长期乙醇摄入对大鼠胃黏膜上皮细胞免疫因子TSLP表达的研究
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摘要
研究背景：
大量饮酒与胃肠道疾病相关,长期适量饮酒对胃肠道的影响尚待研究。
高浓度乙醇对胃黏膜损害的动物模型较为容易建立,长期适量乙醇摄入对胃黏膜的影响的动物模型鲜有报道。
Benjiamin Taylor[7]通过系统性回顾研究对于长期适度饮酒对胃肠的作用和影响得出结论：适量的乙醇摄入对于疾病发展起消极、积极的作用,总得来说适量乙醇摄入不是胃肠疾病发展的高危因素。Taylor B把适量饮酒定义为每天乙醇摄入约为10-40g/d,据此我们给予Wistar大鼠乙醇15%(V/V)lml/d灌胃,相对于适量摄入乙醇量。
流行病学研究[8]表明适量饮酒是肝病、食管肿瘤、胰腺炎的危险因素,但是对于慢性胃炎、胆囊结石却有积极意义,机制并不明确。人体中95%左右乙醇分解是通过氧化途径进行,包括乙醇的首过代谢(first-pass metabolism, FPM),微粒体乙醇氧化体系(microsomal ethanol-oxidizing system, MEOS),脂肪酸过氧化氢酶(catalase),乙醛脱氢酶(aldehyde dehydrogenase, ALDH)[9]。乙醇首过代谢[10]是指一定量的乙醇摄入后进入系统循环之前在胃和肝中代谢。Lieber[11]等广泛的研究了这种现象,他们提出FPM主要发生在胃组织,胃黏膜乙醇脱氢酶起重要作用。ADH和ALDH途径是乙醇代谢的主要途径,ADH介导乙醇氧化,使底物乙醇上的氢转移到辅酶NAD上,转化为NADH,产生底物乙醛。乙醛利用辅酶NAD在ALDH作用下转化为乙酸,产生NADH。乙酸转化为乙酰辅酶A,进入三羧酸循环,最终分解为二氧化碳和水。
随着酒精摄入量的增加和蓄积微粒体乙醇氧化系统参与乙醇氧化代谢,活性氧(reactive oxygen species, ROS)、氧自由基(oxygen free radical, OFR)随之产生,包括线粒体在内的细胞膜性系统出现脂质过氧化,细胞进入氧化应激(oxidative stress, OS)状态[12],转录因子缺氧诱导因子-1a表达增加,从而引起细胞处于乏氧适应状态,以及新的功能。而免疫功能也会发生改变,以适应细胞内低氧的环境。
1992年,Semenza, Wang首先发现了HIF1蛋白。HIF1是异源二聚体蛋白,由HIF1-α和HIF1-β组成,在缺氧条件下HIFlα迅速表达。一旦激活,HIFlα加强基因转录,包括几乎所有的参与糖酵解的酶,增强细胞糖酵解能力[13]。HIF1α激活丙酮酸脱氢酶激酶,抑制线粒体丙酮酸脱氢酶复合体,减少进入三羧酸循环的丙酮酸量。进入三羧酸循环的丙酮酸减少,减少缺氧状态下氧化磷酸化及氧耗量。
HIF1α参与免疫的调节。
胸腺基质淋巴细胞生成素(hymic stromal lymphopoietin, TSLP)源于细胞上皮的一种淋巴因子,可以直接作用于黏膜中树突细胞(dendritic cells, DCs)[14,15]。使后者分泌OX40L促使TH0细胞向TH2细胞极化,形成TH2免疫。
正常胃黏膜上皮中存在DCs。TSLP是抗炎因子。
TSLP是否在正常胃黏膜中表达,尚未有研究。
目的与方法：
我们研究长期乙醇摄入后大鼠胃黏膜病理形态变化,胃黏膜丙二醛(malondialdehyde, MDA)含量变化及胃黏膜损伤程度,探讨胃黏膜上皮细胞在缺氧状态下,脂质过氧化与上皮损伤的关系。我们分别用15%、30%、45%不同浓度乙醇灌胃制备胃黏膜上皮氧化状态模型,观察胃黏膜大体及镜下形态学变化并评估黏膜损伤指数(lesion index,LI),硫代巴比妥酸法(thiobarbituric acid, TBA)测定胃黏膜内MDA含量,MDA与LI、病理损伤积分的关系。
结果：
我们发现(1)15%乙醇摄入组,3、6、9周后黏膜损伤指数、病理损伤积分、及MDA数量分别与对照组相比,均没有显著变化。(P>0.05,n=9)(2)30%、45%组胃黏膜损伤指数与胃黏膜MDA含量呈正相关,随着乙醇浓度的升高及作用时间的延长,胃黏膜MDA含量增加,胃黏膜损伤程度加重(p<0.01,n=9)。
结论：
对于大鼠5ml/kg/d15%v/v乙醇摄入后,大鼠胃黏膜上皮细胞氧化应激状态不明显。
随着浓度升高、摄入时间延长,长期乙醇摄入可引起胃黏膜上皮细胞脂质过氧化,细胞整体上处于缺氧状态。
研究背景
细胞内物质代谢与细胞免疫是细胞内两种不同的功能。乙醇在胃黏膜上皮细胞代谢后是否能够影响胃黏膜上皮细胞的功能,尚未有研究。
乙醇与胃黏膜的关系主要集中于损伤与修复的关系。
长期乙醇摄入经过胃黏膜上皮的首过代谢作用、微粒体乙醇氧化系统作用,胃黏膜上皮细胞细胞膜出现脂质过氧化及大量活性氧产生,细胞内固有还原剂NADPH减少,细胞为适应常氧到缺氧环境的变化,转录因子缺氧诱导因子-lalpha (HIF-1α)功能增强,增强细胞缺氧耐受。HIF-1α是1992年发现的一种重要转绿因子,HIF-1α的下游靶基因目前有超过200个,参与能量代谢、血管新生、一氧化氮合成、铁与血红素代谢以及免疫调节[27]。胸腺基质淋巴细胞生成素(thymic stromal lymphopoietin, TSLP)是一种上皮细胞来源的细胞因子,作用于髓样和淋巴样树突细胞,调节适应性免疫,在起始和促进Th2细胞免疫过程中起重要作用。TSLP与树突细胞上TSLPR直接作用,通过CD40L促使Th0极化为Th2细胞,形成体液免疫,参与对胞外菌及寄生虫清除。其激活途径是独立于MCHII分子、共刺激分子之外的另一条途径。TSLP是否在胃黏膜上皮中表达,以及其表达的机制尚未有人研究。我们设想在长期乙醇摄入条件下HIF-la被激活,其靶基因TSLP表达。丰富黏膜免疫理论,为适量饮酒可以有助于清除幽门螺旋杆菌(Helicobacter pylori, HP)提供理论支持。
目的
1.建立适量饮酒的大鼠动物模型。
2.大鼠胃胃黏膜上皮能否表达TSLP,以及表达量是否与摄入乙醇量、时间有关系。
3.转录因子HIF-la是否调控TSLP表达。
材料与方法
选用健康雄性Wistar大鼠33只,按照不同浓度分为3组,分别给予生理盐水、15%、45%乙醇灌胃,8%水合氯醛1ml麻醉后给予取出胃黏膜,用RT-PCR检查各组HIF-1α、TSLPmRNA相对表达量,免疫组化进行蛋白定位,Western blot技术测定细胞内HIF-1α、TSLP表达量并进行相关性分析。
统计方法：
SPSS17.0软件进行统计分析,数据以均数±标准差表示,采用单因素方差分析进行统计学处理,以P<0.05为显著性差异。
实验结果
生理盐水组大鼠胃黏膜mRNA水平检测到HIF-1α,未检测到TSLP。蛋白质水平未检测到HI-1α、TSLP。15%,45%组mRNA水平、蛋白质水平均有HIF-lα、 TSLP表达。随着乙醇浓度增加与摄入时间延长,HIF-1α表达量增加(p<0.01,n=9), TSLP水平在45%组6、9w相比未有明显增加,(p>0.01,n=9)。TSLP表达与HIF-α表达有相关性r=0.87。
结论
正常大鼠胃黏膜中没有HIF-1α蛋白、TSLP蛋白表达。随着细胞内氧化应激水平升高,HIF-1α水平、TSLP水平升高。
乙醇转录因子HIF-1α调控TSLP蛋白表达。
Background:
A high alcohol intake is significantly associated with diseases of the gastrointestinal tract, but less is known about the effects of modedrate consumption.
The animal model of high alcohol intake is easily set up,however the moderate alcohol consumption is less known.
Taylor B drawes the conclution in the method of a systematic computer-assisted literature review that moderate alcohol consumption may play a positive or negative role in disease etiology, but overall conclusion is that moderate alcohol intake in not a high risk factor for many of the gastrointestinal diseases associated with high levels of consumption.
Alcohol drinking is responsible for a number of gastrointestinal disease. Although heavy drinking episodes and chronic drinking are well linked to mechanisms of disease, mmoderate alcohol consumption and its effects are less well known. Epidemicological studies show moderate alcohol intake is a risk of liver disease, tumor of esophagus, and pancreasis, but it is positive to chronic gastritis and cholecystolithiasis. About95%alcohol in body in break down in the way of oxidation, including oxidation via first-pass metabolism(FPM), oxidation via microsomal ethanol-oxidizing system(MEOS), and fatty acid-catalase, aldehyde dehydrogenase system。 FPM occurs when a certain amount of ingested ethanol is metabolized primarily in the stomach and in the liver before reaching the systemic circulation. Lieber et al. have investigated this phenomenon extensively. They have emphasized that FPM is predominantly of gastric origin and that gastric ADH is mainly responsible for the FPM. Ethanol oxidation by alcohol dehydrogenase, aldehyde dehydrogenase is the main system used, with the other two only joining in during chronic ethanol ingestion. ADH meidate in alochol oxidation in a manner of transfering hydrogen in ethanol to NAD, producing aldehyde and NADH respectively. Aldehyede make use of NAD to produce acetic acid, and the latter is transformed into Acetyl coenzyme A which join in Crebs cycle generating water and carbon dioxide.
As the consumption of alcohol increase and store up, MEOS works to generate OFR and ROS resulting lipid peroxidation of cell membrane system including mitochondria. The cell in the station of oxidative stress. The expression of transcription factor HIF1-α enhances to accommodate hypoxia.
In the year of1992, HIF1was first detected by Semenza, Wang. The HIF1complexes are the mayor transcription factors that are reponse to low oxygen conditions. It is heterodimers that are composed of the constitutively expressed HIF1β subunit and HIF1a subunits, which are rapidly stablilized on exposure to hypoxia. Once activated HIF1amplifies the transcription of genes encoding glucose transporters and most glycolytic enzymes, increasing the capacity of the cell to carry out gycolysis. In addition, HIF1activates the pyruvate dehydrogenase kinases, which inactivate the mitochondrial pyruvate dehydrogenase complex and thereby reduce the flow of glucose-derived pyruvate into the tricarboxylic acid (TCA)cycle. This reduction in pyruvate flux into the TCA cycle decreases the rate of oxidative phosphorylation and oxygen consumption, renforcing the glycolytic phenotype and sparing oxgen under hypoxic condtions.
HIF1-α playes role in immunoregulation.
TSLP derived from epitheial cells can trigger DCs directly in mucosa and promote the latter secret OX40L to polarize to the TH2immune from THO immnue.
In the normal station, DCs are present in the mucosa. TSLP is a anti-inflammatory cytokine.
Whether TSLP can be inducible in the gastric mucosa is unkown.
Objectives:
To study the role of alcohol metabolism in the pathogenesis of ethanol-induced gastric mucosa injury
Methods:
Wistar rats were used in the study. A gastric mucosal injury model was established by alcohol gavage to rats. Gross and microscopic apperarance of gastric mucosa wer evaluated. Malondiadehyde (MDA) in gastric mucosa was measured with thiobarbituric acid. Guth and Mascuda criterion were adopted to evulate the gastric epithelium injuries respectively.
Results:
For the groups of15%, MDA, LI and the pathological injury changes insignificantly (p>0.05). The gastric mucosal lesion index was correated with the MDA content in gastric mucosa. As the concentration of alcohol was elevated and exposure time to alcohol was extended, the context of MDA in gastric mucosa increased and the extent of damage aggravated as far as groups of30%and45%. The lesion index and the pathological injury increased in groups of30%and declined in group of45%as the exposure time extended(p<0.01).
Conclusions:
In the level of5ml/kg/d15%v/v, the rat gastric mucosa oxidative stress is not apprant.
Long-term alcohol consumption causes lipid peroxidation in the gastric epithelial cells. The cells are in the station of oxidative stress as the concentration of alcohol was elevated and exposure time extend..
Background:
Long-term alcohol intake leads to lipid peroxidation and ROS through FPM, MEOS, catalase which depletes inherent reducing agent NADPH in rat gastric mucosa. The function of transcrpiton factor HIF-lastrengthenes to adapt to the station of hypoxia. HIF-1αwas found in the year of1992,of which the target genes includes more than200kinds involving in energy metabolism, angiogenesis, nitric oxide synthesis, iron and heme metabolism and immunoregulation. Thymic stromal lymphopoietin derived from epithilial cells act on myeloid dendritic cells and lymphoid dendritic cells to regulate adaptive immnune which plays crucial roles in the initiation and promotion TH2immune.TSLP binds to TSLPR directly promoting TH2polarization from THO via CD40L.The resultant humoral immunity involves in eradication of extracelluar bacteria and parasite.The pathway activating DCs is independent of the way of the classical MHCII, costimulatory molecules.Up to now, it is not reported whether TSLP is expressed in gastric mucosa and what the mechanism lies. We assume that long-term alcohol intake activates HIF-1α leading to expressing of target TSLP. The assumption will rich the mucosa immnne theories, and explain why moderate alcohol intake helps to eradicate HP partly.
Objectives:
to study the expression of tslp,hif-la in the state of oxidative stress in gastric mucosa caused by long-term alcohol intake, and to analyse the expression correlation between them.
Methods:
Immunohistochemistry was applied to locate TSLP, and HIF-la. RT-PCR and Western blot were used to measure the amont of TSLP, HIF-la in cytoplasm in the level of mRNA and protein respectively.
Results:
TSLP, HIF-la in different groups were all detected by means of immunohistochemistry compared to control group. TSLP, HIF-la were located in gland cells and the location were consistent. In group15%and30%the mount of TSLP, HIF-la increased as exposed time extended while In45%group, the mout of TSLP, HIF-1αa declined. The expression of TSLP was related to expression of HIF-1α.
Conclusions:
Protein HIF1-α, TSLP are not induced in normal rat gastric mucosa. As the level of oxidative stress get intense,protein HIF1-α and TSLP express increase.
Alcohol can trigger TSLP expression via HIF-la in rat gastric mucosa
大量饮酒与胃肠道疾病相关,长期适量饮酒对胃肠道的影响尚待研究。
高浓度乙醇对胃黏膜损害的动物模型较为容易建立,长期适量乙醇摄入对胃黏膜的影响的动物模型鲜有报道。
Benjiamin Taylor[7]通过系统性回顾研究对于长期适度饮酒对胃肠的作用和影响得出结论：适量的乙醇摄入对于疾病发展起消极、积极的作用,总得来说适量乙醇摄入不是胃肠疾病发展的高危因素。Taylor B把适量饮酒定义为每天乙醇摄入约为10-40g/d,据此我们给予Wistar大鼠乙醇15%(V/V)lml/d灌胃,相对于适量摄入乙醇量。
流行病学研究[8]表明适量饮酒是肝病、食管肿瘤、胰腺炎的危险因素,但是对于慢性胃炎、胆囊结石却有积极意义,机制并不明确。人体中95%左右乙醇分解是通过氧化途径进行,包括乙醇的首过代谢(first-pass metabolism, FPM),微粒体乙醇氧化体系(microsomal ethanol-oxidizing system, MEOS),脂肪酸过氧化氢酶(catalase),乙醛脱氢酶(aldehyde dehydrogenase, ALDH)[9]。乙醇首过代谢[10]是指一定量的乙醇摄入后进入系统循环之前在胃和肝中代谢。Lieber[11]等广泛的研究了这种现象,他们提出FPM主要发生在胃组织,胃黏膜乙醇脱氢酶起重要作用。ADH和ALDH途径是乙醇代谢的主要途径,ADH介导乙醇氧化,使底物乙醇上的氢转移到辅酶NAD上,转化为NADH,产生底物乙醛。乙醛利用辅酶NAD在ALDH作用下转化为乙酸,产生NADH。乙酸转化为乙酰辅酶A,进入三羧酸循环,最终分解为二氧化碳和水。
随着酒精摄入量的增加和蓄积微粒体乙醇氧化系统参与乙醇氧化代谢,活性氧(reactive oxygen species, ROS)、氧自由基(oxygen free radical, OFR)随之产生,包括线粒体在内的细胞膜性系统出现脂质过氧化,细胞进入氧化应激(oxidative stress, OS)状态[12],转录因子缺氧诱导因子-1a表达增加,从而引起细胞处于乏氧适应状态,以及新的功能。而免疫功能也会发生改变,以适应细胞内低氧的环境。
1992年,Semenza, Wang首先发现了HIF1蛋白。HIF1是异源二聚体蛋白,由HIF1-α和HIF1-β组成,在缺氧条件下HIFlα迅速表达。一旦激活,HIFlα加强基因转录,包括几乎所有的参与糖酵解的酶,增强细胞糖酵解能力[13]。HIF1α激活丙酮酸脱氢酶激酶,抑制线粒体丙酮酸脱氢酶复合体,减少进入三羧酸循环的丙酮酸量。进入三羧酸循环的丙酮酸减少,减少缺氧状态下氧化磷酸化及氧耗量。
HIF1α参与免疫的调节。
胸腺基质淋巴细胞生成素(hymic stromal lymphopoietin, TSLP)源于细胞上皮的一种淋巴因子,可以直接作用于黏膜中树突细胞(dendritic cells, DCs)[14,15]。使后者分泌OX40L促使TH0细胞向TH2细胞极化,形成TH2免疫。
正常胃黏膜上皮中存在DCs。TSLP是抗炎因子。
TSLP是否在正常胃黏膜中表达,尚未有研究。
目的与方法：
我们研究长期乙醇摄入后大鼠胃黏膜病理形态变化,胃黏膜丙二醛(malondialdehyde, MDA)含量变化及胃黏膜损伤程度,探讨胃黏膜上皮细胞在缺氧状态下,脂质过氧化与上皮损伤的关系。我们分别用15%、30%、45%不同浓度乙醇灌胃制备胃黏膜上皮氧化状态模型,观察胃黏膜大体及镜下形态学变化并评估黏膜损伤指数(lesion index,LI),硫代巴比妥酸法(thiobarbituric acid, TBA)测定胃黏膜内MDA含量,MDA与LI、病理损伤积分的关系。
结果：
我们发现(1)15%乙醇摄入组,3、6、9周后黏膜损伤指数、病理损伤积分、及MDA数量分别与对照组相比,均没有显著变化。(P>0.05,n=9)(2)30%、45%组胃黏膜损伤指数与胃黏膜MDA含量呈正相关,随着乙醇浓度的升高及作用时间的延长,胃黏膜MDA含量增加,胃黏膜损伤程度加重(p<0.01,n=9)。
结论：
对于大鼠5ml/kg/d15%v/v乙醇摄入后,大鼠胃黏膜上皮细胞氧化应激状态不明显。
随着浓度升高、摄入时间延长,长期乙醇摄入可引起胃黏膜上皮细胞脂质过氧化,细胞整体上处于缺氧状态。
研究背景
细胞内物质代谢与细胞免疫是细胞内两种不同的功能。乙醇在胃黏膜上皮细胞代谢后是否能够影响胃黏膜上皮细胞的功能,尚未有研究。
乙醇与胃黏膜的关系主要集中于损伤与修复的关系。
长期乙醇摄入经过胃黏膜上皮的首过代谢作用、微粒体乙醇氧化系统作用,胃黏膜上皮细胞细胞膜出现脂质过氧化及大量活性氧产生,细胞内固有还原剂NADPH减少,细胞为适应常氧到缺氧环境的变化,转录因子缺氧诱导因子-lalpha (HIF-1α)功能增强,增强细胞缺氧耐受。HIF-1α是1992年发现的一种重要转绿因子,HIF-1α的下游靶基因目前有超过200个,参与能量代谢、血管新生、一氧化氮合成、铁与血红素代谢以及免疫调节[27]。胸腺基质淋巴细胞生成素(thymic stromal lymphopoietin, TSLP)是一种上皮细胞来源的细胞因子,作用于髓样和淋巴样树突细胞,调节适应性免疫,在起始和促进Th2细胞免疫过程中起重要作用。TSLP与树突细胞上TSLPR直接作用,通过CD40L促使Th0极化为Th2细胞,形成体液免疫,参与对胞外菌及寄生虫清除。其激活途径是独立于MCHII分子、共刺激分子之外的另一条途径。TSLP是否在胃黏膜上皮中表达,以及其表达的机制尚未有人研究。我们设想在长期乙醇摄入条件下HIF-la被激活,其靶基因TSLP表达。丰富黏膜免疫理论,为适量饮酒可以有助于清除幽门螺旋杆菌(Helicobacter pylori, HP)提供理论支持。
目的
1.建立适量饮酒的大鼠动物模型。
2.大鼠胃胃黏膜上皮能否表达TSLP,以及表达量是否与摄入乙醇量、时间有关系。
3.转录因子HIF-la是否调控TSLP表达。
材料与方法
选用健康雄性Wistar大鼠33只,按照不同浓度分为3组,分别给予生理盐水、15%、45%乙醇灌胃,8%水合氯醛1ml麻醉后给予取出胃黏膜,用RT-PCR检查各组HIF-1α、TSLPmRNA相对表达量,免疫组化进行蛋白定位,Western blot技术测定细胞内HIF-1α、TSLP表达量并进行相关性分析。
统计方法：
SPSS17.0软件进行统计分析,数据以均数±标准差表示,采用单因素方差分析进行统计学处理,以P<0.05为显著性差异。
实验结果
生理盐水组大鼠胃黏膜mRNA水平检测到HIF-1α,未检测到TSLP。蛋白质水平未检测到HI-1α、TSLP。15%,45%组mRNA水平、蛋白质水平均有HIF-lα、 TSLP表达。随着乙醇浓度增加与摄入时间延长,HIF-1α表达量增加(p<0.01,n=9), TSLP水平在45%组6、9w相比未有明显增加,(p>0.01,n=9)。TSLP表达与HIF-α表达有相关性r=0.87。
结论
正常大鼠胃黏膜中没有HIF-1α蛋白、TSLP蛋白表达。随着细胞内氧化应激水平升高,HIF-1α水平、TSLP水平升高。
乙醇转录因子HIF-1α调控TSLP蛋白表达。
Background:
A high alcohol intake is significantly associated with diseases of the gastrointestinal tract, but less is known about the effects of modedrate consumption.
The animal model of high alcohol intake is easily set up,however the moderate alcohol consumption is less known.
Taylor B drawes the conclution in the method of a systematic computer-assisted literature review that moderate alcohol consumption may play a positive or negative role in disease etiology, but overall conclusion is that moderate alcohol intake in not a high risk factor for many of the gastrointestinal diseases associated with high levels of consumption.
Alcohol drinking is responsible for a number of gastrointestinal disease. Although heavy drinking episodes and chronic drinking are well linked to mechanisms of disease, mmoderate alcohol consumption and its effects are less well known. Epidemicological studies show moderate alcohol intake is a risk of liver disease, tumor of esophagus, and pancreasis, but it is positive to chronic gastritis and cholecystolithiasis. About95%alcohol in body in break down in the way of oxidation, including oxidation via first-pass metabolism(FPM), oxidation via microsomal ethanol-oxidizing system(MEOS), and fatty acid-catalase, aldehyde dehydrogenase system。 FPM occurs when a certain amount of ingested ethanol is metabolized primarily in the stomach and in the liver before reaching the systemic circulation. Lieber et al. have investigated this phenomenon extensively. They have emphasized that FPM is predominantly of gastric origin and that gastric ADH is mainly responsible for the FPM. Ethanol oxidation by alcohol dehydrogenase, aldehyde dehydrogenase is the main system used, with the other two only joining in during chronic ethanol ingestion. ADH meidate in alochol oxidation in a manner of transfering hydrogen in ethanol to NAD, producing aldehyde and NADH respectively. Aldehyede make use of NAD to produce acetic acid, and the latter is transformed into Acetyl coenzyme A which join in Crebs cycle generating water and carbon dioxide.
As the consumption of alcohol increase and store up, MEOS works to generate OFR and ROS resulting lipid peroxidation of cell membrane system including mitochondria. The cell in the station of oxidative stress. The expression of transcription factor HIF1-α enhances to accommodate hypoxia.
In the year of1992, HIF1was first detected by Semenza, Wang. The HIF1complexes are the mayor transcription factors that are reponse to low oxygen conditions. It is heterodimers that are composed of the constitutively expressed HIF1β subunit and HIF1a subunits, which are rapidly stablilized on exposure to hypoxia. Once activated HIF1amplifies the transcription of genes encoding glucose transporters and most glycolytic enzymes, increasing the capacity of the cell to carry out gycolysis. In addition, HIF1activates the pyruvate dehydrogenase kinases, which inactivate the mitochondrial pyruvate dehydrogenase complex and thereby reduce the flow of glucose-derived pyruvate into the tricarboxylic acid (TCA)cycle. This reduction in pyruvate flux into the TCA cycle decreases the rate of oxidative phosphorylation and oxygen consumption, renforcing the glycolytic phenotype and sparing oxgen under hypoxic condtions.
HIF1-α playes role in immunoregulation.
TSLP derived from epitheial cells can trigger DCs directly in mucosa and promote the latter secret OX40L to polarize to the TH2immune from THO immnue.
In the normal station, DCs are present in the mucosa. TSLP is a anti-inflammatory cytokine.
Whether TSLP can be inducible in the gastric mucosa is unkown.
Objectives:
To study the role of alcohol metabolism in the pathogenesis of ethanol-induced gastric mucosa injury
Methods:
Wistar rats were used in the study. A gastric mucosal injury model was established by alcohol gavage to rats. Gross and microscopic apperarance of gastric mucosa wer evaluated. Malondiadehyde (MDA) in gastric mucosa was measured with thiobarbituric acid. Guth and Mascuda criterion were adopted to evulate the gastric epithelium injuries respectively.
Results:
For the groups of15%, MDA, LI and the pathological injury changes insignificantly (p>0.05). The gastric mucosal lesion index was correated with the MDA content in gastric mucosa. As the concentration of alcohol was elevated and exposure time to alcohol was extended, the context of MDA in gastric mucosa increased and the extent of damage aggravated as far as groups of30%and45%. The lesion index and the pathological injury increased in groups of30%and declined in group of45%as the exposure time extended(p<0.01).
Conclusions:
In the level of5ml/kg/d15%v/v, the rat gastric mucosa oxidative stress is not apprant.
Long-term alcohol consumption causes lipid peroxidation in the gastric epithelial cells. The cells are in the station of oxidative stress as the concentration of alcohol was elevated and exposure time extend..
Background:
Long-term alcohol intake leads to lipid peroxidation and ROS through FPM, MEOS, catalase which depletes inherent reducing agent NADPH in rat gastric mucosa. The function of transcrpiton factor HIF-lastrengthenes to adapt to the station of hypoxia. HIF-1αwas found in the year of1992,of which the target genes includes more than200kinds involving in energy metabolism, angiogenesis, nitric oxide synthesis, iron and heme metabolism and immunoregulation. Thymic stromal lymphopoietin derived from epithilial cells act on myeloid dendritic cells and lymphoid dendritic cells to regulate adaptive immnune which plays crucial roles in the initiation and promotion TH2immune.TSLP binds to TSLPR directly promoting TH2polarization from THO via CD40L.The resultant humoral immunity involves in eradication of extracelluar bacteria and parasite.The pathway activating DCs is independent of the way of the classical MHCII, costimulatory molecules.Up to now, it is not reported whether TSLP is expressed in gastric mucosa and what the mechanism lies. We assume that long-term alcohol intake activates HIF-1α leading to expressing of target TSLP. The assumption will rich the mucosa immnne theories, and explain why moderate alcohol intake helps to eradicate HP partly.
Objectives:
to study the expression of tslp,hif-la in the state of oxidative stress in gastric mucosa caused by long-term alcohol intake, and to analyse the expression correlation between them.
Methods:
Immunohistochemistry was applied to locate TSLP, and HIF-la. RT-PCR and Western blot were used to measure the amont of TSLP, HIF-la in cytoplasm in the level of mRNA and protein respectively.
Results:
TSLP, HIF-la in different groups were all detected by means of immunohistochemistry compared to control group. TSLP, HIF-la were located in gland cells and the location were consistent. In group15%and30%the mount of TSLP, HIF-la increased as exposed time extended while In45%group, the mout of TSLP, HIF-1αa declined. The expression of TSLP was related to expression of HIF-1α.
Conclusions:
Protein HIF1-α, TSLP are not induced in normal rat gastric mucosa. As the level of oxidative stress get intense,protein HIF1-α and TSLP express increase.
Alcohol can trigger TSLP expression via HIF-la in rat gastric mucosa
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