Evidence-based pathogenesis and treatment of ulcerative colitis: A causal role for colonic epithelial hydrogen peroxide

Figure 2 Redox homeostasis. Redox homeostasis is more than just a balance between oxidizing [hydrogen peroxide (H₂O₂)] and reducing agents (glutathione). In the above graph, redox homeostasis (slanted line) is maintained at both low and high H₂O₂ production rates (a and b), but the cell is functioning at a higher oxidative capacity (high capacity redox homeostasis) (b), when more H₂O₂ is being produced compared to times when lesser amounts of H₂O₂ are being generated (a). Mitochondria, the site of most cellular H₂O₂ production, do not synthesize their own glutathione and only contain 10% of the total cellular supply of this vital reducing equivalent that must be generated in the cytoplasm and imported into mitochondria, which takes time[53]. Once depleted, mitochondrial glutathione can take several hours to restore to normal levels[46]. In contrast to the limited supply of mitochondrial glutathione, studies have shown that mitochondrial electron transport chain production of H₂O₂ can increase up to 15 × during periods of high metabolic demand[54]. Any increase in H₂O₂ production forces the cell to utilize additional glutathione in order to maintain redox balance which may lead to high capacity redox homeostasis (b). Since about 30% of cell thiols (i.e., glutathione) normally undergo oxidation per hour[55], the additional oxidative stress imposed by high capacity redox homeostasis can, over time, deplete available glutathione and overwhelm colonocyte reductive capacity creating a state of impaired redox homeostasis (c) followed by H₂O₂ build-up and extracellular diffusion, which can lead to de novo ulcerative colitis or relapse. High capacity redox homeostasis is consistent with increased H₂O₂ production observed in the non-inflamed ascending colonic epithelium of individuals with ulcerative colitis[30]. H₂O₂: Hydrogen peroxide.