Inflammatory Bowel Disease: Mechanisms, Redox Considerations, and Therapeutic Targets

Abstract

Oxidative stress is thought to play a key role in the development of intestinal damage in inflammatory bowel disease (IBD), because of its primary involvement in intestinal cells' aberrant immune and inflammatory responses to dietary antigens and to the commensal bacteria. During the active disease phase, activated leukocytes generate not only a wide spectrum of pro-inflammatory cytokines, but also excess oxidative reactions, which markedly alter the redox equilibrium within the gut mucosa, and maintain inflammation by inducing redox-sensitive signaling pathways and transcription factors. Moreover, several inflammatory molecules generate further oxidation products, leading to a self-sustaining and auto-amplifying vicious circle, which eventually impairs the gut barrier. The current treatment of IBD consists of long-term conventional anti-inflammatory therapy and often leads to drug refractoriness or intolerance, limiting patients' quality of life. Immune modulators or anti-tumor necrosis factor α antibodies have recently been used, but all carry the risk of significant side effects and a poor treatment response. Recent developments in molecular medicine point to the possibility of treating the oxidative stress associated with IBD, by designing a proper supplementation of specific lipids to induce local production of anti-inflammatory derivatives, as well as by developing biological therapies that target selective molecules (i.e., nuclear factor-κB, NADPH oxidase, prohibitins, or inflammasomes) involved in redox signaling. The clinical significance of oxidative stress in IBD is now becoming clear, and may soon lead to important new therapeutic options to lessen intestinal damage in this disease. Antioxid. Redox Signal. 19, 1711–1747. I. Introduction II. Molecular Mechanisms of Intestinal Barrier Dysfunction in IBD A. Alteration of the apical junctional complex B. Impairment of intestinal antimicrobial peptides C. Impairment of receptor-mediated microbial recognition 1. TLRs and activation of redox-sensitive transcription factors 2. RIG-I-like receptors 3. NLRs and their modulation by ROS D. The role of the endothelium in IBD progression III. Pro-Inflammatory and Anti-Inflammatory Cytokines in IBD A. Cytokines produced by Th cells B. Cytokines produced by T-regulatory cells IV. The Main Genetic Polymorphisms Associated with IBD V. Redox Imbalance in IBD A. Antioxidant defenses in IBD 1. Alteration of redox couples in the IBD-affected intestinal tract 2. Impairment of enzymatic antioxidant defense in IBD 3. Antioxidant vitamins and antioxidant-related trace metals in IBD mucosa 4. Dietary polyphenols and inflammation of the gut mucosa B. Oxidative insult in IBD 1. RNS in IBD progression 2. ROS in IBD progression 3. The role of lipid oxidation end-products in IBD VI. Redox State-Related Transcription Factors in the Etiopathogenesis of IBD A. Nuclear factor-κB B. Nuclear factor-erythroid 2-related factor 2 VII. Therapeutic Considerations A. TNFα-mediated NF-κB signaling B. The IL-1 family and inflammasomes as ROS-dependent targets C. NADPH oxidase as target of the pathogen recognition pathway D. The mitochondrial target PHB E. Suitable dietary regimens in IBD patients F. Lipoxins and resolvins: new drug candidates for IBD treatment VIII. Conclusions