Vitamin D treatment modulates immune activation in cystic fibrosis.

Persistent inflammatory response in cystic fibrosis (CF) airways is believed to play a central role in the progression of lung damage. Anti-inflammatory treatment may slow lung disease progression, but adverse side effects have limited its use. Vitamin D has immunoregulatory properties. We randomized 16 CF patients to receive vitamin D2, vitamin D3 or to serve as controls, and investigated the effect of vitamin D supplementation on soluble immunological parameters, myeloid dendritic cells (mDCs) and T cell activation. Three months of vitamin D treatment were followed by two washout months. Vitamin D status at baseline was correlated negatively with haptoglobin, erythrocyte sedimentation rate and immunoglobulin A concentration. Total vitamin D dose per kg bodyweight correlated with the down-modulation of the co-stimulatory receptor CD86 on mDCs. Vitamin D treatment was associated with reduced CD279 (PD-1) expression on CD4+ and CD8+ T cells, as well as decreased frequency of CD8+ T cells co-expressing the activation markers CD38 and human leucocyte antigen D-related (HLA-DR) in a dose-dependent manner. There was a trend towards decreased mucosal-associated invariant T cells (MAIT) cell frequency in patients receiving vitamin D and free serum 25-hydroxyvitamin D (free-s25OHD) correlated positively with CD38 expression by these cells. At the end of intervention, the change in free-s25OHD was correlated negatively with the change in CD279 (PD-1) expression on MAIT cells. Collectively, these data indicate that vitamin D has robust pleiotropic immunomodulatory effects in CF. Larger studies are needed to explore the immunomodulatory treatment potential of vitamin D in CF in more detail.

Clinical impact of vitamin D treatment in cystic fibrosis: a pilot randomized, controlled trial.

BACKGROUND/OBJECTIVES: Vitamin D insufficiency in cystic fibrosis is common. Vitamin D3 is currently preferred over D2. We aimed to study the efficacy of vitamin D2 and D3 at increasing serum 25-hydroxyvitamin D (s25OHD) concentrations and their effect on respiratory health in cystic fibrosis. SUBJECTS/METHODS: Sixteen CF patients were randomized to receive vitamin D2 or D3 or to serve as controls. The starting dose of 5000 IU (<16 years old) or 7143 IU/day (⩾16 years old) was further individually adjusted. Three months of intervention were followed by two of washout (ClinicalTrials.gov NCT01321905). RESULTS: To increase s25OHD, the mean daily dose of vitamin D2 and D3 had to be increased up to 15650 and 8184 IU, respectively. The combined group of vitamin D2 and D3 treated patients decreased plasma IL-8 (P<0.05). Patients provided vitamin D3 improved FVC at the end of the trial (P<0.05). Change in s25OHD was positively correlated with changes in the adult Quality-of-Life respiratory score at the end of supplementation (P=0.006, r=0.90), and with changes in FEV1 (P=0.042, r=0.62) and FVC (P=0.036, r=0.63) at one month of washout. CONCLUSIONS: Vitamin D supplementation may contribute to reduced inflammation and improved lung function in CF.

Vitamin D deficiency as a risk factor for cystic fibrosis-related diabetes in the Scandinavian Cystic Fibrosis Nutritional Study.

AIMS/HYPOTHESIS: Many cystic fibrosis patients are vitamin D-insufficient. Cystic fibrosis-related diabetes is a major complication of cystic fibrosis. The literature suggests that vitamin D might possess certain glucose-lowering properties. We aimed to assess the relationship between vitamin D and cystic fibrosis-related glucose intolerance. METHODS: We enrolled 898 cystic fibrosis patients from Sweden, Norway and Denmark. Vitamin D intake was assessed using a seven-day food record. Serum 25-hydroxyvitamin D (s25OHD) and HbA(1c) were measured, and an OGTT was carried out. Multiple linear and logistic regressions were used for HbA(1c) and cystic fibrosis-related diabetes/OGTT result as outcome variables, respectively. Each model was controlled for country, and for known cystic fibrosis-related diabetes risk factors: age, sex, genotype, liver dysfunction, long-term corticosteroid treatment, and lung and pancreatic function. RESULTS: Degree of vitamin D insufficiency (OR 1.36; p = 0.032) and s25OHD < 30 nmol/l (OR 1.79; p = 0.042) were significant risk factors for cystic fibrosis-related diabetes. Accordingly, HbA(1c) value was positively associated with s25OHD < 30 nmol/l and < 50 nmol/l, as well as with degree of vitamin D insufficiency (adjusted R (2) = 20.5% and p < 0.05 in all). In subgroup analyses, s25OHD < 30 nmol/l determined the HbA(1c) value in paediatric patients (adjusted R (2) = 20.2%; p = 0.017), but not in adults. CONCLUSIONS/INTERPRETATION: Vitamin D status is associated with HbA(1c) and diabetes in cystic fibrosis, particularly in children. The study justifies prospective studies on the proposed role of vitamin D deficiency in the pathophysiology of diabetes mellitus.

Inverse relation between vitamin D and serum total immunoglobulin G in the Scandinavian Cystic Fibrosis Nutritional Study.

BACKGROUND/OBJECTIVES: The hallmark of cystic fibrosis (CF) is chronic lung inflammation. The severity of lung disease is closely correlated with immunoglobulin G (IgG) levels. Beyond its contribution to the bone health, the importance of vitamin D has not been fully recognized owing to the lack of human studies providing evidence of its benefit. In the context of the recently described immunomodulatory functions of vitamin D, we aimed to assess the relationship between vitamin D and IgG levels. SUBJECTS/METHODS: Eight hundred and ninety-six CF patients were included (0.53-65.9 years) from seven centers in Denmark, Norway and Sweden. Serum 25-hydroxyvitamin D (25OHD) and total IgG were measured, spirometry was carried out and vitamin D intake data were gathered using a 7-day dietary food record. Multiple linear regression analyses were performed for IgG and forced expiratory volume in 1λs (FEV1) as dependent variables, and serum 25OHD, daily food and supplemented vitamin D sources of intake as independent variables. The model was controlled for age, gender, genotype, CF-related diabetes, season, infection/colonization status, long-term oral corticosteroid treatment, long-term treatment with macrolide antibiotics, pancreatic insufficient phenotype and body mass index z-score. RESULTS: Serum total IgG levels were negatively associated with serum 25OHD (adjusted R (2) = 0.376; beta = -0.02; P<0.001), supplemented vitamin D intake per kg bodyweight (adjusted R (2) = 0.375; beta = -0.82; P < 0.001) and total vitamin D intake per kg bodyweight (adjusted R (2) = 0.398; beta = -0.60; P = 0.002). Serum 25OHD was positively associated with FEV1 (adjusted R (2) = 0.308; beta = 0.0007; P = 0.025). CONCLUSIONS: Increasing vitamin D intake may positively modulate inflammation in CF. This study supports the proposed role of vitamin D in the immune system during infection and substantiates prospective studies.

Spironolactone differently influences remodeling of the left ventricle and aorta in L-NAME-induced hypertension.

Aldosterone receptor antagonist, spironolactone, has been shown to prevent remodeling of the heart in several models of left ventricular hypertrophy. The aim of the present study was to determine whether the treatment with spironolactone can prevent hypertension, reduction of tissue nitric oxide synthase activity and left ventricular (LV) and aortic remodeling in N(G)-nitro-L-arginine methyl ester (L-NAME)-induced hypertension. Four groups of rats were investigated: control, spironolactone (200 mg/kg), L-NAME (40 mg/kg) and L-NAME + spironolactone (in corresponding dosage). Animals were studied after 5 weeks of treatment. The decrease of NO-synthase activity in the LV and kidney was associated with the development of hypertension and LV hypertrophy, with increased DNA concentration in the LV, and remodeling of the aorta in the L-NAME group. Spironolactone prevented the inhibition of NO-synthase activity in the LV and kidney and partially attenuated hypertension and LVH development and the increase in DNA concentration. However, remodeling of the aorta was not prevented by spironolactone treatment. We conclude that the aldosterone receptor antagonist spironolactone improved nitric oxide production and partially prevented hypertension and LVH development without preventing hypertrophy of the aorta in NO-deficient hypertension. The reactive growth of the heart and aorta seems to be controlled by different mechanisms in L-NAME-induced hypertension.

[Influrence of recombinant human procalcitonin on phagocytic and candidacidal ability of polymorphonuclear leukocytes and on killing mechanisms of serum and blood aganist bacteria Staphylococcus aureus and Escherichia coli]. / Vplyv rekombinantného lbdského prokalcitonínu na fagocytovú a kandi- dacídnu schopnost polymorfonukleárnych leukocytov a na cídne mechanizmy séra a krvi voti baktériám Staphylococcus aureus a Escherichia coli.

UNLABELLED: Procalcitonin (PCT) is a highly selective and specific marker for early diagnosis of sepsis. There is enough information confirming that procalcitonin should be considered as an important mediator in the pathophysiology of sepsis. The aim of our work was to evaluate the effect of recombinant human procalcitonin (rhPCT) on phagocytic and candidacidal activity of polymorphonuclear leukocytes (PMNL) in blood, as well as on killing mechanisms of fresh serum and blood against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). Our results show that rhPCT dose dependently decreased both phagocytic and candidacidal activity of polymorphonuclear leukocytes (p < 0.001). RhPCT inhibited also the microbicidal activity of both serum and blood on E. coli that was found by inoculation of suspension on culture plates. We found that rhPCT supported the E. coli colony count increase during the incubation in the presence of both serum and blood. The effect of rhPCT on the S. aureus colony count increase was not statistically significant. CONCLUSION: Our results indicate a suppressive effect of rhPCT on phagocytic and microbicidal activity of polymorphonuclear leucocytes.