Metabolic resuscitation in sepsis : could antioxidants be the answer ? LUI

Antioxidants are molecules that inhibit oxidation which under certain conditions leads to the production of free radicals, highly reactive species characterized by an unpaired electron which enter into further chain reactions that lead to cell damage. (1) In biological systems these include reactive oxygen species (ROS) which include the hydroxyl radical (OH.), hydrogen peroxide (H2O2) and the superoxide anion (O2.-) among others. The generation of such species may trigger a variety of pathological responses and any disequilibrium between production of ROS and the ability to attenuate the damage that such species may incur is referred to as oxidative stress. Oxidative stress may result in damage to any component of the cell and may result in DNA damage through base damage as well as strand breaks and also some ROS may act as cellular messengers causing disruption in cellular signaling. Cellular protection against oxidative stress may be through chelation of trace metals involved in free radical generation or through the actions of antioxidants. Antioxidants are broadly classified into two groups, depending on whether they are soluble in water (hydrophilic), such as vitamin C or fat soluble such as Vitamin E (lipophilic). Hydrophilic antioxidants are thought to predominantly react with oxidants in the cell cytosol and plasma whereas lipophilic antioxidants protect cell membranes from oxidation: a process termed lipid peroxidation. (2) The synergism between different antioxidant systems is complex. Indeed, both vitamin C and vitamin E were shown to have a direct interaction with vitamin C “repairing” the α-tocopherol radical with rates approaching diffusion limited outlining the reactivity of these species. (3) One of the areas that has attracted considerable interest with regard to the role of oxidative stress is the host response to sepsis. (4) Sepsis remains a major cause of death worldwide affecting over 18 million people annually with a mortality rate approaching 80% in those individuals with multi-organ failure and in the US hospital costs total over $24 billion dollars. (5, 6) Therapy for severe sepsis is predominantly supportive with the relatively recent introduction of care bundles including antibiotic therapy being introduced. However, the precise pathogenesis of sepsis-induced organ failure remains elusive and although likely multifactorial in nature certainly microvascular dysfunction appears to be central to the process. (7) Microvascular dysfunction involves impairment of arteriolar reactivity, derangement of endothelial barrier integrity and microthombi induced plugging of the capillaries thus any therapy that addresses these issues may translate into improved outcomes.