Review RtjJ01RKhcoCo980ebyeu.18Bvon3rS20int1Nel-oa1605w,cel-40iJ1oe/08aj1ftc96psy5bCaSfnloRi.n1roi1Fc-ra1efl1eB5RSiooaRcdhicxeaml iiRstdersyea anrcdhtNJiuaptvraitnioen stress in stomach disorders Hidekazu Suzuki,1,* Toshihiro Nishizawa,1,2 Hitoshi Tsugawa,1 Sachiko Mogami1 and Toshifumi Hibi1 1Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjukuku, Tokyo 1608582, Japan 2Division of Gastroenterology, National Hospital Organization Tokyo Medical Center, 251 Higashigaoka, Meguroku, Tokyo 152890 2, Japan (Re1ceived 20 September, 2011; Accepted 29 September, 2011; Published online 9 December, 2011) svCTthirdei2TCecea0hotdste1itpsdvot2yhemireusiagsoaCcehnrho,itgmod©iispinmsea2atnorl0sinw0baes?ucnoctsJriAeikoCtsintsvBit,sreaNiapbrdntruiiodgctipleoersnertdpliyvirLseotcirdcioituebercnugdtsta.ieond,ntuwhinahdtiaecinrshytshupmesectereemdprimiuttimbslo,eufpnatrnhoede- exposed to exogenous pathogens from the diet. In response to such pathogens, the stomach induces oxidative stress, which might be related to the development of gastric organic disorders such as gastritis, gastric ulcers, and gastric cancer, as well as func tional disorders such as functional dyspepsia. In particular, the bacterium Helicobacter pylori plays a major role in eliciting and confronting oxidative stress in the stomach. The present paper summarizes the pathogenesis of oxidative stress in the stomach during the development of various stomach diseases. Key Words: gastric mucosa, oxidative stress, Helicobacter pylori Oxidative Stress in the Process of Gastric Mucosal Injury Physiological responses to stressors include increased activity of the hypothalamic-pituitary-adrenal axis as well as changes in gastrointestinal tissue. According to Selye’s formulation of the general adaptation syndrome, an increase in adrenocortical activity is related to an increase in the incidence of gastric ulceration. The main candidate for the cause of stress ulcers is oxidative stress. There is some evidence that psychological stress, in addition to physical stress such as surgical intervention and microbial infection including Helicobacter pylori (H. pylori),(1) leads to oxidative stress in the stomach. Oxidative stress, which is a state of elevated levels of reactive oxygen species (ROS), causes a variety of conditions that stimulate either additional ROS pro- duction or a decline in antioxidant defenses. Oxidative stress is not only involved in the pathogenesis of gastric inflammation, ulcerogenesis, and carcinogenesis in H. pylori infection, but also in that of lifestyle-related diseases including atherosclerosis, hypertension, diabetes mellitus, ischemic heart diseases, and malignancies.(2) Several phenotypes of gastrointestinal diseases, such as peptic ulcer disease and gastroparesis, are known to be related to antioxidant property dysfunction. Ethanol. The effects of ethanol on gastric mucosa are compli- cated and multifaceted. They may be associated with a disturbance in the balance between gastric mucosal protective and aggressive factors. Gastric mucosa is exposed to gastric acid, pepsin, and stimulants among others, while gastroprotective factors maintain the integrity of the gastric mucous layer, microcirculatory system, HCO3−, prostaglandins (PGs), epidermal growth factor synthesis, and epithelial cell restitution. Ethanol injures the vascular endo- thelial cells of the gastric mucosa and induces microcirculatory disturbance and hypoxia, linking to the overproduction of oxygen radicals. Pan et al.(3) report the role of mitochondrial energy charge in the pathogenesis of ethanol-induced gastric mucosal injury. The gastric mucosal lesion index is correlated with the thiobarbituric acid (TBA)-reactive substance (TBARS) content in gastric mucosa. As the concentration of ethanol increases and the doi: 10.3164/jcbn.11115SR ©2012 JCBN exposure time to ethanol is extended, the TBARS content in gastric mucosa and the extent of gastric mucosal damage increase. The ultrastructural pathological changes in mitochondria are positively related to ethanol concentration and exposure time. The expressions of mitochondrial DNA ATPase subunits 6 and 8 mRNA decline with increasing TBARS content in gastric mucosa produced as a result of ethanol gavage. As mentioned above, ethanol-induced gastric mucosal injury is related to oxida- tive stress, which disturbs the energy metabolism of mitochondria and plays a critical role in the pathogenesis of ethanol-induced gastric mucosal injury. Ischemia/reperfusion injury. Ischemia/reperfusion damages the gastric mucosa by inducing oxidative stress. Specifically, ROS such as superoxide (O2−) and hydrogen peroxide (H2O2) induce inflammatory responses and tissue damage by fragmenting cellular DNA. In the gut, ROS can also be generated by non-steroidal anti- inflammatory drugs (NSAIDs), cold stress, ethanol, and H. pylori infection. NADPH oxidase found in phagocytic cells, vascular smooth muscle cells, endothelial cells, fibroblasts, and adipocytes convert oxygen into superoxide anions. Nakagiri et al.(4) recently reported that NADPH oxidase activity is elevated in ischemia and ischemia/reperfusion and is involved in the resultant gastric mucosal damage. This increased NADPH oxidase activity may also upregulate cyclooxygenase-2. Peskar et al.(5) report that during ischemia/reperfusion, inhibitors of the cyclooxygenase and lipoxygenase pathways increase gastric mucosal damage in a dose-dependent manner. The synergism observed as a result of the combination of cyclooxygenase and lipoxygenase inhibitors suggests that both pathways are important in gastric mucosal defense during ischemia/reperfusion. PGE2 theoretically antagonizes the effects of cyclooxygenase and lipoxygenase inhibitors. Similarly, lipoxin A4, a lipoxygenase- derived product of arachidonate metabolism, also antagonizes the effects of cyclooxygenase and lipoxygenase inhibitors; moreover, it could replace PGE2 for the prevention of gastric mucosal damage caused by cyclooxygenase inhibitors during ischemia/ reperfusion. Portal hypertensive gastropathy. Portal hypertensive gastropathy (PHG) is a common complication of liver cirrhosis and is associated with impaired gastric mucosal healing. PHG may be related to increased ROS and lipid peroxide (LPO) production. Kinjo et al.(4) report increased levels of LPO and nitrotyrosine, an indicator of nitration of tyrosine residues due to peroxynitrite, in the gastric mucosa of portal hypertensive rats; in addition, they report impaired ERK1/2 phosphorylation related to increased nitration by peroxynitrite. The gastroprotective, anti-inflammatory agent rebamipide prevents free radical production by scavenging *To whom correspondence should be addressed. Email: hsuzuki@a6.keio.jp He received “SFRR Japan Award of Scientific Excellent” in 2011 in recognition of his outstanding work. J. Clin. Biochem. Nutr. | January 2012 | vol. 50 | no. 1 | 35–39