Cyclophilin D Regulates Oxidative Stress and Apoptosis via Mitochondrial Permeability Transition Pore in Acute Acalculous Cholecystitis.

ABSTRACT

OBJECTIVE: Acute acalculous cholecystitis (AAC) is characterized by acute onset, rapid progression, high mortality, and various complications. Cyclophilin D (CypD) regulates the mitochondrial permeability transition pore (MPTP) and is involved in the occurrence of ischemia-reperfusion injury and inflammation; however, the role of CypD in AAC remains unclear. METHODS: Guinea pigs of 300-350 g were randomly divided into three groups, namely the sham group, the common bile duct ligation-24h group (CBDL-24h group), and the CBDL-48h group. Western blot and qRT-PCR were applied to analyze the differential expression of CypD in each group, and transmission electron microscopy was employed to detect changes in mitochondrial structure. Inhibiting the activity of CypD by Cyclosporine A (CsA), we evaluated the difference of mitochondrial utilizing mitochondrial swelling, reactive oxygen species (ROS) detection and mitochondrial membrane potential. RESULTS: Compared with the sham group, the prolongation of obstruction aggravated gallbladder inflammation and upregulated CypD expression in the CBDL-24h and CBDL-48h groups. The degree of mitochondrial swelling was increased, and the opening of MPTP was prolonged in the CBDL-24h and 48h groups. Decreasing the expression of CypD could repress the opening of MPTP, prevent manipulation of the mitochondrial membrane potential, and ultimately diminish the levels of intracellular ROS and apoptosis. CONCLUSION: CypD plays a proinflammatory role in the development of AAC by regulating the opening of MPTP. Inhibiting the activity of CypD could reduce the levels of ROS and apoptosis, rescue the function of mitochondria and finally alleviate AAC. Therefore, CypD might serve as a potential therapeutic target for ACC.