of chronic rhinosinusitis (Af-CRS).. Balb/c mice were fed control or VD3 deficient diet for 4 weeks. Mice were then sensitized with intraperitoneal Af, and one week later given Af intranasally every three days for four weeks while being maintained on control or VD3 deficient diet. Airway function, sinonasal immune cell infiltrate and sinonasal VD3 metabolism profiles were then examined.. Mice with VD3 deficiency had increased Penh and sRaw values as compared to controls as well as exacerbated changes in sRaw when coupled with Af-CRS. As compared to controls, VD3 deficient and Af-CRS mice had reduced sinonasal 1α-hydroxylase and the active VD3 metabolite, 1,25(OH)2D3. Differential analysis of nasal lavage samples showed that VD3 deficiency alone and in combination with Af-CRS profoundly upregulated eosinophil, neutrophil and lymphocyte numbers. VD3 deficiency exacerbated increases in monocyte-derived dendritic cell (DC) associated with Af-CRS. Conversely, T-regulatory cells were decreased in both Af-CRS mice and VD3 deficient mice, though coupling VD3 deficiency with Af-CRS did not exacerbate CD4 or T-regulatory cells numbers. Lastly, VD3 deficiency had a modifying or exacerbating impact on nasal lavage levels of IFN-γ, IL-6, IL-10 and TNF-α, but had no impact on IL-17A.. VD3 deficiency causes changes in sinonasal immunity, which in many ways mirrors the changes observed in Af-CRS mice, while selectively exacerbating inflammation. Furthermore, both VD3 deficiency and Af-CRS were associated with altered sinonasal VD3 metabolism causing reductions in local levels of the active VD3 metabolite, 1,25(OH)2D3, even with adequate circulating levels.

Topics: Animals; Aspergillus fumigatus; Blood Cell Count; Cholecalciferol; Diet; Dietary Supplements; Disease Models, Animal; Eosinophils; Humans; Inflammation; Lymphocytes; Mice; Nasal Lavage; Nasal Polyps; Neutrophils; Rhinitis; Sinusitis; T-Lymphocytes, Regulatory; Vitamin D Deficiency

Currently vitamin D3 (VD3) or cholecalciferol is considered an immunomodulator that may be implicated in nasal polyposis (NP) pathophysiology.. This study aimed to investigate if deficiency of VD3 is associated with the presence of NP in patients with cystic fibrosis (CF) and patients with chronic rhinosinusitis (CRS).. In total, 152 adult participants were included in five phenotypic groups: CF with NP (CFwNP) (n = 27), CF without NP (CFsNP) (n = 31), CRS with NP (CRSwNP) (n = 32), CRS without NP (CRSsNP) (n = 30), and controls (n = 32). The serum levels of 25(OH)-VD3 < 20 ng/mL are considered as a deficiency, 21-29 ng/mL as insufficiency, and >30 ng/mL as sufficiency. Endoscopic and imaging staging of the mucosal disease performed with the Lund-Kennedy (LK) and Lund-Mackay (LM) scoring systems, respectively. The genotype of the patients with CF and the nasal microbial colonization of the patients with CF and patients with CRS were also recorded.. The patients with CFwNP had the lowest percentage of sufficiency in VD3 and the highest percentage in insufficiency among all the groups. The LM imaging scores were inversely correlated with the VD3 levels in both arms of the study (CF and CRS). Moreover, the LK endoscopic scores had a similar correlation in the CF groups; however, this was not the case with the CRS groups. The genotype of the patients with CF was not correlated with the VD3 serum levels. The patients with positive microbial colonization (mainly Pseudomonas and Staphylococcus aureus) had significantly lower VD3 serum levels in both the CF and CRS process.. VD3 deficiency seemed to be associated with the presence of nasal polyps in the patients with CRS and in the patients with CF in a similar manner. The lower the level of serum VD3, the more severe the mucosal disease was found in the imaging studies and the more frequent microbial colonization of the patients with CF and the patients with CRS.

Topics: Adolescent; Adult; Cholecalciferol; Chronic Disease; Cystic Fibrosis; Female; Humans; Male; Middle Aged; Nasal Polyps; Rhinitis; Sinusitis; Young Adult

Vitamin D3 (VD3 ) levels have been recently found to be responsible for a number of immunological, anti-inflammatory and anti-infectious roles. Some studies reported that some forms of allergic fungal rhinosinusitis (AFRS), occurs more commonly in patients who are more susceptible to VD3 deficiency. The aim of this work was to measure VD3 levels in patients with AFRS and chronic rhinosinusitis (CRS).. We report a prospective case control study conducted at Ain Shams University. It included 74 participants divided into 4 groups: group A, 25 patients with AFRS; group B, 15 patients with CRS with nasal polyps (CRSwNP); group C: 15 patients with CRS without nasal polyps (CRSsNP); and group D, 19 controls.. There was a statistically significant (p < 0.001) difference of VD3 between groups A and B compared with groups C and D. There were no statistically significant differences between the 4 groups regard calcium levels. Finally, there was a statistically significant difference in phosphate levels when we compared groups A and B with groups C and D (p = 0.001).. Serum level of VD3 in patient with CRSwNP and AFRS is significantly lower than that of patients with CRSsNP and control subjects. Although these results do not imply a specific etiological or therapeutic relationship, VD3 levels may constitute an inexpensive prophylactic and cost-effective option in the therapeutic armamentarium in the control of AFRS and CRSwNP, either by itself or as a synergistic agent with traditional agents.

Topics: Adult; Calcium; Case-Control Studies; Cholecalciferol; Female; Humans; Male; Middle Aged; Mycoses; Nasal Polyps; Prospective Studies; Rhinitis, Allergic; Sinusitis; Young Adult

Vitamin D3 (VD3) is a steroid hormone with known antiproliferative properties. Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) have been shown to be VD3-deficient. Moreover, VD3 deficiency is associated with worse disease in patients with CRSwNP. One cell type thought to play a role in chronic rhinosinusitis (CRS) is the human sinonasal fibroblast (HSNF). The aim of this study was to investigate VD3 deficiency and HSNF proliferation in CRSwNP.. Blood and sinus tissue explants were collected at the time of surgery from patients with CRSwNP (n = 15). Control subjects (n = 12) were undergoing surgery for cerebrospinal fluid leak repair or to remove non-hormone-secreting pituitary tumors. Ex vivo HSNF proliferation was analyzed with flow cytometry using expression of fibroblast-specific protein (FSP) and the proliferation marker Ki67. Plasma levels of 25-hydroxyvitamin D3 (25VD3) were measured by enzyme-linked immunosorbent assay. In vitro analysis of HSNF proliferation after treatment with calcitriol (1,25VD3) was performed using carboxyfluorescein succinimidyl ester (CFSE) and analyzed with flow cytometry.. In CRSwNP patients there was an inverse correlation between 25VD3 and proliferating HSNFs (p = 0.0135). This correlation was not seen for control patients (p = 0.3869). In vitro analysis showed that HSNFs from patients with CRSwNP had a higher proliferation index at baseline than HSNFs from control patients (p < 0.01). When treated with 1,25VD3, there was a significant decrease in HSNF proliferation index in patients with CRSwNP (p < 0.01), but not control patients.. VD3 deficiency is associated with increased HSNF proliferation in CRSwNP. Further investigation into how HSNFs and VD3 impact CRSwNP pathophysiology is warranted.

Topics: Adult; Aged; Calcitriol; Cell Line; Cell Proliferation; Cholecalciferol; Chronic Disease; Female; Fibroblasts; Humans; Male; Middle Aged; Nasal Polyps; Paranasal Sinuses; Rhinitis; Sinusitis; Vitamin D Deficiency

The objective of this work was to determine if specific chronic rhinosinusitis with nasal polyps (CRSwNP) populations are at risk for vitamin D3 (VD3 ) deficiency and if VD3 levels correlate with radiographic measures of disease severity or eosinophilia.. This study was a retrospective review of an academic rhinology practice. CRSwNP patients who had VD3 levels and CT scan within 6 months of each other were included. CT scans were graded using Lund-Mackay scoring (LMS) and peripheral eosinophil counts were measured. Demographic data including race, gender, age, body mass index, atopic status, and presence of asthma were collected. CRSwNP was subdivided into allergic fungal rhinosinusitis (AFRS), aspirin-exacerbated respiratory disease (AERD), and other CRSwNP. Multivariate analysis was performed to examine correlations and control for confounding factors.. Insufficient VD3 levels were found in 55% of all CRSwNP patients. VD3 correlated with African American race because nearly 80% of all African Americans had insufficient VD3 levels. Lower VD3 levels also correlated with more severe mucosal disease on CT scans as measured by LMS. There was no correlation between VD3 levels and age, gender, body mass index, atopy, asthma, or CRSwNP subtype.. VD3 insufficiency/deficiency is common in CRSwNP patients, especially those of African American race. Lower levels of VD3 are associated with worse LMS on CT. The role of VD3 in CRSwNP warrants further investigation.

Topics: Age Factors; Allergens; Antigens, Fungal; Aspirin; Black or African American; Cholecalciferol; Chronic Disease; Disease Progression; Eosinophilia; Female; Humans; Male; Nasal Polyps; Respiratory Mucosa; Retrospective Studies; Rhinitis, Allergic, Perennial; Risk; Sinusitis; Tomography, X-Ray Computed; Vitamin D Deficiency

Dendritic cells are professional antigen presenting cells, capable of initiating Th1 or Th2 responses, and have been implicated in the pathogenesis of a number of diseases, including sinusitis. Vitamin D(3) is a steroid hormone that acts on dendritic cells in a manner similar to corticosteroids. Investigators examined whether children with allergic fungal rhinosinusitis (AFRS) or chronic rhinosinusitis with nasal polyposis (CRSwNP) were vitamin D(3) deficient and the relationship of vitamin D(3) deficiency to dendritic cell infiltrate in the sinus mucosa.. Tertiary care university hospital.. Retrospective, controlled study using samples collected from pediatric patients seen from August 2009 to July 2011.. Plasma levels of 25-hydroxy vitamin D(3) were measured by enzyme-linked immunosorbent assay in children (≤18 years old) with AFRS, CRSwNP, or CRS without nasal polyposis (CRSsNP) and in controls undergoing surgery for adenotonsillar hypertrophy. Vitamin D(3) levels were confirmed using clinical diagnostic methods for those with CRSwNP or AFRS. Tissue samples were immunohistochemically stained for the dendritic cell marker CD209 and the costimulatory molecules CD80 and CD86.. There was no difference in mean vitamin D(3) levels between control and CRSsNP, whereas mean CRSwNP and AFRS levels were both well below the minimum recommended level of 30 ng/mL and significantly lower than control and CRSsNP levels. CD209(+) dendritic cells inversely correlated with vitamin D(3) but not costimulatory molecule expression.. These studies identify that children with CRSwNP or AFRS are vitamin D(3) deficient, which may be linked to increased dendritic cell infiltrate. These results suggest a role for vitamin D(3) as a key player in the immunopathology of pediatric CRSwNP.

Topics: Adolescent; Analysis of Variance; Child; Child, Preschool; Cholecalciferol; Chronic Disease; Dendritic Cells; Enzyme-Linked Immunosorbent Assay; Female; Humans; Immunohistochemistry; Male; Mycoses; Nasal Mucosa; Nasal Polyps; Retrospective Studies; Sinusitis; Vitamin D Deficiency

Vitamin D(3) (VD(3) ) is a steroid hormone that regulates bone health and numerous aspects of immune function and may play a role in respiratory health. We hypothesized that T helper type 2 (Th2) disorders, chronic rhinosinusitis with nasal polyps (CRSwNP) and allergic fungal rhinosinusitis (AFRS) would have VD(3) deficiencies, resulting in increased mature dendritic cells (DCs) and bone erosion. We conducted a retrospective study examining VD(3) levels in patients with AFRS (n = 14), CRSwNP (n = 9), chronic rhinosinusitis without nasal polyps (CRSsNP) (n = 20) and cerebrospinal fluid leak repair (non-diseased controls) (n = 14) at time of surgery. Circulating immune cell levels were determined by immunostaining and flow cytometric analysis. Plasma VD(3) and immune regulatory factors (granulocyte-macrophage colony-stimulating factor and prostaglandin E(2) ) were measured by enzyme-linked immunosorbent assay. It was observed that CRSwNP and AFRS demonstrated increased circulating DCs, while chronic rhinosinusitis without nasal polyps displayed increased circulating macrophages. CRSwNP and AFRS were to found to have insufficient levels of VD(3) which correlated inversely with circulating numbers of mature DCs, DC regulatory factors and bone erosion. CRSsNP displayed no change in circulating DC numbers or VD(3) status compared to control, but did display increased numbers of circulating macrophages that was independent of VD(3) status. Lastly, VD(3) deficiency was associated with more severe bone erosion. Taken together, these results suggest support a role for VD(3) as a key player in the immunopathology of CRSwNP and AFRS.

Topics: Blood Circulation; Bone Remodeling; Cell Count; Cells, Cultured; Cholecalciferol; Chronic Disease; Dendritic Cells; Fungi; Humans; Macrophages; Nasal Polyps; Rhinitis; Rhinitis, Allergic, Perennial; Sinusitis; Th1-Th2 Balance

Vitamin D (VD) and its different analogues, besides their classic role as regulators of calcium and phosphor homeostasis, have emerged as a large family of antiproliferative agents. Such properties suggested VD potential as a therapy for chronic inflammatory diseases, including nasal polyposis (NP). NP growth involves both an inflammatory process and the proliferation of fibroblast as an important factor inducing aberrations in the phenotype of the epithelium. The aim of this study was to investigate the possible influence of 1alpha,25-dihydroxyvitamin D(3) (calcitriol) and 1alpha,24(R)-dihydroxyvitamin D(3) (tacalcitol) in monotherapy and in combination with budesonid R (BR) on NP fibroblast proliferation.. The study involved 26 samples of NP. NP cells were cultured on 96-well plates beginning with a concentration of 5 x 10(3) cells per well with RPMI 1640 medium supplemented with antibiotics and 10% foetal bovine serum. After the fourth to sixth passage the medium was replaced with a nutrient medium with calcitriol or tacalcitol in a defined concentration (from 10(-9) M to 10(-3) M) alone or in combination with BR in 1:1, 1:3 or 3:1 ratios, each at concentrations from 10(-5) M to 10(-3) M.. Growth inhibition of nasal fibroblasts exposed to calcitriol or tacalcitol was noted. Significant antiproliferating activity was observed at calcitriol concentrations of 10(-4) M and 10(-3) M after 48 h, and at a concentration of 10(-3) M after 72 h with the percentage of proliferating cells reduced to 30% compared to the control samples (P < 0.05). In cells treated with tacalcitol the maximal effect was seen at 10(-4) M after 48 h and at 10(-3)M after 72 h with a 60% inhibition with respect to the control (P < 0.05). The inhibition of fibroblast proliferation reached the maximal level when they were exposed to calcitriol: BR (1 : 1) or tacalcitol: BR (1 : 1), each at a concentration of 10(-4) M, after 72 h (82% and 69%, respectively).. The antiproliferative activity of calcitriol and tacalcitol in NP cultures was confirmed. Because of its lower toxicity and higher activity tacalcitol seems to be the more promising agent in NP therapy, both as a single medication and in treatment protocols with BR.

Topics: Apoptosis; Budesonide; Calcitriol; Cell Proliferation; Cells, Cultured; Cholecalciferol; Dihydroxycholecalciferols; Dose-Response Relationship, Drug; Fibroblasts; Humans; Nasal Mucosa; Nasal Polyps; Rhinitis; Sinusitis