|Year : 1996 | Volume
| Issue : 1 | Page : 19-28
|Role of oxygen-derived free radicals on gastric mucosal injury induced by ischemia-reperfusion
ATMM Ali1, OA Al-Swayeh1, RS Al-Rashed2, IA Al-Mofleh2, AD Al-Dohayan3, AS Al-Tuwaijri4
1 Department of Pharmacology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
2 Department of Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia
3 Department of Surgery, College of Medicine, King Saud University, Riyadh, Saudi Arabia
4 Department of Physiology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
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| Abstract|| |
A free radical is an unstable and highly-reactive chemical species capable of independent existence that contained one or more unpaired electrons in its outer orbital.
A number of oxygen-derived free radicals (ODFRs) have been identified. However, superoxide (O-2) and hydroxyl (OH*) radicals are extensively studied. The univalent reduction of oxygen to water produces a number of highly-reactive chemical intermediates such as O-2 and OH*, which are commonly-known as oxygen-derived free radicals.
ODFRS may be formed from several sources as follows: a) mitochondrial cytochrome oxidase, b) xanthine oxidase, c) neutrophils and d) transitional metals.
There are several important defense mechanisms to limit or to prevent the damage caused by excessive ODFRs activity. These antioxidant defenses can be divided into a) enzymatic defense mechanisms such as : superoxide dismutase (SOD): catalase: selenium-containing glutathione peroxidase and b) non-enzymatic defense mechanisms including: alphatocopherol; ascorbic acid; glutathione and any sulfhydryl-containing compounds.
|How to cite this article:|
Ali A, Al-Swayeh O A, Al-Rashed R S, Al-Mofleh I A, Al-Dohayan A D, Al-Tuwaijri A S. Role of oxygen-derived free radicals on gastric mucosal injury induced by ischemia-reperfusion. Saudi J Gastroenterol 1996;2:19-28
|How to cite this URL:|
Ali A, Al-Swayeh O A, Al-Rashed R S, Al-Mofleh I A, Al-Dohayan A D, Al-Tuwaijri A S. Role of oxygen-derived free radicals on gastric mucosal injury induced by ischemia-reperfusion. Saudi J Gastroenterol [serial online] 1996 [cited 2020 Jan 21];2:19-28. Available from: http://www.saudijgastro.com/text.asp?1996/2/1/19/34037
| Free radical chemistry|| |
Electrons in atoms occupy regions of space known as orbitals. Each orbital can hold a maximum of two electrons, spinning in opposite directions. A free radical is an unstable and highly-reactive chemical species capable of independent existence that contained one or more unpaired electrons in its outer orbital. Because electrons are more stable when paired together in orbitals, radicals are on the whole, more reactive than nonradical species. Radicals can react with other molecules in a number of ways. Thus, if two radicals meet, they can combine their unpaired electrons and join to form a covalent bond. A radical might donate its unpaired electron to another molecule, or it might steal an electron from another molecule in order to pair. If a radical gives one electron to, or takes one electron from another molecule, that other molecule itself becomes a radical. Thus, they tend to proceed as chain reactions. One radical begets another one, and so on ,,, .
| Oxygen-derived Free Radicals (ODFRs)|| |
The most abundant radical in biologic system is molecular oxygen (O 2 ) itself, which has two unpaired electrons ,, . A number of oxygenderived free radicals (ODFRs) have been identified. However, superoxide (0- 2) and hydroxyl (OH*) radicals are extensively studied. The univalent reduction of oxygen to water produces a number of highly-reactive chemical intermediate such as 02 and OH*. which are commonly-known as ODFRs.
The hydroxyl radical is the most reactive chemical species. It can attack and damage almost every molecule found in living cells. It is a very potent cytotoxic agent. Since it is very reactive, OH*. does not stay around for a long time and combines with a molecule in its vicinity. Furthermore, as it is a radical, it initiates a propagating chain reaction in the molecule which it attacks, and leaves behind a legacy in the cell. Thus, if it is generated near a membrane, it can attack membrane lipids and set off a free radical chain reaction known as lipid peroxidation. It prefers to attack fatty acid side-chains with several double bonds, such as those of arachidonic acid in membrane lipids. The hydroxyl radical abstracts an atom of hydrogen from one of the carbon atoms in the side-chains and combines with it to form water. However, removing an atom of hydrogen leaves behind an unpaired electron on the carbon, so generating another radical, the peroxyl radical. Peroxyl radical then may attack adjacent fatty acid side-chains, abstracting hydrogen, resulting in formation of another carbon-centered radical and so chain reactions can continue. Hence, one OH* can result in conversion of many hundred fatty acid side-chains into lipid hydroxyl peroxides. Accumulation of lipid hydroperoxides in a membrane disrupts membrane functions; leads to decreased fluidity, increased leaking of ions, and damage to membrane proteins such as receptors and enzymes , .
The discovery of an enzyme superoxide dismutase (SOD) in 1968 led to the realization that 02 is formed in vivo in living organisms and SOD functions to remove it. Superoxide radical is less reactive than OH*-radical, but 0; can participate in the formation of OH. Superoxide dismutase removes 02 by converting it into hydrogen peroxide (H,O,)and 0 2 . Hydrogen peroxide is not a radical but by itself may be quite toxic to cells, causing DNA damage, membrane disruption and release of calcium ions within the cells, resulting in calcium-dependent proteolytic enzyme to be activated ,, .
| Sources of reactive-free radicals|| |
ODFRs may be formed from several sources. A short account of their formation is detailed below as follows:
a) Mitochondrial cytochrome oxidases
The free radicals are formed continuously as normal by-products of cellular metabolism. Under normal conditions, about 95% of molecular oxygen in biological systems undergoes controlled reduction through the addition of four electrons in the mitochondrial cytochrome oxidase system to form water. The remaining molecular oxygen leaks from this pathway and undergoes sequential, univalent reduction to produce superoxide anion (02 ) hydrogen peroxide (H 2 0 2 ) and highly-reactive hydroxyl radical (OH*)  .
b) Xanthine oxidases
Xanthine oxidase is the most well-documented biological source of reactive oxygen species in various forms of tissue injuries including ischemiareperfusion ,, . In vivo, the enzyme may exist in either of two forms: the dehydrogenase (d-form) which uses NAD+ as an electron acceptor and does not generate radicals and an oxidase (oform), which uses molecular oxygen as an electron acceptor and thereby produces the superoxide radical as by-product of purine metabolism. The d-form predominates under normal condition and can be converted to the o-form by a number of factors including ischemia, proteolysis or by oxidation of sulfhydryl side groups 
The NADPH-dependent oxidase system on the membrane surface of neutrophils is a highly efficient source of superoxide radical generation. This enzyme is normally dormant, but upon activation, this enzyme catalyzes the sudden reduction of oxygen to hydrogen peroxide and superoxide anion. This phenomenon is known as "respiratory burst". The hydrogen peroxide is further metabolized to toxic hypochlorous acid by the enzyme myeloperoxidase, which is abundant within neutrophils , .
d) Transitional metals
All transitional metals can change their valence by donating an electron and by doing so, catalyze the Haber-Weiss reaction  . Normally, cells contain a low molecular mass of iron pool and if cells are damaged, the iron can be released from them, On the other hand, ferritin-bound ferric iron is liberated as ferrous form in the presence of superoxides thereby increasing the availability of iron. Thus, released or generated iron can form hydroxyl radical in the presence of superoxide and' hydrogen peroxide  .
Finally, the metabolism of arachidonic acid by cyclooxygenase and lipoxygenases may also cause production of intermediate peroxy compounds and hydroxyl radicals  .
| Antioxidant defense mechanisms|| |
In aerobic cells, there is continuous generation of ODFRs due to reduction of oxygen. Although, ODFRS play a number of physiological roles, their high reactivity leads to the development of important defense mechanisms to limit or prevent the damage caused by excessive ODFRS activity ,, l. These antioxidant defenses can be divided into enzymatic and non-enzymatic mechanisms ,, .
Enzymatic defense mechanisms
Superoxide dismutase (SOD) is present in the cytosol, where it contains copper and zinc and in the mitochondria, where it contains manganese. It catalyzes the dismutation of Oz to H 7 O 2 and Oz at a rate 10,000 times faster than spontaneous dismutation at physiologic pH 4 . As a result, no.02 is available to react with H202 to form the OH radical through the iron-catalyzed reactions ,,,,, .
Catalase is a heme-containing enzyme present in cytoplasmic peroxosomes. It catalyzes the breakdown of toxic HO, directly to water and also prevents secondary generation of toxic intermediates such as OH* radicals ,,,,, .
Selenium-containing glutathione peroxidase present in the cytoplasm of cells, catalyzes the oxidation of reduced glutathione (GSH) to oxidized glutathione (GSSG) at the expense of H2 02 that is converted to water. GSSG can be reduced to GSH by glutathione reductase in the presence of NADPH ,,,,, .
Nonenzymatic defense mechanisms
A number of nonenzymatic endogenous antioxidant mechanisms also exist within normal cells such as alphatocopherol (vitamin E), ascorbic acid (vitamin C), glutathione and any sulfhydrylcontaining compounds.
Vitamins E and C can react with free radicals to form radicals themselves which are less reactive than the radicals they reacted with  . They break radical chain reactions by trapping peroxyl and other reactive radicals. The low levels of vitamin C in gastric juice has been reported to be present in patients with chronic gastritis and chronic Helicohacter pylori (H. pylori) infection , . Similarly, the gastric mucosal levels of vitamin E has been reported to be altered in chronic gastritis , . Furthermore, ischemia-reperfusion injury was found to be more severe in vitamin Edeficient than in nondeficient rats  . It is possible that these vitamins are consumed in the process of lipid peroxidation induced by oxygen radicals in ischemia reperfusion to prevent the development of tissue damage.
Glutathione (GSH) represents a powerful antioxidant which is effective in all organisms living under aerobic conditions  . This tripeptide is present within the cytosol of cells and is the major intracellular nonprotein thiol compound (NPSH). It is believed that the sulfhydryl (-SH) group of GSH is important in maintaining -SH groups in other molecules including proteins, regulating thiol-disulfide status of the cell, and detoxifying foreign compounds and free radicals  . Sulfurcontaining amino acids like methionine and cystein are precursors of GSH but also provide-SH groups to react with HO, and the OH" radical and may prevent tissue damage  .
| Ischemia-reperfusion injuries: General consideration|| |
There is increasing evidence from animal studies that severe damage can occur in heart ,,,,,,,,,, , intestine ,,,, and stomach ,,,,,,, , during reperfusion period following a period of ischemia. The most important hypotheses explaining the cellular events in reperfusion damages are calcium overload (calcium paradox) and ODFRs (oxygen paradox).
Calcium paradox: The possible role of calcium in the phenomenon of reperfusion is based on the calcium paradox described in rat heart  . When calcium is first completely removed from extracellular space and then reintroduced, the result is cellular damage, with disruption, enzyme-release and contracture of muscle. The severe damages occur if oxygen is also reintroduced with calcium  .
Oxygen paradox: This also originates from the observations in rat heart  . Deprivation of oxygen in an isolated heart, leads to release of enzymes. Reintroduction of oxygen to such tissues results in severe damages and release of large quantities of enzymes.
Taken together, mitochondrial damage in calcium paradox may be due to calcium overload, whereas in the oxygen paradox, mitochondrial damage may be mediated by ODFRs  . It is thus possible, that both phenomena may operate concurrently, resulting in severe organic damages.
| The role of oxygen-derived free radicals in gas troduodenal disease (human studies)|| |
Direct involvement of free radicals in gastroduodenal diseases come from the work of Davies et al  . Using a chemilumensence assay, they have shown significantly greater free radical production in duodenal mucosal biopsies from patients with duodenal ulceration and severe duodenitis, than in patients with mild duodenitis or controls  . Furthermore, the presence of H. pylori in the antrum was found to be associated with increased chemilumensence  . These results suggest the involvement of free radicals in the pathogenesis of peptic ulcer diseases.
A number of recent studies involving antioxidants also lend support to the involvement of free radicals in such injuries. Thus, concentration of alphatocopherol (vitamin E), which is the most important antioxidant at the membrane level, has been found to be reduced in gastric inflammation associated with H. pylori , . In another study, alphatocopherol levels in mucous obtained from the edge of gastric and duodenal ulcers were found to be higher than in corresponding normal mucosa obtained from the same patients  . Similarly, the activity of the enzyme SOD has been shown to be significantly lower at the edge of the peptic ulcers than in mucosa, distant from the ulcer  . It has been known for sometime that gastric juice contains high levels of vitamin C which are lowered in the presence of gastric ulcers , .
Superoxide free radicals has been suggested to be involved in the development of ethanolinduced gastric mucosal lesions and, which are associated with depletion of NP-SH levels , Treatment with glutathione has been reported to prevent ethanol-induced gastric mucosal damages and depletion of sulfhydryl compounds in humans  . Consistent with this observation, plasma glutathione level has been found to be reduced in duodenal ulcers  .
Taken all together, these results may represent the mobilization of antioxidant defenses in the face of oxidant stress.
| Ischemia-reperfusion injury to stomach (animal studies)|| |
In addition to the evidences regarding the possible involvement of ODFRs in the pathogenesis of gastroduodenal diseases in humans, there are a number of animal studies in which ODFRS have been implicated in the gastric mucosal injury, associated with ischemia- reperfusion. In these studies, the emphasis has been on blocking the biochemical pathways by which ODFRS are produced, and removing the radicals with various scavenging agents and showing that this reduces reperfusion injury. Thus, administration of SOD, allopurinol and catalase reduced reperfusioninduced red blood cell loss across the mucosa and attenuated the formation of gross lesions in rats or cats ,,, . Further evidence of involvement of ODFRS comes from the study that gradual introduction of oxygen reduces reperfusion injury in the cat stomach  . Additionally, vitamin E-deficient rats have been shown to have more ischemia-reperfusion injury than those of vitamin E non-deficient rats  . Most of these studies indicate that xanthine oxidase is the main source of ODFRS in ischemia-reperfusion which are based on the observation that allopurinol reduces post-ischemic red blood cell clearance and gross lesion formation  . It is proposed that changes in purine metabolism during ischemia, give rise to the formation of the superoxide radicals and perhaps of other oxygen radicals when the tissue is reperfused. During ischemia, the high- energy nucleotide ATP is metabolized to hypoxanthine and also the enzyme xanthine dehydrogenase is proteolytically converted to xanthine oxidase. On reperfusion, when oxygen is added. hypoxanthine forms the substrate for xanthine oxidase, which metabolizes it to xanthine and uric acid, but also generates superoxide radical and hydrogen peroxide. When hypoxanthine is metabolized to uric acid, this depletesthe cells from purines that are essential for maintaining an adequate concentration of ATP ,, . Furthermore, there is evidence to suggest that xanthine activation during reperfusion, results in the accumulation of neutrophils which can further contribute to tissue injury , . Prior neutrophil depletion has been shown to provide protection against ischemia-reperfusion injury in laboratory animals  . In this context it has recently been reported that nitric oxide generators, reduce mucosal injury following ischemia-reperfusion and this protection has been attributed to a reduction in PMN infiltration into the mucosa  . Thus, it seems nitric oxide has a role in ischemia reperfusion injury.
Nitric oxide (NO) is an important endogenous vasodilator in the gastric vasculature  and plays a protective role in the gastric mucosa since it is involved in the hyperemic response to damaging agents  . In contrast, it has been suggested that the mucosal blood flow is maintained at low concentration of NO and the excessive release of NO may be toxic to the gastric mucosa  . This toxicity may be exacerbated during ischemiareperfusion due to generation of 0-2 leading to formation of the peroxynitrite radical  . It is conceivable that NO has one unpaired electron and makes a non-radical product and therefore has the potential to be toxic. It thus seems, that further studies are required to establish the role of NO in ischemia-reperfusion injuries.
In our preliminary studies, we also observed that ischemia initiates gastric mucosal lesions which become severe during reperfusion. The severity of the lesions can be reduced by prior administration of antiulcerogenic drug, sucralfate  , which has previously been shown to afford protection against ethanol-induced gastric lesions by protecting/supplying nonprotein sulphydryls (NPSH)  .
As a conclusion, it is clear that ODFRS play an important role in ischemia-reperfusion injury. The primary source of superoxide in reperfused. reoxygenated tissue is the enzyme xanthine oxidase created during ischemia by a calciumtriggered proteolytic attack on xanthine dehydrogenase. Thus, calcium also has a role to play. Reperfused tissues can be protected by inhibitors of xanthine oxidase, allopurinol or by radical scavengers such as SOD, catalase or glutathione. Based on these findings, we have selected some agents which may afford protection against ischemia reperfusion injury. Rational of selection for these agents are discussed in the utilization section.
Calcium channel blockers such as verapamil, act on the cardiovascular system providing antianginal, antiarrhythmic and antihypertensive effects. These drugs have been reported to inhibit superoxide production in human neutrophils  . It has also been shown in our laboratory that the calcium blockers, nifedipine and diltiazem potentiate the anti-inflammatory effects of nonsteroidal anti-inflammatory drugs (NSAIDS) such as indomethacin and diclofenac both in vivo and in vitro , . Furthermore, calcium channel blockers nifedipine, diltiazem and verapamil were able to produce a synergistic effect with alphatocopherol on carrageenan-induced paw edema in rats  .
Alphatocopherol (vitamin E) is widely recognized as a naturally- occurring antioxidant in biological systems, having an apparent specificity as lipid antioxidant. It is speculated that, in vivo vitamin E, once absorbed, exists in the cell membrane of various tissues and reacts with free radicals to protect cell membranes by blocking the free radical chain reaction ,,, . It has been reported that vitamin E-deficient rats, gastric mucosal injury induced by ischemia-reperfusion were more severe than the control  . In addition, it has been shown in our laboratory, that oral chronic or acute administration of vitamin E significantly reduced gastric mucosal injury  .
In view of this, we have investigated the effect of the antioxidant alphatocopherol alone or when it is given together with the calcium channel blockers nifedipine, verapamil or diltiazem on gastric mucosal injury induced by ischemia-reperfusion in rats. Allopurinol was used- as hydroxyl radical scavengers for comparison.
| Materials and Methods|| |
Dialtiazem, nifedipine, verapamil and alphatocopherol acetate were purchased from Sigma Chemical Company, St. Louis, MO, USA. Arachis oil and urethane were purchased from BDH Chemical Company, Poole, Dorset, England.
Animal Treatments: Alphatocopherol acetate (100 mg/kg diluted in arachis oil) was administered orally to rats (n=10-12) 24 hours prior to the procedure. The control group received oral arachis oil. In the second experiment, nifedipine (0.5 mg/kg), verapamil (1.25/kg) and diltiazem (1.25 mg/kg) were given intraperitoneally (i.p.) 30 minutes prior to the procedure. The i.p. solution of diltiazem, verapamil were freshly prepared in 0.9% saline. Nifedipine was dissolved by the aid of a few drops of 5% Tween 80. In the last group, combination of alpha-tocopherol (100 mg/kg) and the calcium channel blockers nifedipine (0.5 mg/ kg), diltiazem (1.25 mg/kg) and verapamil (1.25 mg/kg) were given as in the above- mentioned protocol. Various doses of allopurinol was used for comparison.
Animal Model : Male Wistar rats (200-250 g) were obtained from the College of Medicine animal house at King Saud University. Rats were maintained on standard rat chow prior to experiment but fasted 12 hours immediately prior to surgical procedure; drinking water was available at all times. Rats were anaesthetized by intraperitoneal injection of urethane at a dose of 125 mg/100 g BW. Ischemia was induced as described by Yoshikawa et al., 1991  . Briefly, the stomach was exposed and the esophagus and pylorus occluded, using bulldog clamps. The celiac artery was clamped and 100 mM HCL (1 ml/ 100 g BW) was placed in the stomach to maintain acid levels during ischemia. After 25 minutes of ischemia, the acid was removed and the celiac artery clamp was then removed following 30 minutes of ischemia. The tissue was allowed to reperfuse for 30 minutes and the stomach was removed and examined macroscopically and microscopical under an inverted microscope. The extent of gastric mucosal lesion was expressed as the total area of erosions.
| Statistics|| |
Results are expressed as the mean ± SEM of 1012 rats in each group. Comparisons were carried out by means of one way analysis of variance (ANOVA). Appropriate statistical significance was calculated by Student's t-test for unpaired data (two-tailed). The level of statistical significance was taken as p< 0.05.
| Results and Discussion|| |
Acute treatment of rats with alphatocopherol acetate (100 mg/kg p.o.) produced significant protection of mucosal injury induced by ischemiareperfusion. Number of lesions were also significantly reduced.
Similarly, nifedipine (0.5 mg/kg, i.p.), diltiazem (1.25 mg/kg, i.p.) and verapamil (1.25 mg/ kg, i.p.) produced a significant protection of mucosal injury induced by ischemia-reperfusion as indicated by the number of gastric lesions or the total surface area of lesion.
Alphatocopherol when given in combination with either nifedipine, diltiazem or verapamil, significantly reduced the gastric mucosal injury. The protective effect was synergistic [Table - 1].
Acute administration of allopurinol (12.5, 25. 50 mg/kg, i.p.) produced a dose-dependent protection of mucosal injury induced by ischemiareperfusion as reflected by the number of gastric lesions or the total surface area of lesions [Table - 2].
The present study provides evidence for an important role of ODFRS, vitamin E and calcium channel blockers in gastric mucosal injury induced by ischemia-reperfusion. Furthermore, the data show that the calcium channel blockers, nifedipine, diltiazem and verapamil were able to produce a synergistic effect with alphatocopherol on gastric mucosal injury induced by ischemiareperfusion.
Alphatocopherol has been shown to produce high levels of protection against oxidative injury  and to alleviate many diseases associated with oxidative stress, such as myocardial infraction  , renal ischemia  , gastric mucosal injury induced by ischemia-reperfusion  and immune-triggered endothelial damage  . It has also been shown that alphatocopherol, a lipid-soluble antioxidant which stabilizes unsaturated membrane lipids against autoxidation, is likewise capable of protecting tissues  . The ODFRS react with polyunsaturated fatty acids in the cell membrane and the resulting breakdown products lead to cell damage. It has been suggested that alphatocopherol reacts with free radicals and possibly with other oxidizing intermediates to protect cell membranes by blocking the free radical chain reaction ,, . These actions of alphatocopherol may explain the inhibitory effect it showed, in the present study, against gastric mucosal injury induced by ischemia-reperfusion. The levels of alphatocopherol decreased both in serum and gastric mucosa after ischemia-reperfusion which was suggested to be consumed in the process of lipid peroxidation derived by ODFRS  . This is also confirmed by vitamin E-deficient rats, in which the level of alphatocopherol was markedly reduced in serum or gastric mucosal tissues. In these studies, the level of vitamin E is inadequate for scavenging ODFRS generated during ischemia- referpusion  . It was shown recently in our laboratory, that vitamin E produced a significant protection with calcium channel blockers in rat's paw edema  and gastric mucosal injury induced by ischemia-reperfusion  .
It has been reported that calcium enhances the in vitro free radical-induced damage to brain synaptosomes, mitochondria and cultured spinal cord neurons  . Potentiation of oxygen-radical injury to renal mitochondria by calcium has also been documented  . It is, therefore, conceivable that agents which block calcium entry and release would protect against ODFR injury. Indeed, the dihydropyridine calcium channel blocker, lacidipine, has been shown to possess potent antioxidant properties  . Further, nifedipine was also reported to inhibit microsomal peroxidation in the rat heart  . In agreement with the previous observations reported from this laboratory  and elsewhere, on the role of calcium channel blocker on ODFR-mediated tissue damage, the present study showed that calcium channel blockers significantly reduced the tissue damage induced by ischemia-reperfusion. These antioxidant properties of the calcium channel blockers, besides their known inhibitory effects on intracellular calcium entry, provide a reasonable explanation for their ability to reduce the gastric mucosal injury in ischemia-reperfusion.
Furthermore, treatment of rats with ODFRS scavengers such as SOD or catalase  significantly inhibited gastric mucosal injury. The above observations indicate that ODFRS and lipid peroxidation play an important role in the gastric mucosal lesion induced by ischemia-reperfusion.
The present study gives a therapeutic potential effect of combining vitamin E and calcium channel blockers on gastric mucosal lesion induced by ischemia-reperfusion injury. Further investigations need to be conducted to clarify the protective role of both calcium channel blockers and vitamin E in ischemia-reperfusion and its clinical implication.
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Physiology Department, College of Medicine, King Saud University, P.O. Box 2925, Riyadh 11461
Source of Support: None, Conflict of Interest: None
[Table - 1], [Table - 2]
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