To propose a new pathogenesis called Radical Induction to explain the genesis and progression of ulcerative colitis (UC). UC is an inflammatory bowel disease. Colonic inflammation in UC is mediated by a buildup of white blood cells (WBCs) within the colonic mucosal lining; however, to date there is no answer for why WBCs initially enter the colonic mucosa to begin with. A new pathogenesis termed "Radical Induction Theory" is proposed to explain this and states that excess un-neutralized hydrogen peroxide, produced within colonic epithelial cells as a result of aberrant cellular metabolism, diffuses through cell membranes to the extracellular space where it is converted to the highly damaging hydroxyl radical resulting in oxidative damage to structures comprising the colonic epithelial barrier. Once damaged, the barrier is unable to exclude highly immunogenic fecal bacterial antigens from invading the normally sterile submucosa. This antigenic exposure provokes an initial immune response of WBC infiltration into the colonic mucosa. Once present in the mucosa, WBCs are stimulated to secrete toxins by direct exposure to fecal bacteria leading to mucosal ulceration and bloody diarrhea characteristic of this disease.

Septic shock is a life threatening condition that can develop subsequent to infection. Mortality can reach as high as 80% with over 150000 deaths yearly in the United States alone. Septic shock causes progressive failure of vital homeostatic mechanisms culminating in immunosuppression, coagulopathy and microvascular dysfunction which can lead to refractory hypotension, organ failure and death. The hypermetabolic response that accompanies a systemic inflammatory reaction places high demands upon stored nutritional resources. A crucial element that can become depleted early during the progression to septic shock is glutathione. Glutathione is chiefly responsible for supplying reducing equivalents to neutralize hydrogen peroxide, a toxic oxidizing agent that is produced during normal metabolism. Without glutathione, hydrogen peroxide can rise to toxic levels in tissues and blood where it can cause severe oxidative injury to organs and to the microvasculature. Continued exposure can result in microvascular dysfunction, capillary leakage and septic shock. It is the aim of this paper to present evidence that elevated systemic levels of hydrogen peroxide are present in septic shock victims and that it significantly contributes to the development and progression of this frequently lethal condition.

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.

Systemic lupus erythematosus (SLE) is a disease characterized by the production of autoreactive antibodies and cytokines, which are thought to have a major role in disease activity and progression. Immune system exposure to excessive amounts of autoantigens that are not efficiently removed is reported to play a significant role in the generation of autoantibodies and the pathogenesis of SLE. While several mechanisms of cell death-based autoantigenic exposure and compromised autoantigen removal have been described in relation to disease onset, a significant association with the development of SLE can be attributed to increased apoptosis and impaired phagocytosis of apoptotic cells. Both apoptosis and impaired phagocytosis can be caused by hydrogen peroxide whose cellular production is enhanced by exposure to endogenous hormones or environmental chemicals, which have been implicated in the pathogenesis of SLE. Hydrogen peroxide can cause lymphocyte apoptosis and glutathione depletion, both of which are associated with the severity of SLE. The cellular accumulation of hydrogen peroxide is facilitated by the myriad of stimuli causing increased cellular bioenergetic activity that enhances metabolic production of this toxic oxidizing agent such as emotional stress and infection, which are recognized SLE exacerbating factors. When combined with impaired cellular hydrogen peroxide removal caused by xenobiotics and genetically compromised hydrogen peroxide elimination due to enzymatic polymorphic variation, a mechanism for cellular accumulation of hydrogen peroxide emerges, leading to hydrogen peroxide-induced apoptosis and impaired phagocytosis, enhanced autoantigen exposure, formation of autoantibodies, and development of SLE.

Crohn's disease (CD) is a chronic inflammatory bowel disease. Research has identified genetic predisposition and environmental factors as key elements in the development of the disease. However, the precise mechanism that initiates immune activation remains undefined. One pathway for luminal antigenic molecules to enter the sterile lamina propria and activate an immune response is via transcytosis. Transcytosis, although tightly regulated by the cell, has the potential for transepithelial transport of bacteria and highly antigenic luminal molecules whose uncontrolled translocation into the lamina propria can be the source of immune activation. Viewed as a whole, the evidence suggests that unregulated intestinal epithelial transcytosis is involved in the inappropriate presentation of immunogenic luminal macromolecules to the intestinal lamina propria. Thus fulfilling the role of an early pre-morbid mechanism that can result in antigenic overload of the lamina propria and initiate an immune response culminating in chronic inflammation characteristic of this disease. It is the aim of this paper to present evidence implicating enterocyte transcytosis in the early etio-pathogenesis of CD.