Exploring the role of the vitamin D pathway in pulmonary innate immunity in COPD

Chronic obstructive pulmonary disease (COPD) is a chronic lung disease affecting millions of people worldwide. Enhanced inflammatory responses within the airways is one of the key characteristics in the pathophysiology of COPD. Although cigarette smoking is the major risk factor, only around 20% of smokers actually develop COPD. Therefore, other risk factors must be involved in COPD onset and progression. We hypothesize that vitamin D deficiency, which is highly prevalent worldwide and even more so in COPD patients, could be such a risk factor for COPD onset and progression because of its anti-inflammatory and antibacterial potential. The use of our established mouse model of CS-induced COPD allowed us to elucidate whether vitamin D deficiency is a causal contributing factor to COPD onset and progression. In Chapter 3, we demonstrate that vitamin D deficiency greatly enhances airway and parenchymal inflammation in a mouse model of subacute and chronic CS exposure, resulting in early onset of emphysema and consistent lung hyperinflation. Our data further strengthen the epidemiological associations that link vitamin D deficiency to COPD onset and progression (lung function decline, exacerbations). Respiratory bacterial infections, such as nontypeable Haemophilus influenzae (NTHi), are the major trigger for COPD exacerbations and amplify the ongoing inflammation in COPD. In Chapter 4, we have investigated whether vitamin D deficiency may affect bacterial clearance and acute inflammatory response to a respiratory infection with NTHi. Although results are preliminary and additional research is necessary, our results suggest that vitamin D deficiency may amplify acute inflammatory responses directly following NTHi infection, leading to a more rapid clearance of the infection and accompanying inflammation. As vitamin D deficiency is highly prevalent worldwide, our results implicate that vitamin D may be a promising strategy to prevent COPD onset and progression. However, it is currently not known whether the active form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)2D), can indeed exert anti-inflammatory and antibacterial functions within CS-compromised airways. By using in vitro cell research, we have demonstrated in Chapter 5 that 1,25(OH)2D dampens levels of important inflammatory mediators (IL-8, TNF-a, MCP-1) released by alveolar macrophages from (non-) smoking subjects and released by cigarette smoke extract (CSE)-treated THP-1 macrophages (cell line model for alveolar macrophages). 1,25(OH)2D furthermore enhanced the release of the important antimicrobial peptide cathelicidin from alveolar macrophages from (non-)smoking subjects and CSE-treated THP-1 macrophages. As we have shown that vitamin D metabolism in THP-1 macrophages is not affected by CS exposure, our results suggest that 1,25(OH)2D can exert its anti-inflammatory and antibacterial functions within the airways of smoking subjects and in this way could potentially decrease susceptibility to COPD in those subjects. Although our data support the use of vitamin D supplementation as a means for reducing COPD onset and progression, (high-dose) vitamin D supplementation may lead to high serum vitamin D levels, which have been previously associated with increased risk of adverse outcomes. In Chapter 6, we demonstrate that high serum vitamin D levels, resulting from high-dose vitamin D supplementation, enhance characteristic disease features of COPD (emphysema, lung hyperinflation, pulmonary inflammation) in our mouse model of subacute and chronic CS exposure. These results together with the results from Chapter 3 suggest that there may be an optimal range for serum vitamin D levels. Taken together, our data demonstrate an important role for the vitamin D pathway in COPD onset and progression and support the need for more well-designed intervention studies with vitamin D supplementation.status: publishe