Ethanol potentiates hypoxic liver injury: role of hepatocyte Na+ overload

AbstractCentrilobular hypoxia has been suggested to contribute to hepatic damage caused by alcohol intoxication. However, the mechanisms involved are still poorly understood. We have investigated whether alterations of Na+ homeostasis might account for ethanol-mediated increase in hepatocyte sensitivity to hypoxia. Addition of ethanol (100 mmol/l) to isolated rat hepatocytes incubated under nitrogen atmosphere greatly stimulated cell death. An increase in intracellular Na+ levels preceded cell killing and Na+ levels in hepatocytes exposed to the combination of ethanol and hypoxia were almost twice those in hypoxic cells without ethanol. Na+ increase was also observed in hepatocytes incubated with ethanol in oxygenated buffer. Ethanol addition significantly lowered hepatocyte pH. Inhibiting ethanol and acetaldehyde oxidation with, respectively, 4-methylpyrazole and cyanamide prevented this effect. 4-methylpyrazole, cyanamide as well as hepatocyte incubation in a HCO3−-free buffer or in the presence of Na+/H+ exchanger blocker 5-(N,N-dimethyl)-amiloride also reduced Na+ influx in ethanol-treated hepatocytes. 4-methylpyrazole and cyanamide similarly prevented ethanol-stimulated Na+ accumulation and hepatocyte killing during hypoxia. Moreover, ethanol-induced Na+ influx caused cytotoxicity in hepatocytes pre-treated with Na+,K+-ATPase inhibitor ouabain. Also in this condition 4-methylpyrazole and 5-(N,N-dimethyl)-amiloride decreased cell killing. These results indicate that ethanol can promotes cytotoxicity in hypoxic hepatocytes by enhancing Na+ accumulation

A risk-based approach to cumulative effect assessments for marine management

Marine ecosystems are increasingly threatened by the cumulative effects of multiple human pressures. Cumulative effect assessments (CEAs) are needed to inform environmental policy and guide ecosystem-based management. Yet, CEAs are inherently complex and seldom linked to real-world management processes. Therefore we propose entrenching CEAs in a risk management process, comprising the steps of risk identification, risk analysis and risk evaluation. We provide guidance to operationalize a risk-based approach to CEAs by describing for each step guiding principles and desired outcomes, scientific challenges and practical solutions. We reviewed the treatment of uncertainty in CEAs and the contribution of different tools and data sources to the implementation of a risk based approach to CEAs. We show that a risk-based approach to CEAs decreases complexity, allows for the transparent treatment of uncertainty and streamlines the uptake of scientific outcomes into the science-policy interface. Hence, its adoption can help bridging the gap between science and decision-making in ecosystem-based management