Lead exposure increases oxidative stress in the gastric mucosa of HCI/ethanol-exposed rats Lead exposure increases oxidative stress in the gastric mucosa of HCI/ethanol-exposed rats

Lead exposure increases oxidative stress in the gastric mucosa of HCI/ethanol-exposed rats

  • 期刊名字:世界胃肠病学杂志(英文版)
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  • 论文作者:Samuel Babafemi Olaleye,Oluwat
  • 作者单位:Department of Physiology,Department of Biochemistry
  • 更新时间:2020-10-22
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Online Submissions: wig wjgnet comWorid Gastroenterol14:1338):51215126logy ISSN 1007-932/G. All rights reserved代 PI COMMMUIGATONLead exposure increases oxidative stress in the gastricmucosa of Hcl/ethanol-exposed ratsSamuel Babafemi Olaleye, Oluwatosin Adekunle Adaramoye, Perebiri Peter Erigbali, Olasupo Sunday AdeniyiSamuel Babafemi Olaleye, Perebiri Peter Erigbali, Olasupo Olaleye SB, Adaramoye OA, Erigbali PP, Adeniyi OS. LeadSunday Adeniyi, Department of Physiology, College of Medicine, exposure increases oxidative stress in the gastric mucosaUniversity of Ibadan, Ibadan, Nigeriaof HCl/ethanol-exposed rats. World J Gastroenterol 2007;Oluwatosin Adekunle Adaramoye, Department of Biochemistry, 13(38):5121-5126College of Medicine, University of Ibadan, Ibadan, NigeriaSupportedbytheSenateUniversityofTbadan,Nigeriapartlyhttp://www.wignet.com/1007-9327/13/5121.aspthrough SRG grant to SBO UISRG/COM/2000/10ACorrespondence to: Samuel Babafemi Olaleye, PhD,Gastrointestinal Research Unit, Department of PhysiologUnivcrsity of Ibadan, Ibadan, Nigeria. sb. olaleye(@mail. ui.edu. ngTelephone:+234802-3255893Fax:+234802-2871l135INTRODUCTIONReceived March 1. 2007Revised: July 6, 2007Reactive oxygen species(ROS) have been shown to be tobe involved in the etiology of many infammatory disordersof the gastrointestinal system. This is evidenced byAbstractthe increased oxidative stress by pro-ulcerative factorsin the gut such as I pylori'use of non-steroidal antiALM: To investigate the role of reactive oxygen species inflammatory drugs sf, smoking 6, psychological stress,in the ulcer-aggravating effect of lead in albino ratcorticosteroid use, and loss of sleep". Lipid peroxidationMETHODS: Albino Wistar rats were randomly divided (PO), a result of the reaction of oxyradicals andwk. a third group received saline and served as control. sulfhydryl compound, is an important substance in theAt the end of wk 15, colorimetric assays were applied ccllular defense systemto determine the concentrations of total protein andNitric oxide(NO)depletion also plays significantnitrite, the activities of the oxidative enzymes catalase roles in the pathogenesis of gastric ulcers. NO along withand superoxide dismutase, and lipid peroxidation in superoxide(Oz )and the products of their interactionhomogenized gastric mucosal samplestissue injury. Large amounts of NO), generated primarilyRESULTS: Exposure of rats to lead significantly by iNOS, can be toxic and pro-inflammatory. Likewise,increased the gastric mucosal damage caused by neutrophils too produce oxidants and release granularacidified ethanol. Although the basal gastric acid constituents comprising lytic enzymes performing arsecretory rate was not significantly altered, the important role in inflammatory injurymaximal response of the stomach to histamine wasAlthough lead acetate does not initiate any excesssignificantly higher in the lead-exposed animals than generation of reactive oxygen species in a cerebralin the unexposed control group. Exposure to low andapiosomauspension, it has a marked abilithigh levels of lead significantly increased gastric lipid enhance the pro-oxidant propertics of ferrous iron inperoxidation to183,2%±127%and226.1%±6.8%of control values respectively (P 0.0). On the other induced by I-glutamatev, amplifies oxidative stressthe same system. It alsehand, lead exposure significantly decreased catalase andaccumulated lead exposure is related to several chronicsuperoxide dismutase(SoD)activities and the amount or disorders of aging inciuding disorders that have beennitrite in gastric mucosal samplesassociated with oxidative stress, Sass first reportedCONCLUSION: Lead increases the formation of gastric that lead poisoning in dogs is associated with perforatingulcers by interfering with the oxidative metabolism in the gastrcers. Bercowitz and Laufer obscrvcdthat中国煤化工 had accumulated lcad1nC 2007 WJG. All rights reserved.leadCNMHG, we reported that longterm exposure of rats to lead predisposes the stomach toKey words: Lead; Ulcer; Lipid peroxidation; Catalase; highcr ulcerogenic effects of indomethacin and acidifiedGastric acidethanol. However, the exact mechanism(s) by which lead5122 ISSN 1007-9327 CN 14-1219/R World J Gastroenterol October 14, 2007 Volume 13 Number 38promotes gastric ulceration is not yet understood. The meter (Watson-Marlow Inc, USA)was passcd through theobjective of the present study thus was to investigate the mouth to the stomach. Tcn minute effuent samples (10.0involvement of ROS in the aggravation of ulceration in t 0. 1 mL each) were collected wia a pyloric cannula andthe stomach of lead-exposed rats.titrated against 0.01 mol/L NaoH using phenolphthaldas indicator. Acidity was expressed in mol/L-/L per minMATERIALS AND METHODSlife. After obtaining a consistent basal acid output, cachanimal was injected wia a femoral vein cannula with eitherChemicals and animals9 g/L NaCl or histamine acid phosphateLead acetate and urethane wcrc obtained from bDhhemicals Ltd, Poole. England. Epinephrinc, 5,5-dithio- Biochemical analysisbis-2-nitrobenzoic acid, hydrogen peroxide, sodium At the cnd of chronic lead exposure, the animals werepentobarbitone, and thiobarbituric acid(TBA)were killed under deep ether anaesthesia and the stomachspurchased from Sigma (St Loius, MO USA). All other wcre removed. Each stomach was cut open through theagents were of analytical grade and were obtaincd from greater curvature, rinsed in normal saline, weighed, andthe British Drug Houses, Poole, UK.homogenized in 10 mL KCl (pH=7. 4). The homogenateYoung male albino Wistar rats(80-90 g) were obtained was subsequently used for total protein estimation. Therom the small animal house, College of Medicine, protein content of the gastric mucosa was estimated by theUniversity of Ibadan, Nigeria. They were randomly divided method of Lowry ef al -using bovine serum albumin as ainto three groups with adequate matching of weight. They standardwere kept in wire meshed cages and fed with commcrcialDetermination of lipid peroxidation. L ipidat pellets(Ladokun Feeds Ltd, Ibadan, Nigeria) and peroxidation was assayed by measuring the thiobarbituricallowed to take water ad libitum.cid reactive(TBAR) products using the procedure ofWalls et a/ 4l. Briefly, the homogenate was supplemcntedLead treatmentwith 0.75 g/L TBA in 0. 1 mol/T HCl. The reactants wereAnimals were exposed to lead as previously described. then supplemented with 5 mI. n-butanol-pyridine mixture,The high lead group(HiPb)was given 5000 mg/J. lead shaken vigorously for 1 min and centrifuged for 10) min atacetate in drinking water daily while the low lead group 4000r/min. Absorbance was then read at 532 nm and theLoPb)received 100 mg/L lead acetate in drinking watcr. results expressed as nmol TBA per 100 mg wet tissucThe control animals received only drinking water. At theDetermination of catalase activity. Activity ofend of a 15 wk cxposurc, blood samples were collected catalase in gastric mucosa was determined according tofrom the rats for analysis of the Packed Cell Volume(PCV), the procedure of Sinha2-I. This method is based on thered and white blood cell counts, and neutrophile numbers reduction of dichromate in acetic acid to chromic acetateby standard methods. Afterwards, ulcer was induced as when heated in the presence of H2O2, with the formationfollowsof perchromic acid as an unstable intcrmcdiatc. Thechromic acetate so produced is measured calorimetricallyInduction of experimental ulcerat 530 nmAcidified ethanol was used to induce cxpcrimcntal gasDetermination of SoD) activity For determination ofulcers. Thirty six hours fasted rats were given 1.0 mL SOD activity, samples of gastric mucosal homogenatesof HCl/ethanol mixture containing 0. 15 mol/L HCI in wcre taken as described above. A method originally70%mL/.ethanol. Four hours after administering the dcscribed by Mista and Fridovich) as reported byulcerogen and undcr sodium pentobarbitone anaesthesia Magwere et a/2 was employed. This method is based(60 mg/kg, ip), the animals were sacrificed. The stomachs on the ability of superoxide dismutase to inhibit thewere removed, inflated with 10 mL of 2% formaldehyde autoxidation of epinephrine caused by O2 generated byfor 10 min to fix the tissue walls and opened along the xanthine oxidase reactiongreater curvature. The hemorrhagic lesions were stretchedDetermination of nitrite in gastric mucosa. The gastricout on a glass plate and their sizes were estimated using mucosa was cooled in ice-cold distilled water beforan underlying graph paper with a 1 mm grid. Iesion areashomogenization(100 g/L). The crude homogenate waswere summed up per stomach and expressed as of total centrifuged at 21.000 g for 20 min at 4C. Aliquots ofmucosal areathe supernatants were taken to dctcrminc nitrite lcvclsThe amounts of nitrite were measured in the gastricMeasurement of gastric acid secretionmucosa by performing the Griess reaction. 100 mL ofsh"! The ag as was studied in the 3 groups using sample were incubated with 100 mL of Griess reagentGhosh. ' The animals were fasted for 24 h at the end determined by measuring the absorbance at 550 nm usingof the 15 wk lead treatment, Under urethane anaesthesia a sp中国煤化工 Beckman, Fullerton,[250 g/L urethane(6 mL/kg body, ip)], the animals Caliwere surgically prepared for in situ stomach perfusionCNMHGcous. Adherent gastricThe pylorus was semi-transected at its junction with the glandular mucous was measured by the method of Cotneduodenum and a pyloric cannula inserted and tied into ef al. Excised gastric glandular portion of the stomachlace. An oesophageal cannula for infusion from a flow were transferred for 2 h to 0. 1% Alcian blue dissolvedOlaleye SB et al. Lead increases oxidative stress in rat stomach5123Controtalprotein(mg/g)c。43.3±44(1 mg/kg)Low lead174±63972±065750±0.142007High!ead63±5.11250±051620±001230±024p<0.05 vs controlin buffer solution containing 0. 1 mol/L sucrose and01020+3040-50-6070-g60901000.05 mol/L sodium acetate (pH adjusted to 5.8 withhydrochloric acid). After washing the stomach twice in 0.2mol/L sucrose(15 min and 45 min), the dye complexed Figure 1 Gastric acid secretory output after administration of histamine(1 mg/kg)with mucous was eluted by immersion in 10 mI. aliquots in rats (P< 0.05, "P<0.01 vs control)0.5 mol/l. MgClz for 2 h. The resulting blue solutionvas shaken with equal volumes of diethylcther anthe optical density of the aqueous phase was measured (Figurc 2B). Similarly, lcad cxposurc decreases gastricectrophotometerically at 605 nmmucosal catalase activity to 88.22%+ 3. 21%/ and 55. 29% t2.15% of the control, respectively(Figure 2C).Statistical analysisAll values presented in tables are expressed as mean t Gastric mucosal nitrite concentrationSEM,, The appropriate comparisons between groups were The control gastric mucosal nitrite level was 62. 4+ 4.2made using Student't-test. The difference between the nmol/g tissue(Figure 3). Chronic exposure of rats to leadgroups is taken to be significant at P<0.05for 15 wk depleted the gastric nitrite level to 51.6+ 3.1nmol/g tissue(P <0.05)and 49.7 t 2.5 nmol/g tissueRESULTS(P<0.01)Development of gastric lesionsAdministration of acidified ethanol caused severe damageDISCUSSIONthe rat stomachs under investigation. The site of the The present study investigated the tole of oxidative stressformation of lcsions is the corpus mucosa. The mean in the ulcer-promoting action of prolonged lead exposureulcer scotc in the control animals was 6.94%+ 0.42%. in rats. The doses and the duration of lead treatment usedThe severity of lesions was markedly increased by chronic in our study have been shown to cause significant highexposure to both low and high lead concentrations Table 1blood lead levels in previous studies.-. Thus, thcrc isP<0.05. Also shown in Table 1 is the result of the total no doubt that the animals had high blood lead levels. Theprotein and adherent mucous content of the glandular acidified ethanol model has been used widely to producestomach. Long term exposure to lead significantly gastric mucosal damage We observed that long-termdecreased both gastric mucous and protein contents, the exposure of rats to lead given through drinking waterinhibition being greatest in the high lead treated group.significantly increased the incidence of gastric uicerBasal rate of gastric acid secretion was not significantly produced by the ulcerogen. This agrees with our previousaffcctcd by lead exposure. However, the maximal response report in which lead was shown to aggravate gastric ulcersof the stomach of lead-exposed animals to histamine was induced by indomethacin and acidified ethanol1significantly higher than those of the unexposed controlIt is well established that gastric acid secretion playsgroup(Figure 1)a role in gastric ulcer. Moreover, many anti-ulcerogenicdrugs act by reducing the acid secretion". The presentLipid peroxidation and gastric antioxidant enzymesresult suggests that basal gastric acid secretory rate wasLipid peroxidation(mcasured as the amount of TBA not significantly affected by prolonged lead treatmentactants in the gastric mucosa)in the unexposed control However, maximal stimulation by the establishedanimals was 595+ 82 mmol/g tissue. Exposurc of rats to secretagogue, histamine, was markedly incrcascd in thelow and high lead levels significantly increased gastric TBA lead exposed rats. We had carlicr reported that acid outputreactant level to 183.2%+ 12. 7% and 226. 1%+ 6.8% of from中国煤化工 ead exposed rats wasthe control value, respectively(Figure 2A). On the other incrr studies may thereforehand, SOD activity in the intact gastric mucosa(controlCN MH Gcretory models beforegroup)averaged 334 22 nkat/g. Exposure of rats to low a conclusion can be made on the exact effect of leadand high lead levels significantly dlecreased SOD activity exposure on gastric acid secretionto 78%+ 3% and 66%+ 6% of the control, respectivelyid peroxidation has been implicated in the etiologywww.wjgnet.com5124 ISSN 1007-9327 CN 14-1219/R World J Gastroenterol October 14, 2007 Volume 13 Number 3839E888ControlLow lead exposure High lead exposureControlLow lead exposure High lead exposureB120Figure 3 Gastric mucosal nitrite concentration in lead exposed rats(mean t sEMn=8 rats, P<0.05,P<0.01 vs contral)increased lipid peroxidation in the gastric mucosa withe88depletion of endogenous antioxidants. The result of thstudy showed a significant decrease in the protein glandulaprotein level of the rats given low and high doses of leadacetate. This may also explain the significant low levels ofthe antioxidizing enzymes SoD and Cat obscrved in thecreated groups.In gastroprotection, the first line of antioxidativeLow lead exposure High lead exposureenzyme is SOD which catalyses the dismutationof superoxide radical anion(Oz) into less noxioushydrogen peroxide(II2Oz). HzOz is then inactivated bythe dcgradation into water by catalase or glutathioneDepletion of these enzymes, as evidentby the results of this study, therefore predisposes thestomach to a greater impact of the free radicals produced器via increased lipid peroxidation, hence increased ulcerformation following lead exposure.Apart from the free radical scavenging enzymeanother agent that has been widely believed to beinvolved in the regulation of various gastric functionsand in the modulation of gasmucosal integrity isnitric oxide(NO). This is evidenced by reports showingControlLow lead exposure High lead exposure that suppression of no production by NO synthasemucosa of rats exposed to chronic lead treatments(mean* SEM. n=8, P<0.05 in rats s worsens gastric lcsions induced by ethanolFigure 2 TBA reactants, superoxide dismutase and catalase activites in gastnicNO has also bcen suggested to preventvs control)infiltration by neutrophils, which arc a source ofsuperoxide radical anions". The reduction in the gastrictissue nitrite in the lead treated groups in the presentof damage to subcellular membranes and then injurystudy is therefore indicative for a reduced protectivein the cell. In the prescnt study, lipid peroxidation, as capacity of endogenous NOmeasured by the amount of TBA reactants, was increasedIn summary, chronic exposure of rats to lead intensifiesby lead exposure. The implication of this is that lead HCl/ethanol-induced gastric mucosal damage and thiscauses an increase in the formation of free radicalsmay he related to reduced gastric contents of endogenouswhich, if not mopped up by free radical scavengers as NO and the antioxidative enzymes SOD and CATOD, CAT, or glutathione, will expose the stomach toWapnir et aA reported that juvenile rats fed a diet COMEAin damnation中国煤化工containing 1% lead acetate for 7 wk suffered from Backmalabsorption of certain amino acids, as the intestinalYHCN MH Gd to high levels of lead throughabsorption of glycine, lycine, and phenylalanipaints, car enc wercingestion with food and via inhalation. Previous studies in dogs and rats havedecreased.Furthermore, administration of HCl and shown that long-term exposure to high level! lead in drinking watar predisposes theethanol has bccn shown to produce ulcerative lesions and stomach to ulcer. The mechanism of this effect of lead is not understoodwww.wigneOlaleye SB et al. Lead increases oxidative stress in rat stomach5125Research frontie16:241-248Oxidative stress has been shown to be a major causative factor for many 13 Yoshikawa T, Naito Y. The role of netds and inflammatiodiseases. including gastrointestinal ulcers. The hotspot of this study is toin gastric mucosal injury, Free Radic Res 2000; 33: 785-794kamine if the increased susceptibility of the stomach to ulcer after prolonged 14 Bondy SC, Guo SX. Lead potentiates iron-induced formationad exposure can be explained (partly or totally) by an increased oxidativof reactive oxygen species. Toxicol Left 1996: 87: 109-112stress in the stomach15 Naarala JT, Loikkanen JI, Ruotsalainen MH, Savolainen KM.Lead amplifies glutamate-induced oxidative stress. Free RadicBiol Mec41995;19:689693Innovations and breakthroughs16 Romero-Alvira D, Roche E. High blood pressure, oxygenhe results of this study show that chronic exposure of rats to lead intensifiesradicals and antioxidants: etiological relationships. MedHClethanol-induced gastric mucosal damage and this may be related to reducedHypotheses199;46:414-420gastric contents of endogenous nitric oxide and antioxidative enzymes17 Thylefors B, Negrel AD, Pararajasegaram R, Dadzie KYAvailable data on blindness(update 1994)OphthalmicApplicationsEpidemio 1995; 2: 5-39he study suggests that prolonged exposure to lead may be a factor in the etiology.8 Mecocci P, Mariani E, Cornacchiola v, Polidori MCof gastrointestinal ulcersAntioxidants for the treatment of mild cognitive impairmenteuro res2004;26:598-6029 Sass B Perforating gastric ulcer associated with leadoisoning in a dog. J Am Vef Med Assoc 1970: 157: 76-78Oxidative stress: a condition of increased oxidant production in animal 20 Olaleye SB, Raji Y, Onasanwo SA, Erigbali P, Oyesola sOcells characterized by the reiease of free radicals and resulting in cellularOdukanmi A, Omotosho IO, Elegbe RA Potentiation ofdegeneration. Free radicais damage components of the celis membranesGastric Ulceration By Experimental Lead Exposure in Rats. Iproteins, or genetic material by"oxidizing them-the same chemical reaction thatcauses iron to rust; Lead: a soft heavy toxic malleable metalic element; bluish 21 Anadan R, Rekha rD, Saravanan N, Devaki T. Protectivewhite when freshly cut but tarnishes readily to dull grey, Lead poisoning: Lead caneffects of Picrorrhiza kurroa against HCl/ethanol inducedcome into the body in a number of ways through water that goes through leadulceration in rats, Fitoterapia 1999: 70: 498-503pipes, through badly canned food and through small pieces of paint. Victims of 22 Ghosh MN, Schild HO. Continuous recording of acidlead poisoning may get headaches, dizziness, confusion, and problems seeisecretion in the rat. Br/ Pharmacol Chemother 1958; 13: 54They may also become slowly paralyzed, starting with the hands. In very ser23 Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Pmeasurement with the Folin phenol reagent. 1 Biol ChePeer revie24 Walls R, Kumar KS, Hochstein P Aging human crythrocytesThis is an interesting and generally well written paper with some new informationDifferential sensitivity of young and old ery throcytes toemolysis induced by peroxide in the presence of thyroxiArch Biochem Biophys 1976: 174: 463-468REFERENCES25 Sinha AK. Colorimetric assay of catalase. Anal Biochem 1972;1 Perry MA, Wadhwa S, Parks DA, Pickard w, Granger DN. 26 Misra HP, Fridovich I. 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