• Drug Delivery
• Pathophysiological Conditions
• Reaction Concentration
• Reaction Kinetics
• Reactive Oxygen Species

• Reactive Oxygen Species/metabolism
• Humans
• Drug Delivery Systems
• Feasibility Studies
• Animals
• Kinetics

• R01 DK119202 NIDDK NIH HHS
• R01 DK128823 NIDDK NIH HHS
• R01DK128823 Foundation for the National Institutes of Health
• R01DK119202 Foundation for the National Institutes of Health

• LPS
• M1 and M2 macrophages
• P-glycoprotein
• ROS
• STAT3, SOCS3, Tangeritin
• Sepsis
• Verapamil

• Animals
• Lipopolysaccharides
• Verapamil/pharmacology
• STAT1 Transcription Factor/metabolism
• Suppressor of Cytokine Signaling 3 Protein/metabolism
• Suppressor of Cytokine Signaling 3 Protein/genetics
• Flavones/pharmacology
• Flavones/therapeutic use
• Mice
• STAT3 Transcription Factor/metabolism
• Male
• Sepsis/drug therapy
• Sepsis/immunology
• Sepsis/metabolism
• ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism
• Anti-Inflammatory Agents/pharmacology
• Anti-Inflammatory Agents/therapeutic use
• Down-Regulation/drug effects
• Macrophages, Peritoneal/drug effects
• Macrophages, Peritoneal/metabolism
• Macrophages, Peritoneal/immunology
• Cells, Cultured
• Macrophages/drug effects
• Macrophages/metabolism
• Macrophages/immunology
• Signal Transduction/drug effects
• Up-Regulation/drug effects

Sepsis can develop during the body’s response to a critical illness leading to multiple organ failure, irreversible shock, and death. Sepsis has been vexing health care providers for centuries due to its insidious onset, generalized metabolic dysfunction, and lack of specific therapy. A common factor underlying sepsis is the characteristic hypermetabolic response as the body ramps up every physiological system in its fight against the underlying critical illness. A hypermetabolic response requires supraphysiological amounts of energy, which is mostly supplied via oxidative phosphorylation generated ATP. A by-product of oxidative phosphorylation is hydrogen peroxide (H₂O₂), a toxic, membrane-permeable oxidizing agent that is produced in far greater amounts during a hypermetabolic state. Continued production of mitochondrial H₂O₂ can overwhelm cellular reductive (antioxidant) capacity leading to a build-up within cells and eventual diffusion into the bloodstream. H₂O₂ is a metabolic poison that can inhibit enzyme systems leading to organ failure, microangiopathic dysfunction, and irreversible septic shock. The toxic effects of H₂O₂ mirror the clinical and laboratory abnormalities observed in sepsis, and toxic levels of blood H₂O₂ have been reported in patients with septic shock. This review provides evidence to support a causal role for H₂O₂ in the pathogenesis of sepsis, and an evidence-based therapeutic intervention to reduce H₂O₂ levels in the body and restore redox homeostasis, which is necessary for normal organ function and vascular responsiveness.

• Sepsis
• Septic shock
• Redox homeostasis
• Thiosulfate
• Hydrogen peroxide

Although the immune response has a prominent role in the pathophysiology of ulcerative colitis, sepsis, and systemic lupus erythematosus, a primary immune causation has not been established to explain the pathogenesis of these diseases. However, studies have reported significantly elevated levels of colonic epithelial hydrogen peroxide (a known colitic agent) in ulcerative colitis prior to the appearance of colitis. And patients with sepsis are reported to have toxic levels of blood hydrogen peroxide, whose pathologic effects mirror the laboratory and clinical abnormalities observed in sepsis. More recently, evidence supports a causal role for cellular hydrogen peroxide (a potent apoptotic agent) in the enhanced apoptosis believed to be the driving force behind auto-antigenic exposure and chronic immune activation in systemic lupus erythematosus. The different biological properties of hydrogen peroxide exert distinct pathologic effects depending on the site of accumulation within the body resulting in a unique disease patho-phenotype. On a cellular level, the build-up of hydrogen peroxide triggers apoptosis resulting in systemic lupus erythematosus, on a tissue level (colonic epithelium) excess hydrogen peroxide leads to inflammation and ulcerative colitis, and on a systemic level the pathologic effects of toxic concentrations of blood hydrogen peroxide result in bioenergetic failure and microangiopathic dysfunction leading to multiple organ failure and circulatory shock, characteristic of advanced sepsis. The aim of this paper is to provide a unified evidence-based common causal role for hydrogen peroxide in the pathogenesis of ulcerative colitis, sepsis, and systemic lupus erythematosus. Based on this new theory of pathogenesis, a novel evidence-based treatment of sepsis is also discussed.

• Glutathione
• Hydrogen peroxide
• Redox balance
• Redox homeostasis
• Sepsis
• Systemic lupus erythematosus
• Ulcerative colitis