The blood-brain barrier and selective vulnerability in experimental thiamine-deficiency encephalopathy in the mouse

The integrity of the blood-brain barrier (BBB) is an important aspect of normal central nervous system (CNS) function. Recently, it was shown that the BBB breakdown is one of the predisposing factors in the pathogenesis of thiamine-deficiency encephalopathy. The result is discussed along with some reviews on previous research of BBB integrity in thiamine deficiency.     

RANTES在急性胰腺炎血-脑脊液屏障通透性变化中的作用

目的 观察急性胰腺炎(AP)大鼠脑组织正常T细胞表达与分泌的活化调节因子(regulated on activation,normal T-cell expressed and secreted,RANTES)和occludin在大脑中的表达,探讨RANTES表达与血-脑脊液屏障通透性变化之间的关系.方法 将49只SD大鼠按数字表法随机分为假手术(SO)组,急性水肿性胰腺炎(AEP)3、6 h组和急性坏死性胰腺炎(ANP)3、6、12、24 h组.以0.5%和5%牛磺胆酸钠逆行胰胆管注射制备AEP和ANP模型.采用RT-PCR、Western blotting和免疫组化法检测脑组织RANTES和occludin的mRNA及蛋白的表达.结果 SO组,AEP 3、6组,ANP 3、6、12、24 h组RANTES mRNA表达量分别为0、0、0、0.36±0.05、0.47 4-0.04、0.65 4-0.05、0.83±0.07,蛋白表达量为0、0、0、0.42±0.03、0.57±0.04、0.78±0.08、1.05±0.08,ANP组较SO组和AEP组显著增加(P<0.01);occludin mRNA表达量为1.21±0.07、1.17±0.07、1.15±0.08、0.84±0.07、0.77±0.05、0.64±0.09、0.56±0.09,蛋白表达量为1.18±0.08、1.16±0.10、1.11±0.10、0.90±0.03、0.65±0.05、0.57±0.05、0.48±0.05,ANP组较s0组和AEP组显著下降(P<0.01).RANTES表达与胰腺组织病理损伤呈正相关(r=0.936,P<0.001);occludin表达与胰腺组织病理损伤呈负相关(r=-0.900,P<0.001);RANTES和occludin呈负相关(r=-0.943,P<0.001).结论 ANP时大鼠脑组织RNANTES 表达呈进行性增高,occludin表达呈进行性下降,RANTES通过下调occludin蛋白表达而改变血-脑脊液屏障通透性.     

复元醒脑汤对高血压性脑出血大鼠血-脑屏障通透性干预作用的实验研究

目的探讨复元醒脑汤对高血压性脑出血大鼠脑水肿及血-脑屏障通透性的干预作用。方法将SHR大鼠随机分为四组,分别为假手术组、模型组、安宫牛黄胶囊组、复元醒脑汤组,并与WKY大鼠假手术组对照,每组20只大鼠。模型组、安宫牛黄胶囊组和复元醒脑汤组在收缩压达到21．3kPa基础上以胶原酶加肝素尾状核注射法诱发脑出血,建立高血压性脑出血模型,其中安宫牛黄胶囊组和复元醒脑汤组分别给予相应药物干预,于造模后连续灌胃3天。两假手术组脑内注射及灌胃均为生理盐水,模型组灌胃为生理盐水。观测各组动物神经缺损行为体征、脑组织含水量、血-脑屏障通透性变化。结果SHR模型组与WKY假手术组、SHR假手术组比较,神经缺损行为体征评分升高（均P〈0．01）,脑组织含水董增加（均P〈0．01）,脑组织中伊文思蓝含量亦增加（均P〈0．01）;SHR复元醒脑汤和SHR安宫牛黄胶囊两治疗组分别与SHR模型组比较,神经缺损行为体征评分降低（均P〈0．01）,脑组织含水量减少（均P〈0．01）,脑组织中伊义思蓝含量亦降低（均P〈0．01）;上述指标变化复元醒脑汤组与安宫牛黄胶囊组比较差异无统计学意义（均P〈0．05）。结论复元醒脑汤可降低血-脑屏障通透性,减轻脑水肿程度,改善神经功能缺损,达到治疗高血压性脑出血的目的。     

Neuropathology of thiamine deficiency: an update on the comparative analysis of human disorders and experimental models

This paper provides a re-examination of the neuroanatomical consequences of thiamine deficiency in light of more recent studies of human disorders and models of experimental thiamine deficiency. A major goal is to elucidate the relative roles of thiamine deficiency and chronic alcohol consumption in the pathogenesis of Wernicke-Korsakoff syndrome (WKS). Particular emphasis is placed on the role of thiamine deficiency in lesions to basal forebrain, raphe, locus coeruleus, white matter and cortex and their role in the cognitive and memory disturbances of human WKS and experimental models of thiamine deficiency.     

The contribution of alcohol,thiamine deficiency and cirrhosis of the liver to cerebral cortical damage in alcoholics

The relative roles of alcohol toxicity, thiamine deficiency and cirrhosis of the liver in the pathogenesis of alcohol-related brain damage are unclear. Brain shrinkage and neuronal loss from four regions of the cortex was determined in 22 alcoholics with the Wernicke-Korsakoff Syndrome (WKS), cirrhosis of the liver or neither of these complications and compared to 22 age-matched non-alcoholic controls. Brain shrinkage was most marked in those alcoholics with WKS. Neuronal loss occurred only from the superior cortex and was of equal magnitude in all alcoholic subgroups. In an animal model of alcohol abuse and thiamine deficiency, neuronal loss from the cerebral cortex occurred in a time-dependent manner. Furthermore, those cells which contained the calcium-binding protein parvalbumin appeared to be preferentially damaged in this model.     

大鼠实验性脑出血后血脑屏障通透性与水通道蛋白4的关系及水蛭素的作用研究

目的研究大鼠脑出血后血脑屏障(BBB)通透性与水通道蛋白4(AQP4)的关系及水蛭素的干预作用。方法采用自体动脉血注入尾状核法制成大鼠脑出血模型,RT-PCR法观察AQP4mRNA的表达,伊文思兰法测量BBB通透性,干湿重法计算脑含水量表示脑水肿。结果与对照组相比,脑出血组及水蛭素组BBB通透性均在出血后6h开始升高〔(0·5955±0·0956)和(0·3594±0·0712)〕,1~3d最高〔(0·8889±0·0968)、(0·7914±0·0520)和(0·5937±0·0505)、(0·5275±0·0492)〕,水蛭素组明显低于脑出血组(P<0·05);两组AQP4mRNA表达也于6h即开始升高〔(1·06±0·12)和(0·83±0·08)〕,3d时达到高峰〔(1·34±0·14)和(1·03±0·05)〕,水蛭素组明显低于脑出血组(P<0·05);BBB通透性与AQP4mRNA表达呈显著正相关(R=0·686,P<0·01),与脑水肿变化趋势一致。结论脑出血后产生的凝血酶可能通过上调APQ4mRNA表达,增加BBB通透性,参与脑水肿形成和发展;水蛭素可抑制此过程。     

高血压对主动脉夹层患者术后早期中枢神经系统功能的影响

目的分析高血压对主动脉夹层患者术后早期中枢神经系统功能的影响。方法选取南京鼓楼医院2008-11-2011-05主动脉夹层术后患者(n=77),根据是否有中枢神经系统损伤分为损伤组(n=35)和对照组(n=42),应用单因素和多因素Logistic回归分析高血压对主动脉夹层患者术后早期中枢神经系统功能的影响。结果与对照组比较,损伤组高血压患者的比率[80%(28/35)比45%(19/42),P<0.05]、术中失血量[(5037.1±3888.1)比(2466.7±2194.2)mL,P<0.01]升高,术后24h内尿量[(1092.9±727.2)比(1399.3±510.5)mL]、术后回重症加强护理病房(ICU)第一次血气分析pH值[(7.39±0.10)比(7.44±0.08)]、术后回ICU第一次血气分析的动脉血氧分压(PaO2)值[(81.8±30.7)比(116.1±56.9)mmHg,均P<0.05]降低。单因素分析表明高血压史、术中失血量、术后24h内尿量、术后回ICU第一次血气分析的pH值、术后回ICU第一次血气分析的PaO2值可明显影响中枢神经系统功能的恢复;多因素分析表明高血压史(OR0.196)及术后回ICU第一次血气分析PaO2值(OR1.015)是影响中枢神经系统功能恢复的独立危险因素。结论高血压是影响主动脉夹层患者术后早期中枢神经系统功能恢复的独立危险因素。     

胰岛素受体底物3、4、p53在正常大鼠大脑中的分布

目的观察胰岛素受体底物（IRS）3、4、p53在正常大鼠大脑中的分布。方法应用免疫组织化学方法研究了IRS-3、IRS-4、IRS-p53在正常成年大鼠脑内的分布和定位。结果IRS-3、IRS-4、IRS-p53在正常成年大鼠脑中分布广泛,在脑内与学习记忆相关的各主要结构如大脑皮质、海马、丘脑和下丘脑的部分核团均有表达。结论IRS-3、IRS-4、IRS-p53在正常成年大鼠脑中有很广泛的表达,提示这几种底物在维持大鼠大脑的正常功能中可能起重要作用。     

An examination of the synergistic interaction of ethanol and thiamine deficiency in the development of neurological signs and long-term cognitive and memory impairments

BACKGROUND: The prolonged and heavy consumption of ethanol has been associated with thiamine deficiency and a wide range of cognitive and memory impairments. The present study was undertaken to test the hypothesis that ethanol and thiamine deficiency act synergistically, producing more severe clinical neurological disturbances and cognitive and memory impairments than either thiamine deficiency or chronic ethanol alone. METHODS: The acute neurological and long-term behavioral consequences of combined chronic (32 weeks) ethanol consumption (20% v/v in drinking water) and three separate 4-week long episodes of dietary thiamine deficiency (ET/TD) versus ethanol (ET) or thiamine deficiency (TD) treatments alone were examined in male Sprague Dawley rats aged 12 weeks at the start of treatment. RESULTS: The ET/TD group lost less weight than the TD group during each episode of thiamine deficiency. Contrary to expectations, the progression and severity of ataxia, impaired righting reflexes, and opisthotonic posturing were similar in the ET/TD and TD groups. None of the ET animals displayed any neurological or behavioral symptoms during treatment. After withdrawal from ethanol and a 7-week recovery period, none of the groups differed in spontaneous activity. On subsequent testing, the ET group displayed a significant increase in perseverative responding in a spontaneous alternation task. A small but significant proportion of ET/TD (23%), ET (17%), and TD (8%) animals were unable to reach criterion on an initial nonmatching-to-position task (NMTP) or in two subsequent reversals of the matching and NMTP tasks, which indicated persistent learning impairments. A large proportion of animals in each of the three groups demonstrated significantly reduced accuracy compared with controls at longer delays of matching-to-position tasks (MTP), but only the ET group was consistently impaired at the shorter delays. There were no significant correlations between blood ethanol concentration and any of the learning and memory measures. CONCLUSIONS: These results indicate that the interaction of chronic ethanol consumption and bouts of TD is both domain specific and not always synergistic. Learning and reference memory appear to be sensitive to a synergistic interaction of ET and TD, whereas short-term working memory disturbances are most affected by ET and neurological symptoms are most associated with TD. Furthermore, neither the presence of neurological symptoms nor blood ethanol concentrations appear to be good predictors of learning and memory deficits.     

风疹病毒JR_(23)株对中枢神经系统感染的体内和体外实验研究

目的　研究风疹病毒 (rubellavirus ,RV )JR2 3 株感染中枢神经系统 (CNS)特性。方法　RVJR2 3 株体外感染人胚脑神经细胞、腹腔感染Balb/c小鼠 ,观察JR2 3 株在人脑神经细胞的增殖和对不同免疫状态小鼠CNS的感染及由感染导致的神经病理学特征。结果　RVJR2 3 株在人胚脑神经细胞中无明显的致细胞病变作用 ,病毒在感染后的第 72h达最高增殖滴度 10 3 TCID50 /ml。病毒抗原主要分布在人脑神经细胞胞浆。各组小鼠感染RVJR2 3 株后无明显CNS症状 ,地塞米松、环磷酰胺和药物未干预动物组CNSRV感染率分别为 6 0 %、90 %、5 0 %。受RVJR2 3 感染的小鼠脑组织出现小灶性胶质细胞增生及神经元坏死。大脑全层均有病毒抗原的分布。结论　RVJR2 3 株在人脑神经细胞和Balb/c小鼠脑组织中均能形成感染 ,感染为非杀细胞性     

Melatonin decreases neurovascular oxidative/nitrosative damage and protects against early increases in the blood-brain barrier permeability after transient focal cerebral ischemia in mice

We have recently shown that melatonin decreases the late (24 hr) increase in blood-brain barrier (BBB) permeability and the risk of tissue plasminogen activator-induced hemorrhagic transformation following ischemic stroke in mice. In the study, we further explored whether melatonin would reduce postischemic neurovascular oxidative/nitrosative damage and, therefore, improve preservation of the early increase in the BBB permeability at 4 hr after transient focal cerebral ischemia for 60 min in mice. Melatonin (5 mg/kg) or vehicle was given intraperitoneally at the beginning of reperfusion. Hydroethidine (HEt) in situ detection and immunohistochemistry for nitrotyrosine were used to evaluate postischemic accumulation in reactive oxygen and nitrogen species, respectively, in the ischemic neurovascular unit. BBB permeability was evaluated by spectrophotometric and microscopic quantitation of Evans Blue leakage. Relative to controls, melatonin-treated animals not only had a significantly reduced superoxide accumulation in neurovascular units in boundary zones of infarction, by reducing 35% and 54% cytosolic oxidized HEt in intensity and cell-expressing percentage, respectively (P < 0.001), but also exhibited a reduction in nitrotyrosine by 52% (P < 0.01). Additionally, melatonin-treated animals had significantly reduced early postischemic disruption in the BBB permeability by 53% (P < 0.001). Thus, melatonin reduced postischemic oxidative/nitrosative damage to the ischemic neurovascular units and improved the preservation of BBB permeability at an early phase following transient focal cerebral ischemia in mice. The findings further highlight the ability of melatonin in anatomical and functional preservation for the ischemic neurovascular units and its relevant potential in the treatment of ischemic stroke.     

Inflammation and breakdown of the blood-retinal barrier during "physiological aging" in the rat retina: a model for CNS aging

OBJECTIVE: To examine the possible contribution of inflammation and breakdown of the blood-brain barrier in the central nervous system (CNS) of physiologically aged rats showing cognitive decline. METHODS: Young (3- to 6-month-old) and aged (24- to 30-month-old) Wistar rats were assessed by the novel object recognition test. Vascular and inflammatory changes in the CNS were investigated in whole-mount preparations or sections of retinas from young adult or aged male Wistar rats. RESULTS: Aged rats showed a significant impairment in short-term memory compared with young adults. Deterioration of blood-retinal barrier function in aged rats was evidenced by leakage of intravascular tracer into the retinal parenchyma and reduced immunoreactivity for the tight junctional protein, occludin. Immunohistochemistry revealed the presence of major histocompatibility complex (MHC) class II-positive resident microglia, activated T cells, and monocyte-like cells in the retinal parenchyma of aged rats only. Microglia positive for the ED1 antigen, indicative of phagocytic activity, were also observed in these retinas. CONCLUSION: Breakdown of the blood-retinal barrier, MHC class II expression, microglial activation, and trafficking of activated T cells are associated with physiological aging. Such changes in the CNS may contribute to the pathogenesis of age-related cognitive decline.     

Evidence for functional endothelial cell damage in early diabetic retinopathy

Summary Two aspects of endothelial cell function were examined in two matched groups of male insulin-dependent diabetics, six with background retinopathy and seven without retinopathy. Leakage of fluorescein from the retinal capillaries was estimated by vitreous fluorophotometry. In addition, factors VIII/von Willebrand (vWF) and VIII-related antigen (VIII-RAG), which are synthesized by the endothelial cells, were measured, together with VIII-antihaemophilic factor (VIII-AHF). The patients without retinopathy had normal leakage of fluorescein in the macula (mean ± SEM: 1.10±0.10 g × 10^-8/ml) and the posterior vitreous (0.45±0.11 g × 10^-8/ml), and normal circulating levels of vWF (123% of a normal reference plasma ± 18%), VIII-RAG (137±14%) and VIII-AHF (112±18%). In contrast, the patients with background retinopathy showed higher leakage of fluorescein in the macula (6.34±1.74 g ×10^-8/ml; p<0.01), and the posterior vitreous (3.09±0.94 g ×10^-8/ml; p<0.02), as well as increased levels of vWF (177±16%; p<0.05). There was a trend towards increased VIII-RAG (195±24%; p<0.1), but not VIII-AHF (126 ±13%). Alterations of endothelial cell function thus accompany the development of retinopathy. It cannot be said from the present study whether these alterations also precede the appearance of retinopathy.     

Transfer across the human blood-brain barrier: Evidence for capillary recruitment and for a paradox glucose permeability increase in hypocapnia

The present study was undertaken to investigate whether there is intermittency of capillary flow in the human brain, i.e., whether more capillaries open up at high blood flow thus increasing the surface for diffusional exchange. Unidirectional transfer across the blood-brain barrier of labeled D-glucose, l-phenylalanine, l-leucine, thiourea, and propranolol was measured using the indicator diffusion method with labeled Na⁺, Cl^?, and chelated In as impermeable reference substances. Forty-three patients needing carotid angiography were studied in different situations, rest, hyperventilation, hypercapnia, hypo/hypertension (within the limits of autoregulation). Some older data on the seizure situation are included. Cerebral blood flow (CBF) was measured concomitantly. In situations with high blood flow, extraction (E) decreased and the permeability surface area product (PS) increased for both the lipophilic substances and for those transferred by carrier mechanism. With low CBF the reverse happened except for an unexpected PS increase for glucose in hyperventilation. Variations of PS in parallel with CBF are evidence of capillary recruitment which constitutes a more efficient way of increasing tissue supply. PS and E remained constant with a constant CBF even when arterial blood pressure was changed, indicating that autoregulatory mechanisms do not affect the diffusional exchange surface and probably take place at the arteriolar level. PS for glucose increased in hyperventilation perhaps as an expression of a pH dependence of its carrier.     

Serum antibodies against the 70k polypeptides of the U1 ribonucleoprotein complex are associated with psychiatric syndromes in systemic lupus erythematosus: a retrospective study

Objectives

We assessed the association between serum autoantibodies against the 70-kDa polypeptide of the U1-ribonucleoprotein (RNP) complex (U1-70k) and the central nervous system (CNS) syndromes in systemic lupus erythematosus (SLE) patients.

Methods

We studied 106 hospitalized patients with active SLE, comparing those with (n = 32) and without (n = 74) CNS syndromes. CNS syndromes were further classified into neurologic (n = 21) and psychiatric (n = 15) disorders. Immunoglobulin G (IgG) anti-U1-70k antibodies were measured by enzyme-linked immunosorbent assay (ELISA) using recombinant antigens. IgG antibodies against whole U1-RNP were measured using commercial ELISA kits.

Results

Although there was no significant difference in the levels of serum anti-U1-70k antibodies in SLE patients with or without CNS syndromes (p = 0.83), the levels were significantly elevated in SLE patients compared with patients without psychiatric syndromes (p = 0.030). In contrast, no significant difference was observed in the levels of serum anti-U1-RNP antibodies in SLE patients with or without psychiatric syndromes (p = 0.555).

Conclusions

These results indicate that serum anti-U1-70k antibodies are associated with psychiatric syndromes in SLE but that they are not associated with CNS syndromes as a whole or with neurologic syndromes. The anti-U1-70k antibodies might be involved in the pathological mechanisms of psychiatric syndromes in SLE.     

Evidence for autonomic dysregulation in the irritable bowel syndrome

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder characterized by chronic abdominal pain and visceral hypersensitivity. In this study, resting blood pressure and heart rate were recorded in 20 IBS patients and 23 controls. We assessed pain intensity and unpleasantness to visceral and cutaneous stimuli using rectal distension and immersion of the foot in hot water. Mean resting heart rate was higher in IBS patients compared to controls. IBS patients rated pain intensity and unpleasantness to visceral and cutaneous stimuli significantly higher than controls. In IBS patients, blood pressure was significantly inversely associated with visceral pain and only weakly and positively associated with cutaneous pain; there were no relationships in controls. Sex and anxiety did not explain these relationships. In conclusion, we found evidence suggestive of central autonomic dysregulation in IBS patients.     

A magnetic resonance abnormality correlating with permeability of the blood-brain barrier in a child with chemical meningitis during central nervous system prophylaxis for acute leukemia

 Chemical meningitis developed in a boy with acute lymphoblastic leukemia during central nervous system (CNS) prophylaxis. Cerebrospinal fluid examination showed pleocytosis and a high protein level. There were no malignant cytological findings. Calculated permeability of albumin across the blood-brain barrier (BBB) was more elevated than that of immunoglobulin or alfa2-macroglobulin. Magnetic resonance imaging (MRI) revealed diffuse pachymeningeal enhancement without any intracerebral lesion. Subsequent CNS prophylaxis was postponed. CSF findings and BBB permeability returned to normal, correlating well with the decrease of MRI abnormality. Received: February 2, 1999 / Accepted: June 1, 1999     

Inducibility of Atrial Fibrillation After GP Ablations and “Autonomic Blockade”: Evidence for the Pathophysiological Role of the Nonadrenergic and Noncholinergic Neurotransmitters

Autonomic Blockade and Atrial Fibrillation . Background: Recent clinical reports that used cholinergic and adrenergic blockade (CAB) as an alternative to ganglionated plexi (GP) ablation to terminate atrial fibrillation (AF) showed mixed results. We investigated the role of other neurotransmitters in AF inducibility. Methods: In 23 pentobarbital anesthetized dogs, a left and right thoracotomy allowed the attachment of electrode catheters to the left and right pulmonary veins and atrial appendages (AA). Programmed stimulation was used to determine the effective refractory periods (ERP) and AF inducibility, measured by the window of vulnerability (WOV). AF duration in response to acetylcholine (Ach; 100 mM) applied to the AA was measured before and after GP ablation + CAB and with vagus nerve stimulation (VNS). After GP ablation + CAB, Ach induced AF duration was determined in response to vasoactive intestinal peptide (VIP) and its specific antagonist ([Ac‐Tyr1,D‐phe2]‐VIP). Results: GP ablation + CAB significantly prolonged ERP, eliminated WOV, and suppressed the duration of Ach induced AF (P ≤ 0.01 for all). Also slowing of the heart rate by VNS was essentially blocked; however, with Ach 100 mM applied to the AA, VNS, and VIP applied to the AA markedly prolonged AF duration. This effect was blocked by the VIP antagonist. Conclusions: Neither GP ablation nor CAB can fully suppress AF inducibility arising from the atrial neural network. Our findings suggest that other neurotransmitters, such as VIP released during VNS, can promote sustained AF despite GP ablation and “autonomic blockade,” which may further define the substrate for AF outside the pulmonary vein‐atrial junctions. (J Cardiovasc Electrophysiol, Vol. 24, pp. 188‐195, February 2013)     

Dissociation of functional status from accrual of CML and RAGE in the aged mouse brain

The objectives of this study were: (i) to identify regions of the aged mouse brain in which advanced glycation end-products (AGEs) were increased, and (ii) assess the functional significance of AGEs by determining the extent to which they could predict age-related brain dysfunction. Densitometric analyses of immunoblots for N epsilon-(carboxymethyl)lysine (CML), a predominant AGE, and receptor for AGE (RAGE), were performed in different brain regions of mice aged 8 or 25 months. The 25-month-old mice were tested for ability to perform on tests of cognitive and psychomotor function prior to assessment of CML or RAGE, to determine if immunostaining results could predict functional impairment among the older mice. The amounts of CML increased with age in cortex, hippocampus, striatum, and midbrain, but were unchanged in the brainstem and cerebellum. Increases in RAGE were evident in all brain regions but the hippocampus, and were not linked to increased amounts of CML. Different statistical approaches each failed to reveal any strong association between the degree of age-related functional impairment among individual mice and amounts of CML or RAGE in any particular region of the brain. The findings from this study suggest that accrual of CML and expression of RAGE in different brain regions are time-related phenomena that do not account for individual differences in brain aging or cognitive decline.     

Potentially Reduced Exposure Cigarettes Accelerate Atherosclerosis: Evidence for the Role of Nicotine

The tobacco industry markets potentially reduced exposure products (PREPs) as less harmful or addictive alternatives to conventional cigarettes. This study compared the effects of mainstream smoke from Quest, Eclipse, and 2R4F reference cigarettes on the development of atherosclerosis in apolipoprotein E-deficient (apoE −/−) mice. Mice were exposed to smoke from four cigarette types for 12 weeks beginning at age of 12 weeks, and in a separate study for 8 weeks, beginning at age of 8 weeks. In both studies, mice exposed to smoke from high-nicotine, high-tar Quest 1, and 2R4F cigarettes developed greater areas of lipid-rich aortic lesions than did non-smoking controls. Exposure to smoke from the lower-nicotine products, Eclipse, and Quest 3, was associated with smaller lesion areas, but animals exposed to smoke from all of the tested types of cigarette had larger lesions than did control animals not exposed to smoke. Urinary levels of isoprostane F2 alpha VI, increased proportionally to cigarette nicotine yield, whereas induction of pulmonary cytochrome P4501A1 was proportional to tar yield. Lesion area was associated with both nicotine and tar yields, although in multiple regression analysis only nicotine was a significant predictor of lesion area. Smoke exposure did not alter systolic blood pressure (SBP), heart rate (HR), blood cholesterol, or leukocyte count. Taken together, these observations suggest that smoking may accelerate atherosclerosis by increasing oxidative stress mediated at least in part via the actions of nicotine.