Table 2.

Mechanism of action on target organ systems that may influence critically ill patients.

Target organs	Mechanism of action
Immune system	Vitamin D metabolites are acting as modulators of cells of the innate and adaptive system (30, 31, 34) Innate system: 1,25-dihydroxyvitamin D3 and 3 of its analogs induce expression of the human cathelicidin antimicrobal peptide (CAMP) gene and genes involved in autophagy and phagosome maturation all of which are involved in the intracellular destruction of pathogens; promotion of an anti-inflammatory response by inhibiting the maturation of DCs; Adaptive system: VitD induces anti-inflammatory responses through direct effects on T-cells (34, 77, 78)
Cardiac function	Vitamin D may play a role in atrial fibrilation prevention by negatively regulating the renin–angiotensin–aldosterone–system (RAAS), mediating calcium homeostasis, binding to vitamin D receptors (VDR) on cardiac myocytes and furthermore by having antioxidant properties that may reduce levels of reactive oxygen species (ROS) in the atria, which contribute to inflammation and proarrhythmic substrate formation (79) The exact mechanism of action unknown but the recent research on animal models suggest that calcitriol has been shown to have a key role in enabling the maturation and differentiation of ventricular myocytes isolated from neonatal rat hearts and could therefore potentially influence heart failure (37) Vitamin D receptors are also present in all cells implicated in atherosclerosis. Those include endothelial cells, vascular smooth muscle cells and immune cells. It appears to regulate vascular cell growth, migration and differentiation; immune response modulation; cytokine expression; and inflammatory and fibrotic pathways. All of those mechanisms play a crucial role in different stages of the atherosclerotic plaque vulnerability and rupture (80)
Lung function	A lack of VDRs in the pulmonary epithelial barrier appeared to compromise its defense, leading to more severe lipopolysaccharide (LPS)-induced lung injury. Moreover, vitamin D treatment alleviated LPS-induced lung injury and preserved alveolar barrier function (35). Therefore, vitamin D may be a potential therapeutic strategy in acute lung injury and acute respiratory distress syndrome
Muscle function and metabolism	Some molecular mechanism studies suggest that vitamin D impacts muscle cell differentiation, intracellular calcium handling, and genomic activity. Some animal models have confirmed that vitamin D deficiency and congenital aberrations in the vitamin D endocrine system may result in muscle weakness (36, 81, 82)
Bone	Limited available data in ICU survivors suggest impaired bone health and high fracture risk (38, 39, 40, 41, 83). 1,25(OH)(2)D(3) is known primarily as a regulator of calcium, but it also controls phosphate (re)absorption at the intestine and kidney. Mechanism of action involve 1,25(OH)2D3, FGF23 (fibroblast growth factor 23 – phosphaturic hormone produced in osteoblasts) and 1,25(OH)(2)D(3) via the PTH axis (84)