Changes of Foxo3a in PBMCs and its associations with stress hyperglycemia in acute obstructive suppurative cholangitis patients

// Niu Bailin 1, * , Chen Nan 2, 3, * , Li Peizhi 2 , He Kun 2 , Zhu Xiwen 2 , Ren Guosheng 4 , Gong Jianping 2 and Zhang Wenfeng 2 1 Department of Emergency and Department of Intensive Care Unit, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China 2 Chongqing Key Laboratory of Hepatobiliary Surgery and Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China 3 Department of Anesthesia, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China 4 Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China * These authors have contributed equally to this work Correspondence to: Zhang Wenfeng, email: zhangwenfeng07@163.com Keywords: sepsis, stress hyperglycaemia, forkhead box O3a, nuclear factor κB, Akt Received: March 17, 2017     Accepted: June 29, 2017     Published: August 07, 2017 ABSTRACT Objective: The levels of Foxo3a in the peripheral blood mononuclears cells (PBMCs) before and after treatment were detected in acute obstructive suppurative cholangitis (AOSC) patients to evaluate the associations between Foxo3a and stress hyperglycemia (SHG). Methods: PBMCs were obtained from AOSC patients (n=28) on admission (AP), from patients at 1 week after cure (RP) and from healthy volunteers (HV) (n=14) to evaluate the relationship between the protein levels of Foxo3a and the serum levels of glucose. Signaling pathways, which link inflammation and glycometabolism, simultaneously affecting the expression of Foxo3a, were detected. In addition, cytokines were detected in PBMCs and AOSC mouse models, which were pre-treated with Foxo3a agonist. Results: The levels of glucose and p-Foxo3a in the AP were significantly higher than those in the RP and HV, where as the levels of Foxo3a in the AP were lower than those in the RP and HV. Foxo3a levels in the AP normalized against RP were strongly negatively correlated with the glucose levels in the AP normalized against RP. The levels of sphingosine-1-phosphate receptor 2 (S1PR2) in the AP were higher than those in the RP and HV. In addition, inhibition of Foxo3a phosphorylation, coupled with the down-regulation of S1PR2, attenuated the LPS-induced inflammatory response in the PBMCs and AOSC mouse models. Conclusions: Foxo3a is correlated with the dysregulation of glucose homeostasis in the pathogenesis of AOSC-induced sepsis by inhibiting the activation of PI3K/Akt-S1PR2 and NF-κB pathways, hinting at a switched role and therapeutic potentialities in the early stage of sepsis.