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Op weg naar een inhalatietherapie met vitamine D voor COPD?

Boek - Dissertatie

Chronic Obstructive Pulmonary Disease (COPD) is characterized by a progressive and not fully reversible airflow limitation due to a chronic inflammatory reaction in the small airways as a reaction to harmful gasses and particles (small airway disease). In addition, a protease/anti-protease imbalance leads to the destruction of the alveoli (emphysema). COPD is further complicated by the presence of exacerbations, causing a worsening of the patient's symptoms and leading to a change in medication. These exacerbations are most often caused by viral or bacterial infections. Cigarette smoking is the most important risk factor for COPD, but other factors like infections, genetic background and air pollution play an important role in the development and progression of COPD. Currently, treatment is focused on controlling symptoms by using bronchodilators with azithromycin or inhaled corticosteroids added in case of frequent exacerbations. However, these therapies solely tackle symptoms and a large need for more effective anti-inflammatory treatments remains. Due to its immunomodulatory actions apart from its effect on bone, the potential of vitamin D has been tested both in a preclinical and clinical setting in COPD. Vitamin D has been shown to exert anti-inflammatory and anti-microbial effects in cigarette-smoke exposed alveolar macrophages and oral vitamin D supplementation is able to reduce the exacerbation rate by 45% in COPD patients with a severe vitamin D deficiency. However, many unknowns remain. Therefore, the first aim of this thesis was to make an overview of randomized control trials using vitamin D supplementation in respiratory diseases to analyze the use and the effect of vitamin D in respiratory diseases including tuberculosis, pneumonia, asthma, COPD and cystic fibrosis. While a beneficial effect could not be demonstrated for tuberculosis, pneumonia and cystic fibrosis; a beneficial effect of oral vitamin D supplementation was observed for asthma and severely vitamin D deficient COPD patients. There is limited evidence about the exact mechanisms of the vitamin D metabolism in lungs and airways of COPD patients and the role and importance of local vitamin D concentrations. We therefore examined the expression and localization of the aforementioned proteins and enzymes in lung tissue of 10 COPD explant lungs and 10 unused donor lungs. While no differences in expression were found for CYP27B1 and CYP24A1, protein levels of VDR were significantly lower in COPD explant tissue. However, this did not result in a lower expression of a VDR target gene, cathelicidin, an antimicrobial peptide. While VDR and CYP27B1 were mainly expressed in the bronchial epithelium, CYP24A1 was additionally expressed in endothelial cells suggesting that when oral vitamin D is given, vitamin D could be inactivated before reaching target cells in the lung. Interestingly, while expression of CYP27B1 and CYP24A1 was evenly distributed across the epithelial layer, expression of VDR was confined to the apical cells while basal cells were negative. These results illustrate that vitamin D is active within the lung and the bronchial epithelium and that the bronchial epithelium, a key player in COPD, may be a potential target for vitamin D treatment, in particular via inhalation. Therefore, bronchial epithelial cells were exposed to cigarette smoke extract and vitamin D. In addition to the use of a cell line, we also used primary bronchial epithelial cells of both unused donor lungs and COPD explant lungs. Vitamin D exerted antimicrobial effects via the upregulation of cathelicidin and possibly iNOS. An anti-inflammatory effect was found in the bronchial epithelial cell line, but could not be demonstrated in primary bronchial epithelial cells, perhaps due to technical limitations. In conclusion, the maintained expression profiles of the vitamin D metabolism in the lungs of COPD patients, together with their localization and the beneficial antimicrobial and possibly anti-inflammatory effect of vitamin D on CSE-exposed bronchial epithelial cells suggest that vitamin D supplementation via inhalation may be beneficial for COPD patients.
Jaar van publicatie:2020
Toegankelijkheid:Closed