Is vitamin D deficiency a mechanistic driver of acute lung injury?

The acute respiratory distress syndrome (ARDS) remains a major cause of morbidity and mortality in the critically ill patient. There are no effective strategies for identifying those most at risk or therapeutic interventions proven to prevent its occurrence. Vitamin D deficiency is common and has important functions besides calcium homeostasis with profound effects on human immunity. Preliminary data suggests in the high-risk sepsis and oesophagectomy groups that vitamin D deficiency may be a pre-existing risk factor and mechanistic driver of ARDS. This thesis investigated in an animal model and in-vitro studies whether vitamin D influences the innate immune response to sepsis and resolution of neutrophilic injury. In addition, it reports a proof of concept phase II study to determine if vitamin D therapy in patients undergoing oesophagectomy is anti-inflammatory and protective of markers of lung injury. Vitamin D deficiency significantly increased the bacterial load, bacteraemia and translocation to the lung in a murine model of peritonitis. This was associated with a rise in tissue permeability locally and within the lung, reduced antimicrobial peptide and defective peritoneal macrophage phagocytosis. These data support pre-existing vitamin D deficiency as a determinant of the severity of bacteraemic sepsis. In-vivo high dose vitamin D supplementation was a safe, well-tolerated preoperative intervention with reduced biomarkers of alveolar oedema, capillary leak and macrophage efferocytosis. In-vitro culture with vitamin D increased macrophage efferocytosis and promoted monocyte differentiation to a pro-resolution phenotype. This suggests a potential mechanism for vitamin D on protecting barrier integrity and resolution of neutrophilic inflammation, a hallmark of ARDS. This body of work demonstrates that vitamin D deficiency is a potential modifiable risk factor and should be identified and treated in patients at risk of sepsis and ARDS. Larger trials powered to evaluate the effect of vitamin D on preventing and improving clinical outcomes in sepsis and ARDS are warranted