Vitamin D mediated mitigation of fibrotic remodeling in asthma is associated with metabolic reprogramming

Vitamin D mediated mitigation of fibrotic remodeling in asthma is associated with metabolic reprogramming Rakhee K. Ramakrishnan1, Zaina Kalaji1, Khuloud Bajbouj1, Rabih Halwani1,2, Qutayba Hamid1,3 1 Sharjah Institute for Medical Research – College of Medicine, University of Sharjah, Sharjah, United Arab Emirates 2 Immunology Research Lab, College of Medicine, King Saud University, Riyadh, Saudi Arabia 3 Meakins-Christie Laboratories, McGill University, Montreal, Quebec, CanadaAsthma is a heterogeneous disorder that is associated with chronic airway inflammation and remodeling of the airways. While vitamin D deficiency has shown correlations with various clinical features of asthma, the mechanisms responsible for this action is poorly understood. This study therefore explored the molecular mechanisms associated with the anti-remodeling potential of vitamin D. We hypothesized that vitamin D induced metabolic reprogramming contributes to its anti-fibrotic activity. To this end, primary lung fibroblasts from asthmatic and non-asthmatic individuals were stimulated with TGF-β1 alone or in combination with the biologically active form of vitamin D, calcitriol. The expression of various fibrotic and metabolic markers was assessed both at the transcript and protein level. While vitamin D receptor (VDR) was constitutively expressed in human lung fibroblasts, calcitriol treatment induced a robust VDR response in asthmatic fibroblasts indicating increased VDR functionality in these cells when compared to normal. TGF-β1 stimulation led to an increase in the expression of several fibrotic markers, including COL1A1, COL3A1, COL5A1, FN1 and ACTA2, which was reversed after calcitriol treatment. These anti-fibrotic effects of calcitriol were associated with dysregulated AMPK signaling and an inhibition of TGF-β1-induced mitochondrial ROS release. Our findings thus, highlight the ability of vitamin D in regulating the cellular mitochondrial metabolism induced by TGF-β1 in lung fibroblasts, suggesting a possible mechanism associated with its anti-fibrotic activity. Since current asthma therapeutics do not effectively target the airway structural changes that are increasingly associated with asthma severity, vitamin D supplementation presents an attractive therapeutic avenue to attenuate subepithelial fibrosis and airway remodeling in asthmatic airways. We would like to acknowledge the funding received from University of Sharjah targeted research grant (ID 2101090295) in conducting this study. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.