156 : What does evolution have to do with inflammation?

Abstract

Our evolutionary history suggests that hydrogen peroxide (H2O2), a derivative of reactive oxygen species (ROS) generated in mitochondria after exposure to environmental threats, such as pathogens, chemical toxins, or radiation, might be used to control inflammation. The transition from anaerobic to aerobic respiration must have been accompanied by oxidative damage because, some time later, an antioxidant system developed that remains, until today, as a positive natural selection. The conserved antioxidant enzymes (GSH, Trx, peroxiredoxins) convert the highly energetic and damaging ROS species, superoxide, to H2O2. The multiple and highly concentration-dependent roles of H2O2in inflammation range from inducing the gene expression of heme oxygenase and its antioxidant by-products CO and biliverdin at low concentrations, to the induction of a systemic inflammatory response syndrome at high concentrations. Exposure to environmental threats causes lipid peroxidation that increases ROS production in mitochondria. The ROS species, superoxide, is converted to H2O2by superoxide dismutase enzymes enabling H2O2to enter the cytoplasm where it strongly influences the outcome of the NF-κB and MAPK oxidative stress signaling pathways that are also evolutionarily-conserved. By reversibly oxidizing cysteines in the catalytic core of phosphatases, it prolongs or curtails the activation of critical molecules, such as p38, JNK and ERK. This action affects pro- and anti-inflammatory cytokine production or their reciprocity. H2O2similarly affects p53, PTEN, GSH and Trx and the destiny of the cell. The reversibility of cysteine oxidation results in the oscillatory activation or deactivation of these molecules. The ingestion of low, non-toxic concentrations of H2O2, in advance of a first encounter with various threats, could produce weak and random oxidative damage whose patterns would become familiar to the inflammatory/immune system and prevent an exaggerated response upon a future encounter with oxidative damage patterns. Our in vitro and in vivo results will demonstrate this potential.