Effects of different routes and forms of vitamin D administration on CD4⁺ T cell homeostasis and renin-angiotensin system-associated lung injury in obese mice complicated with polymicrobial sepsis

This study investigated the impacts of enteral cholecalciferol and/or intravenous calcitriol administration on the balance of cluster of differentiation 4-positive T cell subsets, the renin-angiotensin system (RAS), and the severity of acute lung injury (ALI) in obese mice with sepsis. Mice were fed a high-fat diet and then cecal ligation and puncture (CLP) was performed. Obese mice were divided into four sepsis groups: without vitamin D (VD) (S), with oral cholecalciferol 1 d before CLP (G), with intravenous calcitriol 1 h after CLP (V), and with both cholecalciferol before and intravenous calcitriol after CLP (GV). Mice were euthanized after CLP. The V and GV groups showed higher blood T helper (Th)1/Th2 and lower Th17/T regulatory (Treg) ratios than did the S and G groups. In the lungs, The V group had the lowest nuclear factor-κB and interleukin-1β gene expressions among all groups 24 h post-CLP. In parallel, gene expressions of angiotensin type 2 receptor (AT2R), angiotensin-converting enzyme 2 (ACE2), and Mas receptor (MasR) were highest in the V group compared to other groups. The protein levels of MasR in the GV group and the AT2R/AT1R ratio in the V group were higher than those in the G and/or S groups. All of the VD-treated groups had lower injury scores than the S group. These findings suggest that calcitriol administration had more-pronounced impacts on regulating the homeostasis of Th/Treg cells and is prone to RAS-associated anti-inflammatory pathway in the lungs. However, both forms of VD attenuated sepsis-induced ALI in obese animals.