Markers of Oxidative Stress and Inflammation in Patients With Intestinal Metaplasia and Metabolic Syndrome

INTRODUCTION:

Intestinal metaplasia (IM) is considered a precancerous lesion and is associated with a very small increase of gastric cancer risk. Generally there are no widely accepted guidelines on the IM management. Recently, the European Endoscopic Society and other European academic companies have developed evidence-based guidelines for the management of patients with IM. These instructions highlighted the increased risk of cancer in patients with gastric atrophy and IM and the need for staging in cases with high-grade dysplasia. Risk factors for IM include infection with Helicobacter pylori, high NaCl intake, smoking, alcohol consumption and chronic bile reflux. The four steps sequence of the events for the development of the intestinal type gastric adenocarcinoma include: Non-atrophic gastritis, multifocal atrophic gastritis, IM, and dysplasia.

Reactive oxygen species (ROS) are produced as by-products of the normal metabolism of the cell. ROS are generated in response to ultraviolet radiation, smoking, alcohol, nonsteroidal anti-inflammatories, ischemia-reperfusion, chronic infections and chronic inflammatory disorders. Disruption of the normal homeostasis of the cell, due to changes in redox homeostasis can lead to the development of cardiovascular diseases, neurodegenerative diseases and cancer. The production of ROS in the gastrointestinal tract (GI) and their role in the pathophysiology and pathogenesis of gastrointestinal diseases have not been studied sufficiently. Despite the protective barrier provided by the digestive mucosa, different molecules which may be present in the content of GI,as well as various pathogens can cause oxidative damage and inflammatory response in the intestinal mucosa and the immune cells. Pathogenesis of various GI diseases, including ulcerative lesions, cancer, and inflammatory bowel diseases are attributable in part to oxidative stress. In the plasma of patients, in the context of the sequence gastro oesophageal reflux-oesophagitis-metaplasia-dysplasia-adenocarcinoma, have been found simultaneous formation of DNA adducts and increased myeloperoxidase concentration, which are associated with oxidative stress, decreased antioxidant capacity (decreased glutathione concentration).These findings support the role of oxidative stress in the pathogenesis and malignant transformation.

On the other hand, since chronic inflammation has been recognized as an important risk factor for the development of GI tumors, the underlying molecular mechanisms have been studied extensively. Chronic inflammation may induce cell mutations and promote malignant transformation in normal cells of the GI mucosa. The inflammatory reaction generated during carcinogenesis involves the formation of reactive oxygen and nitrogen species (ROS and RNS) derived from mononuclear phagocytes and lymphocytes, as well as the development of immune response, and the production of pro-inflammatory cytokines. Nuclear factor-κB (NF-κB) is considered as the main mediator of the immune response. The activation of NF-κB through phosphorylation leads to translocation of NF-κB in the nucleus, where regulates the transcription of several pro-inflammatory cytokines and chemokines. Furthermore, chronic inflammation can create the appropriate conditions for genomic and epigenetic changes.

Obesity, particularly abdominal obesity, is associated with insulin resistance in the peripheral tissues and abnormal fatty acid metabolism, often leading to type 2 diabetes mellitus (DM2) development. Insulin resistance, hyperinsulinemia, hypoglycemia and cytokine production by adipocytes (adipokines) can also result in endothelial dysfunction, disorders of the lipid profile, hypertension and vascular inflammation, which promote the development of atherosclerotic cardiovascular disease. In patients with coexistence of metabolic risk factors for DM2 and cardiovascular disease (abdominal obesity, hyperglycemia, dyslipidemia and hypertension) suggested the existence of "metabolic syndrome". Metabolic Syndrome (MS) has been recognized as a pro-inflammatory, pro-coagulant state associated with increased levels of C reactive protein (CRP), interleukin (IL) 6 and plasminogen activator inhibitor (PAI) 1. It has been reported that the inflammatory and the pro thrombotic markers, which are associated with increased risk for cardiovascular disease and DM2, represent only a part of the relationship between IM and cardiovascular mortality. Furthermore, no causal relationship between increased levels of CRP levels and MS incidence has been found. The value of several markers for the monitoring of patients with MS remain uncertain.The use of these markers should be made for clinical purposes only, with respect to the determination of cardiovascular risk assessment. The guidelines of the Centers for Disease Control and Prevention (CDC) emphasize that the analysis of CRP still belongs to the optional tests, because the power as an independent predictive remains uncertain.