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Oxidative Medicine and Cellular Longevity
Volume 2013 (2013), Article ID 957054, 10 pages
Oxidative Stress and Antioxidant Activity in Hypothermia and Rewarming: Can RONS Modulate the Beneficial Effects of Therapeutic Hypothermia?
Departament de Fisiologia i Immunologia, Universitat de Barcelona, Avenida Diagonal 643, 08028 Barcelona, Spain
Received 25 March 2013; Accepted 21 October 2013
Academic Editor: Honglian Shi
Copyright © 2013 Norma Alva et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Hypothermia is a condition in which core temperature drops below the level necessary to maintain bodily functions. The decrease in temperature may disrupt some physiological systems of the body, including alterations in microcirculation and reduction of oxygen supply to tissues. The lack of oxygen can induce the generation of reactive oxygen and nitrogen free radicals (RONS), followed by oxidative stress, and finally, apoptosis and/or necrosis. Furthermore, since the hypothermia is inevitably followed by a rewarming process, we should also consider its effects. Despite hypothermia and rewarming inducing injury, many benefits of hypothermia have been demonstrated when used to preserve brain, cardiac, hepatic, and intestinal function against ischemic injury. This review gives an overview of the effects of hypothermia and rewarming on the oxidant/antioxidant balance and provides hypothesis for the role of reactive oxygen species in therapeutic hypothermia.
Hypothermia has been known as a possible therapeutic tool for millennia. However, it has only been used more systematically in the last two centuries, and it is recently that we have started to understand some of its mechanisms of action and side effects.
1.1. Characterization of Hypothermia
Normal body temperature in humans is maintained near a constant level of 36.5–37.5°C through homeostatic processes of thermoregulation. The hypothalamus controls body temperature through the preoptic and the posterior nuclei. The posterior nucleus is especially important, since it acts in regulating the physiological responses that allow the control of body temperature, such as vasoconstriction, shivering or increased intake of food to warm-up, sweating, and vasodilation. Heat is mainly generated in muscle tissue, including other thermogenic organs such as the heart and the liver, while it is lost through the skin (90%) and lungs (10%) and its rate is influenced by the physics involved in the mechanisms of convection, conduction, evaporation, and radiation . In small mammals the brown adipose tissue (BAT) is known to act as a thermogenic organ allowing nonshivering thermogenesis. The presence and physiological relevance of BAT in adult humans were believed to be marginal. In recent years, however, it has been realized that a significant number of adult humans possess active BAT [2, 3] and that cold induces the activation of oxidative metabolism in BAT . Moreover, an inverse relationship between BAT activity and shivering has been demonstrated in humans exposed to cold .
When the human body is exposed to cold and the homeostatic mechanisms are unable to compensate the heat that is being lost, there is a drop in body temperature. The symptoms and consequences of hypothermia may vary depending on the degree of hypothermia and have been associated according to the four degrees or stages of severity: mild 32–35°C; moderate, 28–32°C; severe, 20–28°C; and profound at less than 20°C . Other authors such as Marion et al.  and Gentinello  included an additional category, the extreme hypothermia, when the temperature falls below 14°C.
Symptoms of mild hypothermia may be vague  and some physiological responses to preserve heat can be observed with sympathetic nervous system excitation provoking shivering, hypertension, tachycardia, tachypnea, and vasoconstriction. Additional symptoms that may be present are cold diuresis, mental confusion, hepatic dysfunction, and hyperglycemia due to the decrease in glucose uptake by cells, a decrease in insulin secretion, and impaired tissue sensitivity to insulin .
Moderate low body temperature results in a stronger shivering. Due to a slower speed in nervous transmission and lower brain blood flow, mild confusion, impaired mental skills, and muscle misscoordination become apparent, and movements are slow and labored . Skin blood vessels contract further as the body focuses its remaining resources on keeping the vital organs warm. Microcirculation alterations cause a reduction of blood flow, red cell sedimentation, and an increase in blood viscosity (2% per degree heat loss), which increases the reduced availability of oxygen in the tissues leading to a hypoxic situation and acidosis .
Severe hypothermia occurs with decreasing temperature, and other physiological systems begin to fail: heart rate, breathing rate, and blood pressure decrease all. The hypothalamus is not controlling anymore the thermoregulation. This results in a heart rate of about 30 beats per minute with a temperature of 28°C in humans . Mental skills and motor coordination are still more impaired with a difficulty in speaking, sluggish thinking, incoherent behavior, and amnesia starting to appear; lack of skill in using hands, poor muscle coordination, difficulties in walking, and stumbling are also usually present.
We must also consider the general effects of hypothermia that occur in all categories, such as a decrease in metabolism and oxygen consumption. The basal and activity metabolic rates decrease between 3 and 7% by the fall of 1 degree Celsius . The Q10 or relative change in metabolic rate for every 10 degrees of change in body temperature is about 2.3 . Prakash  mentions that oxygen consumption is reduced by 6% for each degree drop in body temperature. Arrhythmias are also often accompanied by frequent atrial fibrillation, bleeding, and coagulopathy due to mismatches in platelet function . Hypothermia has a strong immunosuppressive effect, increasing the risk of infections, specially wound infections and pneumonia [13, 14]. On respiratory function, hypothermia is also inhibitory, initially leading to a rapid shallow breathing followed by a bradypnea, bronchospasm, and hypoventilation. However, the oxygen partial pressure is stable during hypothermia, indicating that both cardiac output and oxygen consumption, despite being reduced, are actually sufficient to meet metabolic needs.
A further problem derives from the subsequent process of rewarming that necessarily follows in some time hypothermia. Rewarming is a challenge for homoeothermic organisms: a rise in temperature implies an increase in metabolism and oxygen demand by tissues. A circulatory collapse characterized by a decreased cardiac output and blood pressure has been described during the rewarming phase in victims of an accidental hypothermia . The final result will be influenced by the rate of rewarming. Polderman and Callaghan [16, 17] advise rates of 0.2–0.5°C/h for cardiac arrest and 0.1-0.2°C/h for other pathologies. After induction of severe hypothermia (20°C) and rewarming in rats a high mortality was found when rewarming at 0.35°C/min, while all animals survived at a rate of 0.25°C/min .
1.2. The Therapeutic Use of Hypothermia
Mild to moderate hypothermia (35 to 32°C) appears to be useful in preventing tissue damage, cell protection , and survival . Several international organizations such as the American Health Association and the International Liaison Committee on Resuscitation have recommended the use of therapeutic hypothermia in patients with cardiac pathologies among others . In the European Resuscitation Council Guidelines [24, 25], induced hypothermia is included in the standard recommendations after cardiopulmonary resuscitation.
Molecular and cellular pathways regulated by hypothermia have been recently reviewed . Many studies on the protective effects of hypothermia have been conducted in cell cultures, for example, in endothelial cells , in isolated organs such as heart , and in experimental animals . In this regard, the information obtained from studying hibernating mammals is particularly relevant. The hibernating mammals survive cyclical periods of torpor and arousal with large fluctuations in body temperature. It has been suggested that hibernation mitigates apoptosis  by an elevation of antiapoptotic  or prosurvival  proteins. The elucidation of the molecular mechanisms occurring during these periods of hypothermia can be helpful in future human clinical studies of therapeutic hypothermia.
Some of the therapeutic and side effects of the application of hypothermia are well documented . However, it is necessary to clarify the cellular mechanisms induced by cold to enable its safe clinical use. In the present work we discuss the role of RONS and antioxidants during hypothermia and rewarming, and we hypothesize that if the beneficial effects of therapeutic hypothermia could be due to RONS acting as signaling molecules.
2. Hypothermia and Oxidative Stress
2.1. Tissue Oxygen Availability and Acid/Base Regulation during Hypothermia
As we mentioned above, the decrease in temperature affects all the physiological systems of the body. The hypothermia process is associated with a reduction of blood flow . It is well known that cold exposure decreases renal  and liver flow [39, 40]. We analyzed the correlation between portal vein flows (PVF) as temperature drops from 37°C to 22°C in rats . Figure 1 shows how the cooling caused a decrease in PVF and we can see that the curve of PVF versus temperature fits a second order polynomial regression. This biphasic curve suggests that a homeostatic mechanism is working in opposition to hypothermia and is capable of maintaining PVF in mild and moderate hypothermia close to normal ranges. However, the physiological regulator mechanism can not control body temperature when this decreased towards more severe hypothermic value (below 30°C). Redistribution of blood flow and microcirculation disturbances induced by hypothermia can limit tissue oxygen availability .
In addition to changes in the availability of oxygen, hypothermia can affect other blood parameters like partial pressure of gases, electrolytes, and acid/base regulation. Alterations in pH are initially corrected by ventilation and then, in a slower process, by kidneys. When hypothermia develops the pH is altered. In fact, the combination of hypothermia and acidosis is seen as a critical point in the injured by trauma . The failure of respiratory and/or renal functions, acid/base regulation, and ion regulatory mechanisms has been suggested as critical during severe hypothermia .
The hemoglobin oxygen affinity actually increases in hypothermia, and a restricted oxygen discharge in tissues could be expected. A reduction in the supply of oxygen to tissues has been reported during mild hypothermia (34°C) . Although lack of oxygen could drive cells to anaerobic metabolism in order to maintain ATP production, cardiac lactate , liver lactate , and blood lactate  kept constant after hypothermia; suggesting that, even though blood supply to tissues is diminished in cold, the oxygen demand also drops in proportion to the lower metabolic requirements.
Accidental or therapeutic hypothermia implies an unavoidable process, the rewarming phase. The rise in temperature will increase metabolism and oxygen demand by tissues. Thus, a mismatch between blood flow restoration and tissue metabolism would cause anaerobic glycolisis, acid overload, and the release of metabolites into the blood stream .
As we mentioned above, an important consequence of the hypothermia and rewarming process would be the reduction in oxygen delivery to some tissues. The effect of this decrease in cellular oxygen could resemble a hypoxic condition in which oxygen free radicals are produced  and released from the mitochondria .
2.2. Oxidant/Antioxidant Balance in Hypothermia Rewarming
The reduced availability of oxygen in hypothermia may result in the accumulation of reducing equivalents in the mitochondrial electron transport chain, enhancing the production of reactive oxygen and nitrogen species (RONS) and the resulting oxidative stress, that is, the oxidation and subsequent functional impairment of lipids, proteins, and nucleic acids . Similar to what has been described for hypoxia-reoxygenation process , the return to physiological conditions of temperature may lead to an increased production of oxygen free radicals.
It has been reported that hypothermia (24°C to 28°C) can induce an increase in oxidative stress [49–51] but also a decrease in RONS [52, 53]. Using a model of isolated liver preservation, it has been reported that liver perfusion performed at 20°C can enhance the functional integrity of steatotic livers when compared to perfusion at 8°C and 4°C . Perfusion at 20°C also led to a marked improvement in hepatic preservation, cell viability, and reduction in oxidative stress parameters [54, 55]. When considering the effects of hypothermia on oxidative stress, the disparity in the results found could be due to different length of exposition to cold and to the temperature applied.
In physiological conditions there is a balance between the factors that promote the formation of free radicals and the levels of antioxidants. RONS are scavenged by enzymatic antioxidants like superoxide dismutase, glutathione peroxidase, and catalase  and by small molecular antioxidants such as reduced glutathione (GSH). GSH appears to be essential for the activation and maintenance of cellular defenses against oxidative stress, since it provides the substrate for glutathione peroxidase to detoxify peroxides. In rats acclimated to cold  lipid peroxidation increased and the activities and levels of antioxidants decreased in the erythrocytes.
We have studied the oxidant/antioxidant levels in vivo in rats at severe hypothermia and rewarming. After induction of anesthesia, animals were placed on a cooling/rewarming table and were mechanically ventilated with room air. Animals were cooled at a mean rate of −0.25°C/min until they achieve 22°C. After one hour at hypothermia rats were rewarmed at a rate of 0.35°C/min to 37°C. Hypothermia and rewarming increased nitric oxide in plasma and liver and lipid peroxidation in plasma (Table 1). The erythrocyte antioxidant enzymatic activity decreased in hypothermia (superoxide dismutase and catalase) and rewarming (glutathione peroxidase). Results regarding the role of GSH in the hypothermia and rewarming process deserve a more detailed analysis. GSH appears to be essential for the activation and maintenance of cellular defenses against oxidative stress  and is the main thiol-disulfide redox buffer in the cell. The data presented in Table 1 indicate that after hypothermia GSH levels are preserved in plasma and also in liver, which is the most important organ for GSH synthesis and exportation into the plasma. In contrast, rewarming results in a high consumption of GSH and, in erythrocytes, a dramatic reduction in the glutathione peroxidase activity. It has been reported that the protective effect of hypothermia against hypoxia-induced damage in vitro could be improved with the addition of catalase to the cellular medium . In view of our results, the administration of glutathione seems more advisable, at least in vivo situations.
3. RONS and Apoptosis
Apoptosis, or programmed cell death, is an accurately regulated mechanism whereby the cell actively uses a genetically controlled program to kill itself, with ATP being required to accomplish this process. Apoptosis is a key process that is involved in maintaining tissue homeostasis by removing senescent, genetically damaged cells or cells damaged by disease or noxious agents. Apoptosis is induced by two main ways: the activation of death receptors (the extrinsic pathway) or involving the mitochondria (the intrinsic pathway). In the extrinsic pathway signal arrives when “death ligands” such as TNFa, TRAIL, Apo3L, and Fas ligand (Fas L), bind to their specific membrane receptors causing their intramembrane domains to propagate the death signal intracellularly. RONS have been established as key participants in Fas-induced cell death [70, 71]. In the mitochondrial-mediated pathway the signal is originated intrinsically  by the stress produced in organelles like the mitochondria (e.g., RONS) or endoplasmic reticulum (e.g., excess of misfolded proteins), inducing the release of pro-apoptotic factors into the cytosol or inhibiting antiapoptotic molecules that will ultimately trigger apoptosis.
Regardless of the signal origin, the formation of a permeability transition pore at contact sites between the mitochondrial outer and inner membranes and the release of cytochrome c into the cytosol are considered the “points of no return” in apoptotic process. Thus, mitochondria are the central organelle in the execution of apoptosis . RONS generation in mitochondria increased prior to the onset of apoptosis , and the apoptotic process could be stopped by the addition of antioxidants .
4. The Role of RONS as Signaling Molecules
We must bear in mind that the formation of RONS is a physiological process. Indeed, RONS play a critical role in the cell, while at relatively high concentrations they become harmful; low levels can promote cell proliferation and survival [75, 76]. These dual effects of RONS, depending on their concentration, could explain why hypothermia through RONS generation sometimes gets involved in pathologies while when induced previous to or concomitant to an acute damage leads to a cellular protection. Some of the studies regarding the protective effects of hypothermia on oxidant/antioxidant parameters and against different types of injury are summarized in Table 2. While comparing different temperature levels in different species and affecting various tissues, some general conclusions can be drawn. Hypothermia increases oxidative stress, NO levels, and the GSH. When hypothermia is used in a model of injury, like ischemia or hypoxia (known to increase oxidative damage), paradoxically it causes a decreased oxidative stress and the maintenance or improvement of the antioxidant status.
Recently, we have described that the oxidative stress indicators were attenuated in rats with an acute damage (severe hypoxia) at hypothermia (at 22°C) compared with animals at normothermia (at 37°C) . Similarly, in cardiomyocytes  it was described a hypothermic protection through a reduction in the hydrogen peroxide-induced damage when cardiomyocytes were incubated at 20°C for 20 minutes. After rewarming, hypothermic cardiomyocytes showed a higher rate of reduction of intracellular reactive oxygen species compared to normothermically maintained cardiomyocytes. In addition, the neuroprotective effects of hypothermia had also been described in a model of oxygen-glucose deprivation in hippocampal cultures at 31°C  showing that the protection acts at moderate hypothermia, which may explain the protection observed in the range of therapeutic hypothermia (32–35°C) used in humans.
It has been exhaustively reported that a brief episode of ischemia makes organs (brain, heart, liver, and kidney) remarkably resistant to a subsequent ischemia, phenomenon know as ischemic preconditioning. The mechanisms of signaling pathways in cardiac ischemic preconditioning have been recently reviewed  and it is believed that RONS play an important role in the mechanisms of preconditioning and protection. During the early phase of preconditioning ROS and NO production afford protection against further damage in cerebral ischemia [79, 80] and in cardiomyocytes ischemia . The production of adenosine during ischemic preconditioning could mediate the protective effects . Adenosine increases energy production through increased glycolytic flux. Furthermore, it has been observed that adenosine inhibits the release of oxygen radicals during ischemia and reperfusion in myocardial ischemia, thus limiting endothelial cell injury . The production of adenosine during ischemic preconditioning is dependent on the levels of hypoxia-inducible factor 1 (HIF-1)  which mediates many adaptive responses to hypoxia by regulating the expression of genes involved in glycolysis, mitochondrial function, cell survival, and resistance to oxidative stress . Interestingly, activation of HIF-1α is correlated with better protection of fatty liver grafts after cold storage . However, the addition of an inhibitor of NO in the preservation medium reversed that protection. This highlighted the role of NO in liver preservation.
As referred to hypothermia, our results  and others [77–80] lead us to propose the hypothesis that hypothermia through the generation of RONS and increasing GSH can induce protective mechanisms. The most remarkable of hypothermia is that protection is observed both when induced prior to injury, as a preconditioning model (experimental hypothermia), and when applied after damage (therapeutic hypothermia). In the latter case, the sooner hypothermia is applied, the better prognosis patient will have [17, 87].
5. Role of RONS in the Beneficial Effects of Therapeutic Hypothermia
Therapeutic hypothermia has been used in the critically ill patients, and there is also abundant evidence from animal models of the protection induced by hypothermia when applied within minutes following ischemic damage (see Table 2). So far, the protective effects of hypothermia are believed to be a consequence of a reduction in the cellular metabolism and the retardation of destructive enzymatic reactions and the concomitant oxygen needs, thus conserving ATP levels .
More recently, the beneficial effects of hypothermia, when applied to prevent an ischemic episode, included a trigger level of RONS that can act as a mechanism for induction of signaling pathways and the modulation of the extrinsic and intrinsic pathways of apoptosis (see Figure 2). Hypothermia does not simply block cell signaling pathway of apoptosis and necrosis but selectively upregulates some protective genes after ischemia . Many experimental assays showed that when hypothermia is applied during an ischemia or hypoxia episode, it is able to inhibit proapoptotic molecules and to induce an increase in antiapoptotic ones in ischemic tissues [90, 91].
Because of these different mechanisms of action, it can be suggested that hypothermia may be protective in many organs and against many kinds of injury.
The generation of RONS is a typical feature of hypothermia and more prominent in rewarming. There is increasing evidence showing that the beneficial effects of hypothermia included a trigger level of RONS that can act as a mechanism for induction of signaling pathways and the modulation of apoptosis.
This study was supported by Spanish ISCIII and by European FEDER PI08-1389.
- N. A. Hanania and J. L. Zimmerman, “Accidental hypothermia,” Critical Care Clinics, vol. 15, no. 2, pp. 235–249, 1999.
- J. Nedergaard, T. Bengtsson, and B. Cannon, “Unexpected evidence for active brown adipose tissue in adult humans,” The American Journal of Physiology—Endocrinology and Metabolism, vol. 293, no. 2, pp. E444–E452, 2007.
- J. Nedergaard and B. Cannon, “The changed metabolic world with human brown adipose tissue: therapeutic visions,” Cell Metabolism, vol. 11, no. 4, pp. 268–272, 2010.
- W. D. Van Marken Lichtenbelt, J. W. Vanhommerig, N. M. Smulders et al., “Cold-activated brown adipose tissue in healthy men,” The New England Journal of Medicine, vol. 360, no. 15, pp. 1500–1508, 2009.
- V. Ouellet, S. M. Labbé, D. P. Blondin et al., “Brown adipose tissue oxidative metabolism contributes to energy expenditure during acute cold exposure in humans,” The Journal of Clinical Investigation, vol. 122, no. 2, pp. 545–552, 2012.
- J. Marx, R. Hockberger, and R. Walls, Rosen's Emergency Medicine: Concepts and Clinical Practice, Mosby, Elsevier, Philadelphia, Pa, USA, 7th edition, 2010.
- D. W. Marion, Y. Leonov, M. Ginsberg et al., “Resuscitative hypothermia,” Critical Care Medicine, vol. 24, no. 2, pp. S81–S89, 1996.
- L. M. Gentilello, “Advances in the management of hypothermia,” Surgical Clinics of North America, vol. 75, no. 2, pp. 243–256, 1995.
- S. S. Cheung, D. L. Montie, M. D. White, and D. Behm, “Changes in manual dexterity following short-term hand and forearm immersion in 10°c water,” Aviation Space and Environmental Medicine, vol. 74, no. 9, pp. 990–993, 2003.
- P. T. Schumacker, J. Rowland, S. Saltz, D. P. Nelson, and L. D. H. Wood, “Effects of hyperthermia and hypothermia on oxygen extraction by tissues during hypovolemia,” Journal of Applied Physiology, vol. 63, no. 3, pp. 1246–1252, 1987.
- J. Kofstad, “Blood gases and hypothermia: some theoretical and practical considerations,” Scandinavian Journal of Clinical and Laboratory Investigation, Supplement, vol. 56, no. 224, pp. 21–26, 1996.
- O. Prakash, “Hypothermia and acid-base regulation in infants,” Clinics in Perinatology, vol. 14, no. 1, pp. 199–225, 1987.
- K. H. Polderman, “Mechanisms of action, physiological effects, and complications of hypothermia,” Critical Care Medicine, vol. 37, no. 7, pp. S186–S202, 2009.
- K. H. Polderman, “Hypothermia, immune suppression and SDD: can we have our cake and eat it?” Critical Care, vol. 15, no. 2, article 144, 2011.
- D. Maclean and D. Emslie-Smith, Accidental Hypothermia, Blackwell Scientific, Melbourne, Australia, 1977.
- K. H. Polderman, “Application of therapeutic hypothermia in the ICU: opportunities and pitfalls of a promising treatment modality. Part 1: indications and evidence,” Intensive Care Medicine, vol. 30, no. 4, pp. 556–575, 2004.
- K. H. Polderman and J. Callaghan, “Equipment review: cooling catheters to induce therapeutic hypothermia?” Critical Care, vol. 10, no. 6, article 234, 2006.
- N. Alva, T. Carbonell, and J. Palomeque, “A model of deep experimental hypothermia and rewarming in rat,” Journal of Thermal Biology, vol. 29, no. 4-5, pp. 259–264, 2004.
- P. J. D. Andrews, H. L. Sinclair, C. G. Battison et al., “European society of intensive care medicine study of therapeutic hypothermia (32–35°C) for intracranial pressure reduction after traumatic brain injury (the Eurotherm3235Trial),” Trials, vol. 12, article 8, 2011.
- J. W. Lampe and L. B. Becker, “State of the art in therapeutic hypothermia,” Annual Review of Medicine, vol. 62, pp. 79–93, 2011.
- W. Slikker III, V. G. Desai, H. Duhart, R. Feuers, and S. Z. Imam, “Hypothermia enhances bcl-2 expression and protects against oxidative stress-induced cell death in Chinese hamster ovary cells,” Free Radical Biology and Medicine, vol. 31, no. 3, pp. 405–411, 2001.
- I. Khaliulin, S. J. Clarke, H. Lin, J. Parker, M.-S. Suleiman, and A. P. Halestrap, “Temperature preconditioning of isolated rat hearts—a potent cardioprotective mechanism involving a reduction in oxidative stress and inhibition of the mitochondrial permeability transition pore,” Journal of Physiology, vol. 581, no. 3, pp. 1147–1161, 2007.
- R. A. Kozar, “Hypothermia hype: is it worth it?” Critical Care Medicine, vol. 36, no. 5, pp. 1676–1677, 2008.
- J. P. Nolan, C. D. Deakin, J. Soar, B. W. Böttiger, and G. Smith, “European Resuscitation Council Guidelines for Resuscitation 2005: section 4. Adult advanced life support,” Resuscitation, vol. 67, no. 1, pp. S39–S86, 2005.
- C. D. Deakin, J. P. Nolan, J. Soar et al., “European Resuscitation Council Guidelines for Resuscitation 2010 Section 4. Adult advanced life support,” Resuscitation, vol. 81, no. 10, pp. 1305–1352, 2010.
- H. S. Han, J. Park, J.-H. Kim, and K. Suk, “Molecular and cellular pathways as a target of therapeutic hypothermia: pharmacological aspect,” Current Neuropharmacology, vol. 10, no. 1, pp. 80–87, 2012.
- S. Fischer, D. Renz, M. Wiesnet, W. Schaper, and G. F. Karliczek, “Hypothermia abolishes hypoxia-induced hyperpermeability in brain microvessel endothelial cells,” Molecular Brain Research, vol. 74, no. 1-2, pp. 135–144, 1999.
- M. L. Riess, A. K. S. Camara, L. G. Kevin, J. An, and D. F. Stowe, “Reduced reactive O2 species formation and preserved mitochondrial NADH and [Ca2+] levels during short-term 17°C ischemia in intact hearts,” Cardiovascular Research, vol. 61, no. 3, pp. 580–590, 2004.
- V. Alfaro and L. Palacios, “Comparison of acid/base status in conscious and anaesthetized rats during acute hypothermia,” Pflugers Archiv European Journal of Physiology, vol. 424, no. 5-6, pp. 416–422, 1993.
- F. Van Breukelen, G. Krumschnabel, and J. E. Podrabsky, “Vertebrate cell death in energy-limited conditions and how to avoid it: what we might learn from mammalian hibernators and other stress-tolerant vertebrates,” Apoptosis, vol. 15, no. 3, pp. 386–399, 2010.
- C. C. Fleck and H. V. Carey, “Modulation of apoptotic pathways in intestinal mucosa during hibernation,” The American Journal of Physiology—Regulatory, Integrative and Comparative Physiology, vol. 289, no. 2, pp. R586–R595, 2005.
- D. C. McMullen and J. M. Hallenbeck, “Regulation of Akt during torpor in the hibernating ground squirrel, Ictidomys tridecemlineatus,” Journal of Comparative Physiology B, vol. 180, no. 6, pp. 927–934, 2010.
- N. Alva, D. Azuara, J. Palomeque, and T. Carbonell, “Deep hypothermia protects against acute hypoxia in vivo in rats: a mechanism related to the attenuation of oxidative stress,” Experimental Physiology, vol. 98, no. 6, pp. 1115–1124, 2013.
- E. Siendones, D. Fouad, M. J. M. Díaz-Guerra, M. De La Mata, L. Boscá, and J. Muntané, “PGE1-induced NO reduces apoptosis by D-galactosamine through attenuation of NF-κB and NOS-2 expression in rat hepatocytes,” Hepatology, vol. 40, no. 6, pp. 1295–1303, 2004.
- H. S. Han, M. Karabiyikoglu, S. Kelly, R. A. Sobel, and M. A. Yenari, “Mild hypothermia inhibits nuclear factor-κB translocation in experimental stroke,” Journal of Cerebral Blood Flow and Metabolism, vol. 23, no. 5, pp. 589–598, 2003.
- D. J. A. Brown, H. Brugger, J. Boyd, and P. Paal, “Accidental hypothermia,” The New England Journal of Medicine, vol. 367, no. 20, pp. 1930–1938, 2012.
- N. P. Aardal, K. Svanes, and K. E. Egenberg, “Effect of hypothermia and pentobarbital anaesthesia on the distribution of cardiac output in rabbits,” European Surgical Research, vol. 5, no. 5, pp. 362–372, 1973.
- R. Sabharwal, E. J. Johns, and S. Egginton, “The influence of acute hypothermia on renal function of anaesthetized euthermic and acclimatized rats,” Experimental Physiology, vol. 89, no. 4, pp. 455–463, 2004.
- T. Tveita, M. Skandfer, H. Refsum, and K. Ytrehus, “Experimental hypothermia and rewarming: changes in mechanical function and metabolism of rat hearts,” Journal of Applied Physiology, vol. 80, no. 1, pp. 291–297, 1996.
- N. Alva, T. Carbonell, and J. Palomeque, “Deep hypothermia impact on acid-base parameters and liver antioxidant status in an in vivo rat model,” Canadian Journal of Physiology and Pharmacology, vol. 87, no. 6, pp. 471–478, 2009.
- M. D. McArthur, M. L. Jourdan, and L. C. H. Wang, “Prolonged stable hypothermia: effect on blood gases and pH in rats and ground squirrels,” The American Journal of Physiology—Regulatory, Integrative and Comparative Physiology, vol. 262, no. 2, pp. R190–R197, 1992.
- K. Thorsen, K. G. Ringdal, K. Strand, E. Søreide, J. Hagemo, and K. Søreide, “Clinical and cellular effects of hypothermia, acidosis and coagulopathy in major injury,” British Journal of Surgery, vol. 98, no. 7, pp. 894–907, 2011.
- T.-F. Lee, J. Westly, and L. C. H. Wang, “Effects of hetastarch and mannitol on prolonging survival in stable hypothermia in rats,” The American Journal of Physiology—Regulatory, Integrative and Comparative Physiology, vol. 278, no. 4, pp. R1040–R1047, 2000.
- X. Wu, J. Stezoski, P. Safar et al., “Mild hypothermia during hemorrhagic shock in rats improves survival without significant effects on inflammatory responses,” Critical Care Medicine, vol. 31, no. 1, pp. 195–202, 2003.
- J. F. Turrens, “Mitochondrial formation of reactive oxygen species,” Journal of Physiology, vol. 552, no. 2, pp. 335–344, 2003.
- R. D. Guzy, B. Hoyos, E. Robin et al., “Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing,” Cell Metabolism, vol. 1, no. 6, pp. 401–408, 2005.
- J. M. C. Gutteridge and B. Halliwell, Free Radicals and Antioxidants in the Year 2000—A Historical Look to the Future, New York Academy of Sciences, New York, NY, USA, 2000.
- S. L. Thompson-Gorman and J. L. Zweier, “Evaluation of the role of xanthine oxidase in myocardial reperfusion injury,” Journal of Biological Chemistry, vol. 265, no. 12, pp. 6656–6663, 1990.
- A. Gámez, N. Alva, T. Roig, J. Bermúdez, and T. Carbonell, “Beneficial effects of fructose 1,6-biphosphate on hypothermia-induced reactive oxygen species injury in rats,” European Journal of Pharmacology, vol. 590, no. 1–3, pp. 115–119, 2008.
- V. V. Zinchuk, L. V. Dorokhina, and A. N. Maltsev, “Prooxidant-antioxidant balance in rats under hypothermia combined with modified hemoglobin-oxygen affinity,” Journal of Thermal Biology, vol. 27, no. 5, pp. 345–352, 2002.
- S. Dede, Y. Deger, and I. Meral, “Effect of short-term hypothermia on lipid peroxidation and antioxidant enzyme activity in rats,” Journal of Veterinary Medicine Series A, vol. 49, no. 6, pp. 286–288, 2002.
- M. Hasegawa, T. Ogihara, H. Tamai, and M. Hiroi, “Hypothermic inhibition of apoptotic pathways for combined neurotoxicity of iron and ascorbic acid in differentiated PC12 cells: reduction of oxidative stress and maintenance of the glutathione redox state,” Brain Research, vol. 1283, pp. 1–13, 2009.
- C. M. Maier, G. H. Sun, D. Cheng, M. A. Yenari, P. H. Chan, and G. K. Steinberg, “Effects of mild hypothermia on superoxide anion production, superoxide dismutase expression, and activity following transient focal cerebral ischemia,” Neurobiology of Disease, vol. 11, no. 1, pp. 28–42, 2002.
- M. Vairetti, A. Ferrigno, F. Carlucci et al., “Subnormothermic machine perfusion protects steatotic livers against preservation injury: a potential for donor pool increase?” Liver Transplantation, vol. 15, no. 1, pp. 20–29, 2009.
- A. Ferrigno, F. Carlucci, A. Tabucchi et al., “Different susceptibility of liver grafts from lean and obese Zucker rats to preservation injury,” Cryobiology, vol. 59, no. 3, pp. 327–334, 2009.
- B. Halliwell and J. M. C. Gutteridge, Free Radicals in Biology and Medicine, Oxford University Press, Oxford, UK, 4th edition, 2006.
- S. Gümüşlü, S. B. Sarikçioǧlu, E. Şahin, P. Yargiçoǧlu, and A. Aǧar, “Influences of different stress models of the antioxidant status and lipid peroxidation in rat erythrocytes,” Free Radical Research, vol. 36, no. 12, pp. 1277–1282, 2002.
- M. Marí, A. Morales, A. Colell, C. García-Ruiz, and J. C. Fernández-Checa, “Mitochondrial glutathione, a key survival antioxidant,” Antioxidants and Redox Signaling, vol. 11, no. 11, pp. 2685–2700, 2009.
- K. Zitta, P. Meybohm, B. Bein et al., “Hypoxia-induced cell damage is reduced by mild hypothermia and postconditioning with catalase in-vitro: application of an enzyme based oxygen deficiency system,” European Journal of Pharmacology, vol. 628, no. 1–3, pp. 11–18, 2010.
- T. Tanaka, K. Ayajiki, H. Fujioka, N. Toda, and T. Okamura, “Protection by hypothermia of hypoxia-induced inhibition of neurogenic vasodilation in porcine cerebral arteries,” Journal of Pharmacological Sciences, vol. 92, no. 2, pp. 93–99, 2003.
- T. D. J. M. G. Filho, T. B. de Mendonça, G. Gabiatti et al., “Topical hepatic hypothermia plus ischemic preconditioning. Analysis of bile flow and ischemic injuries after initial reperfusion in rats,” Acta Cirurgica Brasileira, vol. 26, no. 3, pp. 194–201, 2011.
- G. Stefanutti, A. Pierro, S. Vinardi, L. Spitz, and S. Eaton, “Moderate hypothermia protects against systemic oxidative stress in a rat model of intestinal ischemia and reperfusion injury,” Shock, vol. 24, no. 2, pp. 159–164, 2005.
- M. Todani, M. Fujita, R. Tsuruta et al., “Moderate hypothermia suppressed excessive generation of superoxide anion radical and inflammatory reactions in blood and liver in heatstroke: laboratory study in rats,” Free Radical Research, vol. 44, no. 4, pp. 462–472, 2010.
- S. Hayashi, K. Osuka, Y. Watanabe, M. Yasuda, M. Takayasu, and T. Wakabayashi, “Hypothermia enhances the colocalization of calmodulin kinase IIα with neuronal nitric oxide synthase in the hippocampus following cerebral ischemia,” Neuroscience Letters, vol. 505, no. 3, pp. 228–232, 2011.
- K. J. Brooks, I. Hargreaves, K. Bhakoo et al., “Delayed hypothermia prevents decreases in N-acetylaspartate and reduced glutathione in the cerebral cortex of the neonatal pig following transient hypoxia-ischaemia,” Neurochemical Research, vol. 27, no. 12, pp. 1599–1604, 2002.
- M. Karabiyikoglu, H. S. Han, M. A. Yenari, and G. K. Steinberg, “Attenuation of nitric oxide synthase isoform expression by mild hypothermia after focal cerebral ischemia: variations depending on timing of cooling,” Journal of Neurosurgery, vol. 98, no. 6, pp. 1271–1276, 2003.
- H. A. Zar, K. Tanigawa, Y.-M. Kim, and J. R. Lancaster Jr., “Mild therapeutic hypothermia for postischemic vasoconstriction in the perfused rat liver,” Anesthesiology, vol. 90, no. 4, pp. 1103–1111, 1999.
- C. Bémeur, P. Desjardins, and R. F. Butterworth, “Antioxidant and anti-inflammatory effects of mild hypothermia in the attenuation of liver injury due to azoxymethane toxicity in the mouse,” Metabolic Brain Disease, vol. 25, no. 1, pp. 23–29, 2010.
- K. Irani, “Oxidant signaling in vascular cell growth, death, and survival: a review of the roles of reactive oxygen species in smooth muscle and endothelial cell mitogenic and apoptotic signaling,” Circulation Research, vol. 87, no. 3, pp. 179–183, 2000.
- D. Medan, L. Wang, D. Toledo et al., “Regulation of Fas (CD95)-induced apoptotic and necrotic cell death by reactive oxygen species in macrophages,” Journal of Cellular Physiology, vol. 203, no. 1, pp. 78–84, 2005.
- L. Wang, N. Azad, L. Kongkaneramit et al., “The Fas death signaling pathway connecting reactive oxygen species generation and FLICE inhibitory protein down-regulation,” Journal of Immunology, vol. 180, no. 5, pp. 3072–3080, 2008.
- M. Jamal, A. Masood, R. Belcastro et al., “Mitochondria, oxygen free radicals, and apoptosis,” American Journal of Medical Genetics, vol. 106, no. 1, pp. 62–70, 2001.
- S. A. Susin, H. K. Lorenzo, N. Zamzami et al., “Molecular characterization of mitochodrial apoptosis-inducing factor,” Nature, vol. 397, no. 6718, pp. 441–446, 1999.
- S. W. Ryter, P. K. Hong, A. Hoetzel et al., “Mechanisms of cell death in oxidative stress,” Antioxidants and Redox Signaling, vol. 9, no. 1, pp. 49–89, 2007.
- S. G. Park, J. H. Kim, Y. Xia, and J.-H. Sung, “Generation of reactive oxygen species in adipose-derived stem cells: friend or foe?” Expert Opinion on Therapeutic Targets, vol. 15, no. 11, pp. 1297–1306, 2011.
- I. Afanas'ev, “ROS and RNS signaling in heart disorders: could antioxidant treatment be successful?” Oxidative Medicine and Cellular Longevity, vol. 2011, Article ID 293769, 13 pages, 2011.
- A. Diestel, C. Drescher, O. Miera, F. Berger, and K. R. L. Schmitt, “Hypothermia protects H9c2 cardiomyocytes from H2O2 induced apoptosis,” Cryobiology, vol. 62, no. 1, pp. 53–61, 2011.
- T. McManus, M. Sadgrove, A. K. Pringle, J. E. Chad, and L. E. Sundstrom, “Intraischaemic hypothermia reduces free radical production and protects against ischaemic insults in cultured hippocampal slices,” Journal of Neurochemistry, vol. 91, no. 2, pp. 327–336, 2004.
- B. Schaller and R. Graf, “Cerebral ischemic preconditioning: an experimental phenomenon or a clinical important entity of stroke prevention?” Journal of Neurology, vol. 249, no. 11, pp. 1503–1511, 2002.
- N. N. Nassar, R. M. Abdelsalam, A. A. Abdel-Rahman, and D. M. Abdallah, “Possible involvement of oxidative stress and inflammatory mediators in the protective effects of the early preconditioning window against transient global ischemia in rats,” Neurochemical Research, vol. 37, no. 3, pp. 614–621, 2012.
- G. Lebuffe, P. T. Schumacker, Z.-H. Shao, T. Anderson, H. Iwase, and T. L. Vanden Hoek, “ROS and NO trigger early preconditioning: relationship to mitochondrial KATP channel,” The American Journal of Physiology—Heart and Circulatory Physiology, vol. 284, no. 1, pp. H299–H308, 2003.
- J. D. Thornton, G. S. Liu, R. A. Olsson, and J. M. Downey, “Intravenous pretreatment with A1-selective adenosine analogues protects the heart against infarction,” Circulation, vol. 85, no. 2, pp. 659–665, 1992.
- S. W. Ely and R. M. Berne, “Protective effects of adenosine in myocardial ischemia,” Circulation, vol. 85, no. 3, pp. 893–904, 1992.
- G. L. Semenza, “Hypoxia-inducible factor 1: regulator of mitochondrial metabolism and mediator of ischemic preconditioning,” Biochimica et Biophysica Acta, vol. 1813, no. 7, pp. 1263–1268, 2011.
- G. Loor and P. T. Schumacker, “Role of hypoxia-inducible factor in cell survival during myocardial ischemia-reperfusion,” Cell Death and Differentiation, vol. 15, no. 4, pp. 686–690, 2008.
- M. A. Zaouali, I. Ben Mosbah, E. Boncompagni et al., “Hypoxia inducible factor-1α accumulation in steatotic liver preservation: role of nitric oxide,” World Journal of Gastroenterology, vol. 16, no. 28, pp. 3499–3509, 2010.
- K. H. Polderman, “Application of therapeutic hypothermia in the intensive care unit: opportunities and pitfalls of a promising treatment modality—part 2: practical aspects and side effects,” Intensive Care Medicine, vol. 30, no. 5, pp. 757–769, 2004.
- M. Erecinska, M. Thoresen, and I. A. Silver, “Effects of hypothermia on energy metabolism in mammalian central nervous system,” Journal of Cerebral Blood Flow and Metabolism, vol. 23, no. 5, pp. 513–530, 2003.
- H. Zhao, G. K. Steinberg, and R. M. Sapolsky, “General versus specific actions of mild-moderate hypothermia in attenuating cerebral ischemic damage,” Journal of Cerebral Blood Flow and Metabolism, vol. 27, no. 12, pp. 1879–1894, 2007.
- E. Eberspächer, C. Werner, K. Engelhard et al., “The effect of hypothermia on the expression of the apoptosis-regulating protein bax after incomplete cerebral ischemia and reperfusion in rats,” Journal of Neurosurgical Anesthesiology, vol. 15, no. 3, pp. 200–208, 2003.
- D. Yang, S. Guo, T. Zhang, and H. Li, “Hypothermia attenuates ischemia/reperfusion-induced endothelial cell apoptosis via alterations in apoptotic pathways and JNK signaling,” The FEBS Letters, vol. 583, no. 15, pp. 2500–2506, 2009.