Cigarette smoke exposure is associated with vitamin D3 deficiencies in patients with chronic rhinosinusitis

doi:10.1016/j.jaci.2014.01.039

Journal of Allergy and Clinical Immunology

Volume 134, Issue 2, August 2014, Pages 342-349.e1

https://doi.org/10.1016/j.jaci.2014.01.039 Get rights and content

Background

Cigarette smoke (CS) plays a role in the exacerbation of chronic rhinosinusitis (CRS); however, the mechanism for this is unknown. We hypothesize that CS impairs human sinonasal epithelial cell (HSNEC) conversion of 25(OH)D3 (25VD3) to 1,25-dihydroxyvitamin D3 (1,25VD3) and, furthermore, that supplementation with 1,25VD3 will reverse smoke-induced inflammatory responses by HSNECs.

Objective

We sought to determine the effect of CS on vitamin D3 (VD3) levels, conversion, and regulation of CS-induced inflammation in control subjects and patients with CRS.

Methods

Blood and sinus tissue explants were collected at the time of surgery from control subjects, patients with chronic rhinosinusitis without nasal polyps, and patients with chronic sinusitis with nasal polyps (CRSwNP). Expression of VD3 metabolizing enzymes were measured by using RT-PCR. Primary HSNECs were cultured from tissue explants. 25VD3 with and without cigarette smoke extract (CSE) was used to examine conversion of 25VD3 to 1,25VD3, as well as HSNEC production of proinflammatory cytokines.

Results

CS exposure was associated with reduced circulating and sinonasal 25VD3 levels in all groups compared with those seen in CS-naive, disease-matched counterparts. CS exposure decreased expression of CYP27B1 and was especially pronounced in patients with CRSwNP. CSE impairs control HSNEC conversion of 25VD3. HSNECs from patients with CRSwNP also demonstrate an intrinsic reduction in conversion of 25VD3 to 1,25VD3. Exogenous 1,25VD3 reduces CSE-induced cytokine production by HSNECs.

Conclusions

Exposure to CS is associated with reduced 25VD3 levels and an impaired ability of HSNECs to convert 25VD3 to 1,25VD3. Addition of 1,25VD3 reduces the proinflammatory effects of CS on HSNECs. Impaired VD3 conversion by CS exposure represents a novel mechanism through which CS induces its proinflammatory effects.

Section snippets

Patients

The Institutional Review Board at the Medical University of South Carolina approved these studies, and written informed consent was obtained for all patients. Blood, hair, and sinus tissue were taken at the time of endoscopic sinus surgery. Inclusion criteria include patients with CRSsNP and those with CRSwNP who met the diagnostic criteria outlined by the European Position Paper on Rhinosinusitis and Nasal Polyps 2012.³² Control subjects were undergoing surgery for cerebrospinal fluid leak

CS exposure is associated with decreased circulating and sinonasal tissue 25VD3 levels

To determine the effect of CS on systemic VD3 levels, we measured plasma 25VD3 levels in smoke-naive and CS-exposed control subjects, patients with CRSsNP, and patients with CRSwNP (demographics are summarized in Table I). Consistent with our previous reports,30, 31 patients with CRSwNP were VD3 deficient (Fig 1, A) and had reduced plasma 25VD3 levels compared with those in control subjects (P = .0001) or patients with CRSsNP (P < .0001). Exposure to CS was associated with decreased 25VD3

Discussion

In this study we examined the effect of CS on systemic 25VD3 levels and its local metabolism in control subjects and patients with CRS. Previously, we reported that patients with CRSwNP were systemically VD3 deficient, as determined by using ELISA and liquid chromatography/tandem mass spectrometry30, 31; comparison of these results found no statistically significant difference between data obtained with either method. Here we determined that CS exposure exacerbates local and systemic VD3

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Vitamin D is an important cornerstone in the immunologic cascade of many skin infections, systemic infections with cutaneous presentations, and other infectious dermatologic diseases where infections could be a culprit. Vitamin D supplementation is proposed as a protective measure against their occurrence and exacerbation, especially with the emergence of several viral pandemics in recent years. Vitamin D plays a key role in the maintenance of a balanced immunologic profile which could be reflected by a lowered incidence and morbidity of infections. Vitamin D screening and supplementation in patients with deficiencies or insufficiencies should be a part of the dermatologic approach to patients with these diseases.
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All studies were published in English. Five studies 7,14–16,20 compared both CRSwNP and CRSsNP with controls. Three studies7,18,19 were carried out as prospective researches and the rest were retrospective ones.
Chronic rhinosinusitis is a highly heterogeneous chronic inflammation of the upper respiratory tract caused by immune dysfunction in human beings. However, the underlying etiology of this disease has not yet been well established. Several trials have revealed that serum vitamin D level abnormality might play a role in the pathophysiology of chronic rhinosinusitis.
The aim of present study was to perform a meta-analysis of studies to compare the serum vitamin D levels between patients with chronic rhinosinusitis and healthy controls and to evaluate the potential associations of serum vitamin D level with the occurrence of chronic rhinosinusitis.
Following the PRISMA guidelines, relevant databases incorporating Pubmed, Web of Science, Embase and Cochrane Library were searched from inception to December 1, 2018. Funnel plot symmetry and Egger’ test were used to detect publication biases. The outcomes were presented as Weighted Mean Difference combined with 95% Confidence Intervals to estimate the difference of serum vitamin D levels between patients with chronic rhinosinusitis and controls. Higgins I² value was used to test for heterogeneity between the included studies.
Out of 176 studies, only eight studies involving 337 chronic rhinosinusitis patients and 179 healthy controls met the criteria and were included in the meta-analysis. In a pooled analysis of the studies, chronic rhinosinusitis patients showed decreased serum vitamin D status (WMD = −7.80, 95% CI −13.28 to −2.31, p = 0.000). Subgroups analyses based on study location (USA vs. Non-USA), types of biomarkers (25(OH)D3 vs. 25(OH)D) and the study design methods (retrospective vs. prospective) did not reveal heterogeneity. However, phenotypes of chronic rhinosinusitis, with versus without polyposis might account for some degree of heterogeneity. Meanwhile, a lower serum vitamin D level was observed in chronic rhinosinusitis with nasal polyps patients.
Our findings indicate that serum vitamin D level might be associated with patients with chronic rhinosinusitis as we detected a significant association between lower serum vitamin D status and chronic rhinosinusitis, especially in chronic rhinosinusitis with nasal polyps patients. However, further comprehensive studies are warranted in order to draw firm conclusions.
Serum vitamin D concentration is associated with antimicrobial peptide level in periodontal diseases
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The aim of the study was to assess whether or not Vitamin D deficiency was associated with the GCF and gingival tissue antimicrobial peptides (AMP), namely, human beta defensin-2 (hBD-2) and cathelicidin (LL-37) level in chronic periodontitis (CP) and gingivitis patients.
A total of 80 volunteers were included in this study. Forty was classified as Vitamin D deficient (25(OH)D <20 ng/mL), and 40 Vitamin D sufficient patients (25(OH)D ≥ 20 ng/mL). Of these, 20 of them were affected by gingivitis and 20 by CP. Following sampling, the hBD-2 and LL-37 concentration in gingival tissues and GCF were determined by the ELISA method.
The hBD-2 and LL-37 levels were higher in periodontitis compared to gingivitis patients within Vitamin D sufficient and deficient groups. The AMP levels of GCF and gingival tissue in the vitamin D deficient group was lower compared to sufficient serum 25(OH)D within gingivitis and CP groups. Additionally, a non-parametric regression model known as the generalized additive model was used to identify the contribution of diagnosis, Vitamin D status, and other potential clinical variables on the local levels of AMPs. Regression analysis showed that the periodontal disease status, serum vitamin D concentration were independent predictors for elevated GCF AMP levels. Finally, a positive correlation between GCF and tissue levels of both hBD-2 (r = 0.82; <0.0001) and LL-37 (r = 0.65; <0.0001) was detected.
This study shows that serum 25(OH)D deficiency is associated with decreased hBD-2 and LL-37 expression of GCF and gingival tissues in both gingivitis and CP patients.
Vitamin D modulates E-cadherin turnover by regulating TGF-β and Wnt signalings during EMT-mediated myofibroblast differentiation in A459 cells
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Vitamin D (VitD) has an anti-fibrotic effect on fibrotic lungs. It reduces epithelial-mesenchymal transition (EMT) on tumors. We aimed to investigate target proteins of VitD for the regression of EMT-mediated myofibroblast differentiation. A group of A549 cells were treated with 5 % cigarette smoke extract (CSE) and 5 %CSE + TGF-β (5 ng/ml) to induce EMT. The others were treated with 50 nM VitD 30 min before %5CSE and TGF-β treatments. All cells were collected at 24, 48 and 72 h following 5 %CSE and TGF-β administrations. The expression of p120ctn and NEDD9 proteins acted on E-cadherin turnover in addition to activations of TGF-β and Wnt pathways were examined in these cells and fibrotic human lungs. CSE and TGF-β induced EMT by reducing E-cadherin, p-VDR, SMAD7 and DKK1, increasing α-SMA, p120ctn, Kaiso, NEDD9 and stimulating TGF-β and Wnt/β-catenin signalings in A549 cells. VitD administration reversed these alterations and regressed EMT. Co-immunoprecipitation analysis revealed p-VDR interaction with β-catenin and Kaiso in fibrotic and non-fibrotic human lungs. VitD pre-treatments reduced TGF-β and Wnt/β-catenin signalings by increasing p-VDR, protected from E-cadherin degradation and led to the regression of EMT in A549 cells treated with CSE and TGF-β. Finally, VitD supplementation combined with anti-fibrotic therapeutics can be suggested for treatment of pulmonary fibrosis, which may be developed by smoking, in cases of VitD deficiency.
Association of serum vitamin D status with dietary intake and sun exposure in adults
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Citation Excerpt :
This could hypothetically be explained by the lower prevalence of osteoporosis in males and/or lower degree of actively checking for osteoporosis in comparison to females, and hence reduced supplemental intake. Smoking as per other reports was associated with higher odds of serum 25(OH)D concentration <20 ng/ml and it is hypothesized that smoking impairs conversion of 25(OH)D to 1,25(OH2)D [43]. In females, obesity was associated with an increased likelihood of low vitamin D status.
Serum 25(OH)D deficiency is becoming an epidemic. The aim was to assess vitamin D status of the adult Greek population in relation to intake, sun exposure and other factors, using data from the Hellenic National Nutrition and Health Survey (HNNHS).
Data from 1084 adult participants (37.8% males) were analyzed. Vitamin D intake was assessed using 24-h recalls. Serum 25(OH)D concentration was evaluated and related to anthropometric measurements and other covariates including supplements used, by sex. Variables significantly associated with 25(OH)D < 20 ng/ml were assessed using simple and multiple logistic regression.
Median vitamin D intake from food was 1.23 mcg/day (0.60, 2.44), with 9.1% consuming supplements. Median serum 25(OH)D was 16.72 ng/ml, with no sex differences (P = 0.923). The odds of having 25(OH)D < 20 ng/ml significantly decreased with being very active (OR 0.55, 95% CI 0.35, 0.98), increasing length of sun exposure [1–3 h/day (OR 0.59, 95% CI 0.44, 0.80), >3 h/day (OR 0.36, 95% CI 0.24, 0.55)], and skin colour [light to medium skin (OR 0.47, 95% CI 0.24, 0.91), fairly dark skin colour (OR 0.34, 95% CI 0.17, 0.67) and dark or very dark skin colour (OR 0.34, 95% CI 0.15, 0.75)], compared to respective baseline levels. The odds significantly increased with obesity (OR 1.95, 95% CI 1.24, 3.08), and spring season of blood sample collection (OR 1.75, 95% CI 1.22, 2.50).
Vitamin D deficiency is highly prevalent in Greek adults. Relevant public health policies are highly recommended, which could include vitamin D fortification. and suggestion for increased but safe sun exposure.

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: Supported by grants from the Flight Attendant Medical Research Institute (092401 to J.K.M. and 113039 to R.J.S.), the National Institutes of Health (R01HL091944 to C.A.), and a grant from the Department of Veterans Affairs.

: Disclosure of potential conflict of interest: J. K. Mulligan has received research support from the Flight Attendant Medical Research Institute, the US Department of Veterans Affairs, and the National Institutes of Health. R. J. Schlosser has received research support from the Flight Attendant Medical Research Institute, the US Department of Veterans Affairs, NeilMed, ArthroCare, Intersect, and Optinose; has consultant arrangements with BrainLAB, Olympus, and United Allergy; has received payment for lectures from NeilMed; and has a patent pending for vitamin D use in respiratory tract disorders. The rest of the authors declare that they have no relevant conflicts of interest.

View full text

Rhinitis, sinusitis, and upper airway diseaseCigarette smoke exposure is associated with vitamin D3 deficiencies in patients with chronic rhinosinusitis

Background

Objective

Methods

Results

Conclusions

Section snippets

Patients

CS exposure is associated with decreased circulating and sinonasal tissue 25VD3 levels

Discussion

Clin Immunol

Lancet Oncol

Otolaryngol Head Neck Surg

J Cyst Fibros

Semin Immunol

J Allergy Clin Immunol

J Chromatogr B Biomed Sci Appl

Transl Res

J Allergy Clin Immunol

Biochem Biophys Res Commun

Exp Mol Pathol

Perspectives on the etiology of chronic rhinosinusitis: an immune barrier hypothesis

Am J Rhinol

Differentiation of chronic sinus diseases by measurement of inflammatory mediators

Allergy

Distinct immunopathologic characteristics of various types of chronic rhinosinusitis in adult Chinese

J Allergy Clin Immunol

Th2 immunological inflammation in allergic fungal sinusitis, nonallergic eosinophilic fungal sinusitis, and chronic rhinosinusitis

Am J Rhinol

Chronic rhinosinusitis in Europe—an underestimated disease. A GA(2)LEN study

Allergy

Passive smoking: the medical and economic issues

Am J Med

Second-hand smoke: how damaging is it to health?

Nurs Times

Tobacco smoking, exposure to second-hand smoke, and asthma and wheezing in schoolchildren: a cross-sectional study

Acta Paediatr

Environmental pollutants and allergic rhinitis

Curr Opin Otolaryngol Head Neck Surg

Second hand smoke exposure in children: environmental factors, physiological effects, and interventions within pediatrics

Rev Environ Health

Secondhand tobacco smoke exposure and chronic rhinosinusitis: a population-based case-control study

Am J Rhinol Allergy

Alterations in gene expression of complement components in chronic rhinosinusitis

Am J Rhinol Allergy

Vitamin D increases tight-junction conductance and paracellular Ca2+ transport in Caco-2 cell cultures

Am J Physiol Gastriointest Liver Physiol

Vitamin D and immune function: an overview

Proc Nutr Soc

Oral administration of an active form of vitamin D3 (calcitriol) decreases atherosclerosis in mice by inducing regulatory T cells and immature dendritic cells with tolerogenic functions

Arterioscler Thromb Vasc Biol

1,25-Dihydroxyvitamin D3 selectively modulates tolerogenic properties in myeloid but not plasmacytoid dendritic cells

J Immunol

Rhinitis, sinusitis, and upper airway disease
Cigarette smoke exposure is associated with vitamin D3 deficiencies in patients with chronic rhinosinusitis