Bench-to-bedside review: sepsis - from the redox point of view

Abstract

The pathogenesis of sepsis and its progression to multiple organ dysfunction syndrome and septic shock have been the subject of investigations for nearly half a century. Controversies still exist with regard to understanding the molecular pathophysiology of sepsis in relation to the complex roles played by reactive oxygen species, nitric oxide, complements and cytokines. In the present review we categorise the key turning points in sepsis development and outline the most probable sequence of events leading to cellular dysfunction and organ failure under septic conditions. We have applied an integrative approach in order to fuse current state-of-the-art knowledge about redox processes involving hydrogen peroxide, nitric oxide, superoxide, peroxynitrite and hydroxyl radical, which lead to mitochondrial respiratory dysfunction. Finally, from this point of view, the potential of redox therapy targeting sepsis is discussed.

Figure 1

Key redox reactions in living systems [23]. (1) Fenton reaction; (6) to (8) lipid peroxidation (ROOH) chain reactions.

Figure 2

The 'sepsis redox cycle'. Pathogens activate the immune system, which excessively generates H₂O₂ and HOCl. Inside the cell, H₂O₂ provokes the activation of NF-κB (also activated by cytokines and methaemoglobin (MetHb)), which stimulates the expression of inducible nitric oxide synthase (iNOS). These events result in the production of ^•NO in micromolar concentrations. ^•NO provokes inhibition of the electron transfer chain (ETC), which leads to increased production of ^•O₂^-. In the reaction between ^•NO and ^•O₂^-, ONOO^- is produced, which is then protonated to form peroxynitrous acid (ONOOH), which in turn spontaneously decomposes to two highly reactive species - ^•OH and ^•NO₂. These species damage mitochondria and in cooperation with ETC inhibition provoke mitochondrial dysfunction resulting in a fall in ATP. Superoxide is also produced in the cytosol via increased activities of three enzymes: NADPH oxidase, cyclooxygenase (COX)-2 and xanthine oxidase (XO). Indirectly, via DNA damage, poly (ADP-ribose) polymerase (PARP) activation and NAD⁺ consumption, ONOO^- promotes the production of ^•O₂^- on complex I in the ETC, which depends on the NADH/NAD⁺ ratio. Superoxide is dismutated in mitochondria by manganese superoxide dismutase (MnSOD) to H₂O₂, which closes two positive feedback redox loops. Intracellular ^•NO overproduction leads to ^•NO leakage into the plasma. There ^•NO provokes red blood cell (RBC) lysis while HOCH provokes pore formation in RBC membranes, thus freeing MetHb and increasing iron availability, which fuels pathogen proliferation. MetHb provokes the activation of NF-κB, thus closing the ^•NO-generating loop. The plus (+) and minus (-) symbols represent positive and negative effects on concentration, gene expression or activity, respectively. TNFR, TNF receptor.