Inhaled Vitamin D as a Protectant Against Respiratory Infections and Environmental Pollutants

Viral infections and air pollution rank among the highest threats to lung health. People with higher melanin expression, bear a disproportionate burden of environmental lung diseases and respiratory infections due to higher exposure to air pollution, genetic predispositions, and other factors, such as nutrition, including increased prevalence of vitamin D deficiency. In addition to reduced nutritional intake of vitamin D-rich foods, high melanin levels in the skin of people with higher melanin expression prevent UVB absorption and biosynthesis of vitamin D. Lower vitamin D levels have been linked to higher incidence and severity of chronic lung disease, such as asthma and viral infections, such as influenza. However, oral vitamin D supplementation has shown mixed results in treating lung diseases, potentially due to the inability of reaching the lungs. Therefore, the objective of this proposal is to investigate inhalation of vitamin D as a route of direct delivery to the airways to protect against air pollution and respiratory infections. Preliminary studies I have conducted indicate that vitamin D may act as a membrane antioxidant, upregulate the expression of the antimicrobial peptide cathelicidin, and attenuate oxidative stress and inflammation induced by air pollutants. Based on these data, I hypothesize that inhaled vitamin D can reduce the severity of respiratory infections and abnormal immune responses to environmental pollutants in human bronchial epithelial cells (HBECs). First, I aim to understand how inhaled vitamin D protects the airway epithelium from lung inflammation caused by respiratory infections and environmental pollutants. Using a novel aerosol deliver system I have developed, HBECs will be pre-treated with aerosolized vitamin D before influenza infection or pollutant exposure, followed by characterization of markers of inflammation, oxidative stress, viral load, and immune dysfunction. I will then determine the potential mechanisms behind this through investigation into the membrane antioxidant properties of vitamin D using live cell imaging techniques. Second, I aim to investigate demographic differences in the pharmacokinetics and pharmacodynamics of vitamin D in the airway epithelium to determine the feasibility of vitamin D inhalation as a therapeutic strategy. HBECs from diverse donors will be treated with aerosolized or basolateral vitamin D, and concentrations of vitamin D metabolites and vitamin D-related signaling proteins will be measured over time. Despite established links between vitamin D status and respiratory health, no studies have investigated the use of inhaled vitamin D as a therapeutic or adjunct treatment for airway inflammation. This proposal is innovative as it uses a new in vitro aerosol delivery system to evaluate a novel route of delivery of vitamin D, investigates its membrane antioxidant and antimicrobial mechanisms as a prophylactic against lung inflammation, and determines demographic differences in the pharmacokinetics of this compound. This application is impactful as delivery of vitamin D could provide a potent, cost-effective solution for treating the pulmonary effects of vitamin D deficiency, potentially reducing health disparities associated with environmental lung diseases and respiratory infections. Project Number: 1F31HL179957-01 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Kevin Schichlein | Institution: UNIV OF NORTH CAROLINA CHAPEL HILL, CHAPEL HILL, NC | Award Amount: $40,752 | Activity Code: F31 | Study Section: Special Emphasis Panel[ZRG1 F10A-R (20)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1F31HL17995701