Oxidative stress: an essential factor in the pathogenesis of gastrointestinal mucosal diseases

Abstract

Reactive oxygen species (ROS) are generated as by-products of normal cellular metabolic activities. Superoxide dismutase, glutathione peroxidase, and catalase are the enzymes involved in protecting cells from the damaging effects of ROS. ROS are produced in response to ultraviolet radiation, cigarette smoking, alcohol, nonsteroidal anti-inflammatory drugs, ischemia-reperfusion injury, chronic infections, and inflammatory disorders. Disruption of normal cellular homeostasis by redox signaling may result in cardiovascular, neurodegenerative diseases and cancer. ROS are produced within the gastrointestinal (GI) tract, but their roles in pathophysiology and disease pathogenesis have not been well studied. Despite the protective barrier provided by the mucosa, ingested materials and microbial pathogens can induce oxidative injury and GI inflammatory responses involving the epithelium and immune/inflammatory cells. The pathogenesis of various GI diseases including peptic ulcers, gastrointestinal cancers, and inflammatory bowel disease is in part due to oxidative stress. Unraveling the signaling events initiated at the cellular level by oxidative free radicals as well as the physiological responses to such stress is important to better understand disease pathogenesis and to develop new therapies to manage a variety of conditions for which current therapies are not always sufficient.

FIGURE 1.

Schematic diagram showing the induction of oxidative stress and its pathophysiological effects. Oxidative stress damages internal organs by causing mucosal injury.

FIGURE 2.

Major endogenous oxidative enzymatic reactions.

FIGURE 3.

Endogenous and exogenous factors leading to reactive oxygen species (ROS) generation. Mitochondrial respiratory chain and various intracellular enzymes are the main generators of endogenous ROS. Environmental pollution, radiation, cigarette smoking, certain foods, and drugs are the major exogenous sources of ROS.

FIGURE 4.

Schematic depiction of multiple signaling pathways that generate ROS and the intracellular events activated by ROS accumulation. Upon activation, G protein-coupled receptors (GPCRs) activate phospholipase C (PLC) leading to the activation of protein kinase C (PKC) molecules. Platelet-derived growth factor receptors (PDGFRs) activate phosphoinositide 3-kinase leading to activation of ras-related C3 botulinum toxin substrate 1 (RAC1). Both RAC1 and PKC activate membrane-bound receptors leading to membrane relocation and assembly of various components of phagocytic NADPH oxidases. Mitochondrial electron transport chain (mito ETC) is another robust source of intracellular ROS generation. ROS in turn lead to enhanced production of (APE1/Ref1) and activation of several signaling events including p53-mediated apoptotic events, mitogen-activated protein kinase (MAPK) pathways, NF-E2-related factor (NRF2)-mediated activation of genes containing antioxidant response element (ARE), and nuclear factor-κB (NF-κB). Transcription factors including AP1, NF-κB, cAMP response element-binding (CREB), and early growth response (EGR) protein, induced by these signaling events are kept in the active and reduced form by APE1/Ref1. Thus ROS signaling events play a central role in regulation of proinflammatory events, cell cycle, proliferation, and cell death. Antioxidant defense enzymes such as catalase, thioredoxins (TRX), peroxidases, and peroxiredoxins (PRX) contribute to preventing excessive levels of ROS from accumulating at the cellular and tissue level.