Intravenous calcitriol administration regulates the renin-angiotensin system and attenuates acute lung injury in obese mice complicated with polymicrobial sepsis

Abstract

Calcitriol, an active form of vitamin D, has immunomodulatory and anti-inflammatory properties. Vitamin D levels have inverse correlation with sepsis outcomes and obesity may aggravate the severity of the diseases. This study administered calcitriol to investigate its impact on sepsis-induced acute lung injury (ALI) in obese mice. Mice were fed a high-fat diet to induce obesity and were randomly assigned to control or sepsis groups, which were intravenously administered either saline (SS) or calcitriol (SD). Sepsis was induced by cecal ligation and puncture (CLP). Saline or calcitriol was injected 1 h after CLP via tail vein. Mice were sacrificed at either 12 or 24 h post-CLP and survival rates were observed. The results demonstrated that sepsis caused upregulation of inflammatory mediators and downregulation of renin-angiotensin system (RAS)-associated gene expressions in the lungs of obese mice. Cluster of differentiation 68 (CD68) expression and myeloperoxidase (MPO) activities also increased. Calcitriol treatment lowered expressions of blood and lung inflammatory mediators at 12 and/or 24 h after CLP. The RAS-proinflammatory-associated angiotensin type 1 receptor (AT1R) was lower while anti-inflammatory Mas receptor and AT2R expressions were higher at 12 h after CLP than those in the SS group. In addition, the SD group exhibited lower CD68 expression and MPO activity. Lower lung injury scores and higher survival rates were also noted in the SD group. The findings suggest that calcitriol treatment after sepsis induction upregulated RAS-associated anti-inflammatory pathway and decreased immune cell infiltration, which may have alleviated the severity of ALI of obese mice.