The Impact of Oxidative Stress in Human Pathology: Focus on Gastrointestinal Disorders

Abstract

Accumulating evidence shows that oxidative stress plays an essential role in the pathogenesis and progression of many diseases. The imbalance between the production of reactive oxygen species (ROS) and the antioxidant systems has been extensively studied in pulmonary, neurodegenerative cardiovascular disorders; however, its contribution is still debated in gastrointestinal disorders. Evidence suggests that oxidative stress affects gastrointestinal motility in obesity, and post-infectious disorders by favoring the smooth muscle phenotypic switch toward a synthetic phenotype. The aim of this review is to gain insight into the role played by oxidative stress in gastrointestinal pathologies (GIT), and the involvement of ROS in the signaling underlying the muscular alterations of the gastrointestinal tract (GIT). In addition, potential therapeutic strategies based on the use of antioxidants for the treatment of inflammatory gastrointestinal diseases are reviewed and discussed. Although substantial progress has been made in identifying new techniques capable of assessing the presence of oxidative stress in humans, the biochemical-molecular mechanisms underlying GIT mucosal disorders are not yet well defined. Therefore, further studies are needed to clarify the mechanisms through which oxidative stress-related signaling can contribute to the alteration of the GIT mucosa in order to devise effective preventive and curative therapeutic strategies.

Keywords: antioxidants; gastrointestinal diseases; gastrointestinal muscle inflammation; oxidative stress.

Figure 1

Scheme of oxidative stress-induced diseases in humans.

Figure 2

Cellular sources of ROS. ROS are the “by-products” of electron transfer reactions. The major source of ROS is the mitochondrial electron transport chain, followed by the NADPH oxidases present on either side of the plasma membrane. In the smooth endoplasmic reticulum, we find cytochrome P-450 and b5 families, which are responsible for a series of reactions to detoxify fat-soluble drugs and harmful metabolites. Peroxisomes, through their oxidases, are a significant source of total cellular H₂O₂ production. Moreover, they are responsible for dismutation of H₂O₂ to H₂O and O₂, and of fatty acids β-oxidation. Other enzymes, present free in the cytoplasm, such as xanthine oxidase, aldehyde oxidase, flavoprotein dehydrogenase, and tryptophan dioxygenase can produce ROS during catalytic cycling.

Figure 3

Scheme of endogenous and exogenous antioxidants. SOD, Superoxide dismutase; CAT, Catalase; GPX, Glutathione peroxidase; GSR, Glutathione reductase; GST, Glutathione transferase.

Figure 4

Potential mechanisms of oxidative stress promoting gastrointestinal diseases. SOD, Superoxide dismutase; ROS, reactive oxygen species; mtROS, mitochondrial reactive oxygen species; NOXs (NOX1, NOX4, NOX5, NOX5-S) NADPH oxidases; Cag A, cytotoxin-associated gene A; Vac A, vacuolating cytotoxin A; Mn-SOD, manganese-dependent superoxide dismutase; XO, xanthine oxidase; iNOS, inducible nitric oxide synthase.

Figure 5

Effects of oxidative stress on gastrointestinal smooth muscle cells. Oxidative stress can cause both cell structure-function alterations and inflammation with the promotion of pro-inflammatory environments. As concern cell phenotype, ROS alter the production of cytoskeletal proteins, like smooth muscle myosin heavy chain (SMMHC) and smoothelin (SM) that leads to the impairment of contraction and cell length. The final consequence of these alterations is the cellular switch from contractile to the synthetic phenotype. In the presence of oxidative stress, molecular signaling results are also altered. In particular, signaling that leads to the amplification of damage (NF-κB-signaling) are activated, complexes involved in the correct maintenance of contractile phenotype (RhoA/ROCK-signaling) are down regulated, and eNOS expression and cAMP-signaling pathways resulted are altered. ROS have a dual effect on cells: they induce apoptosis but also favour the cell cycle progression as compensatory mechanism. An increase of ROS, or conversely a decrease of antioxidants, induce cells to an oxidative state that manifests itself also with hyperpolarization of mitochondrial membrane. The last effect of oxidative stress on cells is the alterations of protein production, in particular extracellular proteins, like collagen, and pro-inflammatory cytokines IL-6 result increased, while anti-inflammatory cytokines IL-10 result decreased. The presence of an oxidative status is confirmed by the reversion or prevention of cellular oxidative damages after antioxidants and/or inhibitor of molecular patterns treatment. NAC, N-acetylcysteine, Nox, NADPH oxidases; SOD, superoxide dismutase.