INF/IR-3: CYCLOPHILIN D DEPENDENT MPT AMPLIFIES INFLAMMATORY RESPONSE IN SEPTIC SHOCK.

Oxidative and nitrosative stress in septic shock trigger opening of mitochondrial permeability transition (mPT) pore which contribute to additional ROS production, mitochondrial swelling, cell death, multiple organ failure (MOF) and mortality. Cyclophilin D (CypD) is a component of mitochondrial permeability transition pore complex, and disruption of CypD prevents ischemia-reperfusion, calcium overload and ROS induced mPT and necrotic cell death. No data is available in the role of CypD disruption in septic shock models. We show that prevention of CypD-dependent mPT attenuates LPS-induced oxidative/nitrosative damages, DNA breaks, mitochondrial damage, activation of apoptosis (AIF, Endonuclease G and Cytochrome C release) and improve the survival of CypD-/- mice. Positive, or negative, effects of LPS on gene expressions for ROS, NO, GSH synthesis, death receptor, NRF2, mitochondrial biogenesis, NF-kappaB, acute phase response and complement pathways were significantly weakened in CypD knockout mice. These data show that CypD dependent mPT is an amplifier of LPS-induced mitochondrial damage, gene expressions, apoptotic pathways, and play a major role in the late phase mortality in LPS-induced septic shock. That is, CypD can be valuable drug target, and its inhibition may provide a novel possibility to reduce mortality in septic shock.

Citation

B Veres, B Sümegi, C Antus, P B Jakus, F Fónai, K Erős, P Dombóvári, Z Hegedűs. INF/IR-3: CYCLOPHILIN D DEPENDENT MPT AMPLIFIES INFLAMMATORY RESPONSE IN SEPTIC SHOCK. Shock (Augusta, Ga.). 2015 Oct;44 Suppl 2:7-8

PMID: 26375083

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