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Figure 2 | Critical Care

Figure 2

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

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.

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