耐力训练对大鼠肝脏,股四头肌谷胱甘肽抗氧化系统酶活性的影响

目的和方法：本文通过检测大鼠肝脏、股四头肌中ＧＳＨＰＸ、谷胱甘肽转硫酶（ＧＳＴ）、谷胱甘肽还原酶（ＧＲ）活性及脂质过氧化（ＬＰＯ）产物丙二醛（ＭＤＡ）的含量变化,观察耐力训练对大鼠机体产生内源性自由基及谷胱甘肽抗氧化系统酶活性的影响。结果：ＳＤ雄性大鼠经１１周跑台训练后,安静状态时肝脏中ＭＤＡ含量下降,ＧＳＨＰＸ、ＧＳＨ活性下降,股四头肌中ＧＳＨＰＸ、ＧＳＴ活性升高;９０ｍｉｎ定量负荷运动使大鼠肝脏中ＭＤＡ含量升高,ＧＳＨＰＸ、ＧＳＴ、ＧＲ活性均下降,但训练组ＧＳＨＰＸ、ＧＳＴ活性恢复较快。结论：大鼠经耐力训练后提高了谷胱甘肽抗氧化系统酶的抗氧化功能,表现了良好的运动适应性,且恢复较快。值得注意的是训练组大鼠ＧＲ活性在运动后恢复期存在下降趋势,其机理有待进一步研究。     

刺五加在大鼠实验性肝癌诱发过程中作用的探讨

目的探讨大鼠实验性肝癌发病中刺五加对肌体免疫功能和抗氧化酶活性的影响。方法４６只ＳＤ雄性大鼠被随机分成对照组（喂普通饲料）、３－甲基４－双甲氨基偶氮苯（３－Ｍｅ－ＤＡＢ）组（喂含０．０６％３Ｍｅ－ＤＡＢ饲料 １０周）和刺五加组（饲喂同 ３－Ｍｅ－ＤＡＢ外、另加入刺五加 ４．５ｇ／ｋｇ饲料,用常规方法检测全血谷光甘肽过氧化物酶（ＧＳＨ－ＰＸ）、血清超氧化物歧化酶（ＳＯＤ）活性和丙二醛（ＭＤＡ）含量,用微量化学发光造检测吞噬细胞活性（ＰＭＮ－ＣＬ）。结果１．ＰＭＮ－ＣＬ检测峰值、积分值和吞噬细胞指数,３－ＭｅＤＡＢ组较正常组和刺五加组均有显著升高（Ｐ＜０．０５和Ｐ＜０．０１）２．全血ＧＳＨ－ＰＸ活性、ＳＯＤ活性,刺五加组较３－ＭｅＤＡＢ组均有显著升高（Ｐ＜０．０５）。ＭＤＡ含量刺五加组和３－ＭｅＤＡＢ组均较正常组升高（均Ｐ＜０．０５）。结论刺五加在大鼠实验性肝癌诱发过程中有提高抗氧化酶活性和对抗致癌剂引起的机体中性粒细胞吞噬功能代偿性增高的作用。     

人血浆HDL对动脉粥样硬化家兔肝细胞膜 LDL受体活性影响的研究

高胆固醇饲料喂养造成的动脉粥样硬化（Ａｓ） 模型家兔通过静脉注射人血浆ＨＤＬ 制剂, 观察ＨＤＬ 对Ａｓ家兔肝细胞膜ＬＤＬ受体活性的影响． 结果发现, 摄取高胆固醇饲料的Ａｓ 家兔, 其肝细胞膜ＬＤＬ 受体 Ｋｄ 值虽无明显变化但Ｂｍａｘ 值显著减小（ Ｐ＜ ０－０１ , 与正常对照组比较） ; 注射ＨＤＬ 制剂后, Ａｓ 家兔肝细胞膜ＬＤＬ受体Ｋｄ 值仍无明显改变, 但Ｂｍａｘ 值却显著回升（ Ｐ＜ ０－０１ , 与高脂组比较） ． 表明人血浆ＨＤＬ 具有增加Ａｓ 家兔肝细胞膜ＬＤＬ 受体活性的作用．     

肾上腺素受体拮抗剂对大鼠急性肝损害影响的研究

雄性ＳＤ大鼠３３只,体重１８０—２５０ｇ,随机分成四组。正常对照组６只;哌唑嗪组８只,于实验第１、２、３日上午用哌唑嗪灌胃（１ｍｇ／ｋｇ体重）共３次,第２日下午腹腔注射半乳糖胺（６００ｍｇ／ｋｇ体重）１次,第４日上午处死动物,取肝脏及血清作有关检查;普萘洛尔组及Ｎ．Ｓ对照组分别用普萘洛尔（２ｍｇ／ｋｇ体重）及Ｎ．Ｓ（１０ｍｌ／ｋｇ体重）代替哌唑嗪灌胃,处理程序同哌唑嗪组。结果表明：一、哌唑嗪能显著减轻肝脏病变及血清ＡＬＴ的升高。二、哌唑嗪对肝损害后肝组织ＳＤＨ、Ｍｇ２＋－ＡＴ－Ｐａｓｅ、ＣｈＥ、ＡＣＰ、ＣＣｏ等酶活性的恢复有显著效果。三、哌唑嗪组ＬＰＯ明显低于Ｎ．Ｓ对照组（Ｐ＜０．０１）而ＳＯＤ活性明显高于Ｎ．Ｓ对照组（Ｐ＜０．０１）。普萘洛尔组各项指标同对照组比较均无显著差异（Ｐ＞０．０５）。提示：哌唑嗪对大鼠实验性肝损害有一定的保护作用。     

硒对培养人胚肝细胞Ⅲ型前胶原,羟脯氨酸合成的影响

原代培养人胚肝细胞经１．１５６×１０￣(－７）ｍｏｌ／Ｌ硒预处理４ｈ,加入２０ｍｍｏｌ／Ｌ四氟化碳作用２０ｈ,观察硒对其Ⅲ型前胶原（ＰＣⅢ）和羟脯氨酸（Ｈｙｐ）生成的影响。结果培养液中ＰＣⅢ水平、细胞内Ｈｙｐ含量及细胞内外丙二醛（ＭＤＡ）水平均降低,与未加硒对照组比较差别有显著性（Ｐ＜０．０１）。而硒谷腕甘肽过氧化物酶（Ｓｅ－ＧＳＨ－ＰＸ）活性则较对照组显著增高（Ｐ＜０．００１）,且ＰＣⅢ水平与Ｓｅ－ＧＳＨ－Ｐ＿Ｘ／ＭＤＡ比值呈负相关（ｒ＝－０．９１５６,Ｐ＜０．０１）。提示硒可提高Ｓｅ－ＧＳＨ－Ｐ＿Ｘ／ＭＤＡ比值,抑制脂质过氧化激发的肝细胞胶原合成。     

维生素A缺乏胎鼠作为先天性心脏病动物模型的实验研究

目的　探讨将维生素Ａ缺乏（ＶＡＤ）胎鼠作为先天性心脏病动物模型的可行性。方法取１１－１９ｄ不同胎龄正常及ＶＡＤ胎鼠心脏经石蜡包埋、切片及 ＨＥ染色观察其发育情况。结果 １．实验组饲料含维生素Ａ（ＶＡ）７μｇ／１００ｇ,经ＶＡＤ饮食喂养后实验组大鼠血清ＶＡ水平明显低于对照组［（０．１６８±０．０５９）μｍｏｌ／Ｌ Ｖｓ（２．１８±０．２３）μｍｏｌ／Ｌ,ｔ＝３２．８８, Ｐ＜０．００１］。 ２．大鼠死亡百分比：饲养于屏障系统的ＶＡＤ大鼠死亡百分比较饲养于开放系统中的要低４．６倍（１０％ Ｖｓ ４５．８３％．ｘ ２＝１６．６４, Ｐ＜０．００１）,对照组为０。 ３．实验组大鼠受孕百分比及每只孕鼠产仔数均低于对照组［５８．３３％ Ｖｓ ８１．５％, ｘ ２＝４．３７,Ｐ＜０．０５：（６．９７±２．７９） Ｖｓ（１３ ±１．０５）,ｔ＝７．１６, Ｐ＜０．００１］。 ４．经切片观察１１～１５ ｄ胎龄胎鼠实验组心脏出现明显发育延迟的占３６．６７％, １６～１９ ｄ胎龄胎鼠实验组心脏畸形占４１．４３％,血管异常占１８．５７％。结论ＶＡＤ胎鼠可用来作为先天性心脏病动物模型,但需改进饲养环境以减少异常死亡。     

戊巴比妥钠对小鼠肝脏影响的组织化学研究

实验用健康小鼠３５只,分为正常对照组（Ａ组）５只,１％戊巴比妥钠麻醉组（Ｂ组）１０只,０．８％戊巴比妥钠麻醉组（Ｃ组）１０只,０．４％戊巴比妥钠麻醉组（Ｄ组）１０只。除正常对照组外,其余三组腹腔内注射成巴比妥钠６０分钟后,分别断头取材,取肝右叶,恒冷箱切片,做ＳＤＨ（琥珀酸脱氢酶）、ＬＤＨ（乳酸脱氢酶）、ＣｈＥ（胆碱酯酶）、糖原（ＰＡＳ反应）、实验结果显示大剂量１％戊巴比妥钠组（Ｂ组）,ＳＤＨ、ＣｈＥ的活性和糖原（ＰＡＳ）反应比正常对照组相比显著下降。而ＬＤＨ活性明显增强。其余各组均有相应的变化,提示成巴比妥钠对肝脏的形态和机能有一定程度的损害。     

应激引起血压升高大鼠血管升压素V1受体mRNA水平改变

实验在雄性ＳｐｒａｇｕｅＤａｗｌｅｙ 大鼠上进行。实验动物被随机分为对照组和应激组, 应激组大鼠每天给予电击足底结合噪声的应激刺激, 每日２ 次, 每次２ ｈ 。应激组大鼠在接受连续１５ ｄ 的慢性应激刺激后, 其尾动脉收缩压与对照动物相比有显著升高。对照组为１６－２５ ±０－６３ｋＰａ （ｎ ＝ ７） ; 应激组为１９－５５ ±１－４５ ｋＰａ （ｎ ＝ ８, Ｐ＜ ０－０５） 。用ＲＴＰＣＲ 结合Ｓｏｕｔｈｅｒｎ 印迹核酸分子杂交技术观察到, 血管升压素（ｖａｓｏｐｒｅｓｓｉｎ, ＡＶＰ）Ｖ１ 受体ｍＲＮＡ 广泛存在于大鼠下丘脑、皮质、延髓等部位以及心脏、肝脏、肾脏等组织中。用定量ＰＣＲ 方法观察到, 大鼠在接受慢性应激刺激之后, 其大脑顶叶皮质、下丘脑及延髓组织中ＡＶＰＶ１ 受体ｍＲＮＡ 水平均显著低于正常大鼠（ 顶叶皮质： Ｐ＜ ０－０５ ; 下丘脑： Ｐ＜ ０－０１ ; 延髓： Ｐ＜ ０－００１） , 而心脏、肝脏及肾脏组织中的ＡＶＰＶ１ 受体ｍＲＮＡ水平与正常大鼠相比均无明显差别（ 心脏： Ｐ＞ ０－０５ ; 肝脏： Ｐ＞ ０－０５ ; 肾脏：Ｐ＞ ０－０５） 。上述结果提示, 慢性应激刺激可引起大鼠不同部位脑组织ＡＶＰＶ１ 受体合成水平下调, 可能导致     

结扎兔冠状动脉前降支与左室支的急性心肌梗塞比较

本文比较了结扎兔冠状动脉前降支（ＬＡＤ组）和左室支（ＬＶＡ组）两种方法建立的急性心肌梗塞模型。结果发现１：ＥＣＧ标测,三天内不同时间ＬＶＡ组∑△ＳＴ升高毫伏数均高于ＬＡＤ组（Ｐ＜０．０１或Ｐ＜０．０５）;２：Ｎ－ＢＴ染色,ＬＶＡ组心肌梗塞占心室重的百分率为１７．３％±０．５６％,而ＬＡＤ组为８．２％±２．４２％,两者相差非常显著（Ｐ＜０．０１）,证实了ＬＶＡ组心梗面积较ＬＡＤ组大且相对稳定。采用增强（Ｇｄ－ＤＴＰＡ）磁共振成像（ＭＲＩ）扫描发现ＬＶＡ组急性心梗范围在三天内基本稳定。作者认为,兔急性心梗模型采用结扎ＬＶＡ优于结扎ＬＡＤ。     

螺旋藻对小鼠SOD和GSH—Px活力的影响

采用微量测定法,观察螺旋藻对３２只昆明种小白鼠全血中超氧化物歧化酶（ＳＯＤ）和谷光甘肽过氧化物酶（ＧＳＨ－Ｐｘ）活性的影响。结果表明,灌胃螺旋藻试验组（ＳＯＤ）活性（１５７７．１６±１６９．８８ＩＵ／ｇＨｂ）,与相应对照组（１３３６．２７±１５８．２３ＩＵ／ｇＨｂ）比较,ＧＳＨ－Ｐｘ活性（２８．３３±２．３７ＩＵ／ｍｌ）与相应对照组（２４．８７±３．２６ＩＵ／ｍｌ）比较,差别均有非常显著意义（Ｐ＜０．０１）;提示螺旋藻有提高动物ＳＯＤ和ＧＳＨ－Ｐｘ活性的功效     

Alcohol dehydrogenase in the blood and liver of rats with different alcoholic motivation

Alcohol dehydrogenase (ADH) activity was determined by a highly sensitive method. The enzyme activity in the blood serum was similar in alcohol and water preferring rats, while ADH activity in the liver of alcohol preferring rats was higher than in water preferring rats. In rats, chronically intoxicated with ethanol, ADH activity in the liver decreased, while in the serum it was twice higher than the normal level. It is suggested that high level of blood ADH is not connected with the rate of enzyme synthesis in the liver.     

Effect of central adrenergic alpha receptor blockader IEM-611 on the activity of alcohol and aldehyde dehydrogenase in rat liver

The effect of IEM-611 (30 mg/kg) on alcohol consumption in rats under the conditions of voluntary choice between water and 15% ethanol was studied as that on alcohol dehydrogenase (ADH) in postmitochondrial supernatant and in NAD-dependent aldehyde dehydrogenases (A1DH) in liver mitochondria. Administration of IEM-611 during 6 or 12 days reduces ethanol consumption by 29 and 30%, respectively, activates ADH and appreciably decreases overall activity of NAD-dependent A1DH. At the same time the ADH/A1DH ratio increases. Activation of ADH and A1DH and the decreased ADH/A1DH ratio were disclosed in alcohol preferring rats as compared to water preferring animals. IEM-611 shifts enzymatic activity of ethanol metabolism towards the level characteristic for water preferring rats. It is suggested that variation of the ADH/A1DH ratio is one of the mechanisms responsible for the decreased ethanol consumption in rats.     

The contribution of the stomach to ethanol oxidation in the rat

To estimate the amount of ethanol that can be oxidized in the stomach, steady-state conditions were created in a group of fed rats by giving a loading dose of ethanol (2 g/kg body wt I.V.) followed by continuous infusion either intravenously or intragastrically. The rate of ethanol oxidation was calculated from the rate of infusion required to maintain steady blood levels of approximately 30 mM for at least 3 hours. Gastrointestinal ethanol concentrations and total contents also remained steady. The rate of ethanol oxidation was 19.3% faster during intragastric than during intravenous infusion (p less than 0.01). When measured at the prevailing luminal ethanol concentration (145 mM) and expressed per body weight, the gastric ADH activity represented 14% of the hepatic activity at 30 mM ethanol, suggesting that gastric ADH activity could account for most of the increased rate of oxidation when ethanol is given intragastrically. Thus, gastric ethanol oxidation by a high Km ADH in the rat represents a significant fraction of the total rate of ethanol oxidation and it is therefore one of the factors which determines the bioavailability of orally administered ethanol.     

Alcohol dehydrogenase (ADH). Influence of homo- and heterologous ADH administration on albino rats craving for alcohol and on ADH isozyme activity in the liver.

The effects of homo- and heterologous alcohol dehydrogenase (ADH) administration into albino rats were investigated. It was found that homologous ADH increases and heterologous ADH decreases the craving for ethanol. The latter effect was accompanied by the appearance of anti-ADH-3 antibodies and by a decrease in ADH-3 activity in the liver. Craving for alcohol decreased after both active and passive immunization against ADH.     

Two zebrafish alcohol dehydrogenases share common ancestry with mammalian class I, II, IV, and V alcohol dehydrogenase genes but have distinct functional characteristics

Ethanol is teratogenic to many vertebrates. We are utilizing zebrafish as a model system to determine whether there is an association between ethanol metabolism and ethanol-mediated developmental toxicity. Here we report the isolation and characterization of two cDNAs encoding zebrafish alcohol dehydrogenases (ADHs). Phylogenetic analysis of these zebrafish ADHs indicates that they share a common ancestor with mammalian class I, II, IV, and V ADHs. The genes encoding these zebrafish ADHs have been named Adh8a and Adh8b by the nomenclature committee. Both genes were genetically mapped to chromosome 13. The 1450-bp Adh8a is 82, 73, 72, and 72% similar at the amino acid level to the Baltic cod ADH8 (previously named ADH1), the human ADH1B2, the mouse ADH1, and the rat ADH1, respectively. Also, the 1484-bp Adh8b is 77, 68, 67, and 66% similar at the amino acid level to the Baltic cod ADH8, the human ADH1B2, the mouse ADH1, and the rat ADH1, respectively. ADH8A and ADH8B share 86% amino acid similarity. To characterize the functional properties of ADH8A and ADH8B, recombinant proteins were purified from SF-9 insect cells. Kinetic studies demonstrate that ADH8A metabolizes ethanol, with a V(max) of 13.4 nmol/min/mg protein, whereas ADH8B does not metabolize ethanol. The ADH8A K(m) for ethanol as a substrate is 0.7 mm. 4-Methyl pyrazole, a classical competitive inhibitor of class I ADH, failed to inhibit ADH8A. ADH8B has the capacity to efficiently biotransform longer chain primary alcohols (>/=5 carbons) and S-hydroxymethlyglutathione, whereas ADH8A does not efficiently metabolize these substrates. Finally, mRNA expression studies indicate that both ADH8A and ADH8B mRNA are expressed during early development and in the adult brain, fin, gill, heart, kidney, muscle, and liver. Together these results indicate that class I-like ADH is conserved in zebrafish, albeit with mixed functional properties.     

Alcohol dehydrogenase activity in the developing chick embryo

Before day 9 of incubation, chick embryos contain no measurable alcohol dehydrogenase (ADH) activity. Following day 9 of incubation, chick embryo liver ADH activity increases as a linear function of liver mass. A single dose of ethanol given at the start of incubation is cleared only slowly prior to day 9 of incubation but is completely cleared by day 13. Chick embryo liver ADH has two detectable isozymes throughout development. The percentage contribution of each isozyme to total ADH activity does not change significantly during development. The Km apparent of chick liver ADH is significantly increased shortly after hatching relative to the Km apparent of embryonic ADH. Ethanol exposure during incubation has no effect on the development of ADH activity or isozyme distribution.     

Ethanol-metabolizing pathways in deermice. Estimation of flux calculated from isotope effects

The apparent deuterium isotope effects on Vmax/Km (D(V/K] of ethanol oxidation in two deermouse strains (one having and one lacking hepatic alcohol dehydrogenase (ADH] were used to calculate flux through the ADH, microsomal ethanol-oxidizing system (MEOS), and catalase pathways. In vitro, D(V/K) values were 3.22 for ADH, 1.13 for MEOS, and 1.83 for catalase under physiological conditions of pH, temperature, and ionic strength. In vivo, in deermice lacking ADH (ADH-), D(V/K) was 1.20 +/- 0.09 (mean +/- S.E.) at 7.0 +/- 0.5 mM blood ethanol and 1.08 +/- 0.10 at 57.8 +/- 10.2 mM blood ethanol, consistent with ethanol oxidation principally by MEOS. Pretreatment of ADH- animals with the catalase inhibitor 3-amino-1,2,4-triazole did not significantly change D(V/K). ADH+ deermice exhibited D(V/K) values of 1.87 +/- 0.06 (untreated), 1.71 +/- 0.13 (pretreated with 3-amino-1,2,4-triazole), and 1.24 +/- 0.13 (after the ADH inhibitor, 4-methylpyrazole) at 5-7 mM blood ethanol levels. At elevated blood ethanol concentrations (58.1 +/- 2.4 mM), a D(V/K) of 1.37 +/- 0.21 was measured in the ADH+ strain. For measured D(V/K) values to accurately reflect pathway contributions, initial reaction conditions are essential. These were shown to exist by the following criteria: negligible fractional conversion of substrate to product and no measurable back reaction in deermice having a reversible enzyme (ADH). Thus, calculations from D(V/K) indicate that, even when ADH is present, non-ADH pathways (mostly MEOS) participate significantly in ethanol metabolism at all concentrations tested and play a major role at high levels.     

Dehydrogenase-dependent ethanol metabolism in deer mice (Peromyscus maniculatus) lacking cytosolic alcohol dehydrogenase. Reversibility and isotope effects in vivo and in subcellular fractions

Elimination of [2H]ethanol in vivo as studied by gas chromatography/mass spectrometry occurred at about half the rate in deer mice reported to lack alcohol dehydrogenase (ADH-) compared with ADH+ deer mice and exhibited kinetic isotope effects on Vmax and Km (D(V/K] of 2.2 +/- 0.1 and 3.2 +/- 0.8 in the two strains, respectively. To an equal extent in both strains, ethanol elimination was accompanied by an ethanol-acetaldehyde exchange with an intermolecular transfer of hydrogen atoms, indicating the occurrence of dehydrogenase activity. This exchange was also observed in perfused deer mouse livers. Based on calculations it was estimated that at least 50% of ethanol elimination in ADH- deer mice was caused by the action of dehydrogenase systems. NADPH-supported cytochrome P-450-dependent ethanol oxidation in liver microsomes from ADH+ and ADH- deer mice was not stereoselective and occurred with a D(V/K) of 3.6. The D(V/K) value of catalase-dependent oxidation was 1.8, whereas a kinetic isotope effect of cytosolic ADH in the ADH+ strain was 3.2. Mitochondria from both ADH+ and ADH- deer mice catalyzed NAD+-dependent ethanol oxidation and NADH-dependent acetaldehyde reduction. The kinetic isotope effects of NAD+-dependent ethanol oxidation in the mitochondrial fraction from ADH+ and ADH- deer mice were 2.0 +/- 0.1 and 2.3 +/- 0.3, respectively. The results indicate only a minor contribution by cytochrome P-450 to ethanol elimination, whereas the isotope effects are consistent with ethanol oxidation by the catalase-H2O2 system in ADH- deer mice in addition to the dehydrogenase systems.     

The harmful action of ethanol on the liver: the role of alcohol dehydrogenase and aldehyde dehydrogenase

White rats were divided into water-preferring (WP) and ethanol-preferring (EP) groups, on the basis of their preferable drink: either water or 15% solution of ethanol. Each of these groups was then subdivided into groups which were given to drink for 1 year 15% solution of ethanol (ethanol-treated) or water (controls). Alcohol dehydrogenase/aldehyde dehydrogenase activity ratios (ADH/AlDH) in livers of WP controls were considerably higher than those in EP controls. The difference in ADH/AlDH has somewhat decreased after ethanol treatment. However, this ratio remained the highest in the WP alcohol-treated group. The signs of proteinic and lipid dystrophy of the liver in alcohol-treated WP rats were expressed much more clearly than in all other groups. It is concluded that in the liver of animals with a high ADH/AlDH ratio there are favourable conditions for accumulation of a toxic hepatocyte-damaging acetaldehyde.     

Diabetes impairs the enzymatic disposal of 4-hydroxynonenal in rat liver

This study assesses whether the HNE accumulation we formerly observed in liver microsomes and mitochondria of BB/Wor diabetic rats depends on an increased rate of lipoperoxidation or on impairment of enzymatic removal. There are three main HNE metabolizing enzymes: glutathione-S-transferase (GST), aldehyde dehydrogenase (ALDH), and alcohol dehydrogenase (ADH). In this study we show that GST and ALDH activities are reduced in liver microsomes and mitochondria of diabetic rats; in contrast, ADH activity remains unchanged. The role of each enzyme in HNE removal was evaluated by using enzymatic inhibitors. The roles of both GST and ALDH were markedly reduced in diabetic rats, while ADH-mediated consumption was significantly increased. However, the higher level of lipohydroperoxides in diabetic liver indicated more marked lipoperoxidation. We therefore think that HNE accumulation in diabetic liver may depend on both mechanisms: increased lipoperoxidation and decreased enzymatic removal. We suggest that glycoxidation and/or hyperglycemic pseudohypoxia may be involved in the enzymatic impairment observed. Moreover, since HNE exerts toxic effects on enzymes, HNE accumulation, deficiency of HNE removal, and production of reactive oxygen species can generate vicious circles able to amplify the damage.