Free radical biology in hypothermia

Abstract

In accidental hypothermia, elevated levels of ROS induce oxidative stress that leads to different degrees of cellular and tissue injury. In controlled hypothermia, a new thermal balance that is instated is regulated by the establishment of the hypothermic steady state characterized by altered ROS generation and an altered free radical balance. During cold periods, ectotherms decrease their metabolic rate, slow down their respiration, and cease physical activity by intrinsic physiological mechanisms. ROS production is decreased but regulated by rearrangements of metabolic redox processes and a restructuring of the cellular antioxidant defense system (ADS). The increased baseline activity of key ADS enzymes, as well as secondary enzymatic defenses and/or increased glutathione levels in preparation for an oxidative stressful situation arising from tissue reoxygenation, seem to be the preferred evolutionary adaptations in ecto- and heterotherms. Hypothermia is also manifested as a behavioral hypothermia response in which ectotherms react to hypoxic stress by opting for cooler environments. The hypometabolic state is the most effective of the available hypoxia defense mechanisms. The molecular mechanisms that regulate the transitions to and from hypometabolic states are highly conserved across phylogenic lines. A number of synergistic adaptations in hibernation might have therapeutic potential for human disease states, such as ischemia-reperfusion injury, traumatic CNS injury, and neurodegenerative diseases. The protective effects of hypothermia on ROS-mediated processes have been shown in several experimental models; however, hypothermia induces autonomous biological changes and acts at different cellular levels that may extend the therapeutic window by reducing free radical production, a key component of hypoxia-ischemia/reperfusion (I/R) injury. Hypothermia has to be combined with a multicomponent supplementary therapy which is dosed and timed to suit the specific cell type and tissue as well as the severity of the injury, but it must not interfere with the obvious benefit of hypothermia on overall ROS-mediated processes.