Concepts of oxidative stress and antioxidant defense in Crohn's disease

Abstract

Oxygen free radical and lipid peroxides (oxidative stress) are highly reactive and represent very damaging compounds. Oxidative stress could be a major contributing factor to the tissue injury and fibrosis that characterize Crohn's disease. An imbalance between increased reactive oxygen species levels and decreased antioxidant defenses occurs in Crohn's patients. Decreased blood levels of vitamins C and E and decreased intestinal mucosal levels of CuZn superoxide dismutase, glutathione, vitamin A, C, E, and β-carotene have been reported for Crohn's patients. Increased levels of proinflammatory cytokines, such as interleukin-1 and -8 and tumor necrosis factor, have been detected in inflammatory bowel disease. Oxidative stress significantly increased the production of neutrophils, chemokines, and interleukin-8. These effects were inhibited by antioxidant vitamins and arachidonic acid metabolite inhibitors in human intestinal smooth muscle cells isolated from the bowels of Crohn's disease patients. The main pathological feature of Crohn's disease is an infiltration of polymorphonuclear neutrophils and mononuclear cells into the affected part of the intestine. Activated neutrophils produce noxious substances that cause inflammation and tissue injury. Due to the physiological and biochemical actions of reactive oxygen species and lipid peroxides, many of the clinical and pathophysiological features of Crohn's disease might be explained by an imbalance of increased reactive oxygen species and a net decrease of antioxidant molecules. This review describes the general concepts of free radical, lipid peroxide and antioxidant activities and eventually illustrates their interferences in the development of Crohn's strictures.

Keywords: Antioxidant enzymes; Crohn’s disease; Lipid peroxide; Reactive oxygen species.

Figure 1

Reactions of superoxide (^•O₂^-) that generate highly reactive oxygen species. ^•O₂^- can be dismutated into H₂O₂, which, in the presence of Fe²⁺, can generate the highly reactive hydroxyl radical, HO^•. ^•O₂^- may react with NO^• to form the strong pro-oxidant peroxynitrite (ONOO^-); alternatively, it may react with HO^• to form singlet oxygen (¹O₂); NADPH: Nicotinamide adenine dinucleotide phosphate.

Figure 2

Initiation and propagation of the free-radical chain reaction of lipid peroxidation. Reactions D and E represent the metal-catalyzed Fenton reaction.

Figure 3

Two proposed mechanisms through which linoleic acid could increase the production of interleukin-8 via the activation of arachidonic acid pathways. By the generation of reactive oxygen species (ROS) from the cyclooxygenase and lipoxygenase enzymes to activate Nuclear factor-κB (NF-κB), increasing interleukin (IL)-8 production; or by the use of AA metabolites to increase IL-8 production. LTs: Leukotrienes; Tx: Thromboxane.