The prevalence of vitamin D deficiency is high all over the world and there is now a large body of evidence linking vitamin D deficiency to chronic conditions, including autoimmune, infectious, cardiovascular and respiratory disease. Of relevance to chronic respiratory disease, some studies have shown that vitamin D deficiency is more prevalent in patients with asthma. Lower vitamin D levels are also associated with reduced lung function, increased asthma exacerbations and airway remodelling. In asthma, structural alterations in the lung have origins in early life, and factors that influence lung development may alter lung function and cause an increased susceptibility to disease in the long term. Vitamin D may be a factor affecting lung development, and maternal vitamin D deficiency may therefore contribute to asthma pathogenesis in children.
This thesis examines the link between early-life vitamin D deficiency with airway remodelling and lung structure and function outcomes; as well as the role of vitamin D deficiency in chronic allergic airways disease. Specifically, this thesis addresses the hypotheses that 1) whole-life vitamin D deficiency impairs lung structure and function, and causes airway remodelling and airway hyperresponsiveness; 2) impairment in lung structure and function is caused by altered lung development as a result of vitamin D deficiency in utero; 3) vitamin D deficiency alters the expression of genes involved in airway remodelling; and 4) vitamin D deficiency exacerbates respiratory outcomes in chronic allergic airways disease.
The development of a physiologically relevant mouse model of vitamin D deficiency, together with the establishment of an in utero and postnatal exposure model allowed for the investigation of early-life vitamin D status on lung structure and function. Vitamin D deficiency caused airway hyperresponsiveness in adult female mice and this was accompanied by an increase in airway smooth muscle mass, as well as smaller lung volume and altered lung structure. In utero vitamin D deficiency was sufficient to cause these changes. The use of an established protocol for development of a chronic asthma model, using the common aeroallergen house dust mite, showed that vitamin D deficiency increased airway hyperresponsiveness and inflammation, but did not increase airway smooth muscle mass. Transcriptome sequencing via RNA-Seq demonstrated that vitamin D deficiency altered gene pathways involved in lung development and inflammation. Midline 1 was further identified as a potential mediator of asthma that is modulated by vitamin D.
This study provides evidence that early life vitamin D deficiency has long term impacts on lung health. While postnatal supplementation may reduce inflammation, it may not be sufficient to alter lung structure defects, which are likely to be established early in life. Vitamin D deficiency has the propensity to modulate gene expression and this study has identified potential markers of disease modified by vitamin D. These results add substantially to the growing body of literature which implicates vitamin D deficiency in chronic lung disease and highlights the importance of vitamin D not only in disease, but also in lung development.
|Qualification||Doctor of Philosophy|
|Publication status||Unpublished - 2015|