Sepsis, oxidative stress, and hypoxia: Are there clues to better treatment?

Abstract

Sepsis is a clinical syndrome characterized by systemic inflammation, usually in response to infection. The signs and symptoms are very similar to Systemic Inflammatory Response Syndrome (SIRS), which typically occur consequent to trauma and auto-immune diseases. Common treatments of sepsis include administration of antibiotics and oxygen. Oxygen is administered due to ischemia in tissues, which results in the production of free radicals. Poor utilization of oxygen by the mitochondrial electron transport chain can increase oxidative stress during ischemia and exacerbate the severity and outcome in septic patients. This course of treatment virtually mimics the conditions seen in ischemia-reperfusion disorders. Therefore, this review proposes that the mechanism of free radical production seen in sepsis and SIRS is identical to the oxidative stress seen in ischemia-reperfusion injury. Specifically, this is due to a biochemical mechanism within the mitochondria where the oxidation of succinate to fumarate by succinate dehydrogenase (complex II) is reversed in sepsis (hypoxia), leading to succinate accumulation. Oxygen administration (equivalent to reperfusion) rapidly oxidizes the accumulated succinate, leading to the generation of large amounts of superoxide radical and other free radical species. Organ damage possibly leading to multi-organ failure could result from this oxidative burst seen in sepsis and SIRS. Accordingly, we postulate that temporal administration with anti-oxidants targeting the mitochondria and/or succinate dehydrogenase inhibitors could be beneficial in sepsis and SIRS patients.

Keywords: Electron transport chain; Inflammation; Ischemia; Mitochondria; Oxidative stress; Reperfusion; Sepsis; Systemic Inflammatory Response Syndrome.

Figure 1.

This model is a simplified abstraction from Chouchani et al.²³ (A) The catalysis of fumarate to succinate in ischemia is initiated by succinate dehydrogenase (also known as complex II or succinate:ubiquinone oxidoreductase), resulting in the oxidation of dihydroubiquinone (QH₂) to ubiquinone (Q), which is reduced back to QH₂ by complex I via NADH/NAD⁺. Succinate dehydrogenase is the only enzyme in the tricarboxylic acid cycle that is embedded in the inner mitochondrial membrane, where it is also part of the electron transport chain. Our hypothesis is that sepsis/SIRS is equivalent to the induced ischemia in the study by Chouchani et al. (B) The accumulated succinate is then oxidized to fumarate by the same enzyme during reperfusion in the reverse manner. Our hypothesis is that oxygen (O₂) treatment and mechanical ventilation are equivalent to reperfusion. This oxidation step is accompanied by superoxide radical (O₂^•−) production by reverse electron transport from complex I in the electron transport chain.