Abstract
Background: Sepsis/septic shock is a common complication in the intensive care unit, and the opening of the mitochondrial permeability transition pore (mPTP), as well as the endoplasmic reticulum stress (ERS), play important roles in this situation. Whether the combination of anti-ERS and anti-mPTP by 4-phenylbutyric acid (PBA) and Cyclosporine A (CsA) could benefit sepsis is unclear. Methods: The cecal ligation and puncture-induced septic shock models were replicated in rats, and lipopolysaccharide (LPS)-challenged primary vascular smooth muscle cells and H9C2 cardiomyocytes in vitro models were also used. The therapeutic effects of CsA, PBA, and combined administration on oxygen delivery, cardiac and vascular function, vital organ injury, and the underlying mechanisms were observed. Results: Septic shock significantly induced cardiovascular dysfunction, hypoperfusion, and organ injury and resulted in high mortality in rats. Conventional treatment including fluid resuscitation, vasoactive agents, and antibiotics slightly restored tissue perfusion and organ function in septic rats. Supplementation of CsA or PBA improved the tissue perfusion, organ function, and survival of septic shock rats. The combined application of PBA and CsA could significantly enhance the beneficial effects, compared with using PBA or CsA alone. Further study showed that PBA enhanced CsA-induced cardiovascular protection, which contributed to better therapeutic effects. Conclusion: Anti-ERS and anti-mPTP-opening by the combination of PBA and CsA was beneficial to septic shock. PBA enforced the CsA-associated cardiovascular protection and contributed to the synergetic effect.
Highlights
Sepsis/septic shock is a common and severe complication in the intensive care unit
Conventional therapy (CT) could increase and maintain mean arterial pressure (MAP) to about 80 mmHg in rats during fluid infusion, and MAP tended to decrease after infusion
This study showed that inhibition of the Mitochondrial permeability transition pore (mPTP) opening with Cyclosporine A (CsA) or anti-endoplasmic reticulum stress (ERS) with phenylbutyric acid (PBA) could improve cardiovascular function, increase the blood flow of vital organs, and increase the delivery and utilization of oxygen, and improve the survival in septic rats
Summary
Sepsis/septic shock is a common and severe complication in the intensive care unit. Studies have demonstrated that tissue hypoperfusion and/or organ dysfunction play critical roles in severe sepsis- or septic shock-associated morbidity and mortality. Impairment in tissue hypoperfusion or oxygen availability induced by hemodynamic disturbances in the macro- and micro-circulatory are considered to be the main reasons for organ dysfunction following severe sepsis and septic shock (Zanotti-Cavazzoni and Hollenberg, 2009). Mitochondria are the center of energy metabolism and play important roles in the regulation of cell functions. Sepsis/septic shock is a common complication in the intensive care unit, and the opening of the mitochondrial permeability transition pore (mPTP), as well as the endoplasmic reticulum stress (ERS), play important roles in this situation. Whether the combination of anti-ERS and anti-mPTP by 4-phenylbutyric acid (PBA) and Cyclosporine A (CsA) could benefit sepsis is unclear
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