Strain differences in antioxidants in rat models of cardiovascular disease exposed to ozone

Abstract

We examined the hypothesis that antioxidant substances and enzymes in lung, heart and in bronchoalveolar lavage fluid (BALF) are altered in response to O₃ in cardiovascular disease and/or metabolic syndrome (CVD)-prone rat models. CVD strains [spontaneously hypertensive (SH), SH stroke-prone (SHSP), SHHF/Mcc heart failure obese (SHHF), insulin-resistant JCR:LA-cp obese (JCR) and Fawn-Hooded hypertensive (FHH)] were compared with normal strains [Wistar, Sprague–Dawley (SD) and Wistar Kyoto (WKY)]. Total glutathione (GSH?+?GSSG or GSx), reduced ascorbate (AH2), uric acid (UA) and antioxidant enzymes were determined in lung, heart and BALF immediately (0?h) or 20-h post 4-h nose-only exposure to 0.0, 0.25, 0.5 and 1.0?ppm O₃. Basal- and O₃-induced antioxidant substances in tissues varied widely among strains. Wistar rats had a robust O₃-induced increase in GSx and AH2 in the lung. Two CVD strains (JCR and SHHF) had high basal levels of AH2 and GSx in BALF as well as high basal lung UA. Across all strains, high BALF GSx was only observed when high BALF AH2 was present. CVD rats tended to respond less to O₃ than normal. High-basal BALF AH2 levels were associated with decreased O₃ toxicity. In summary, large differences were observed between both normal and CVD rat strains in low-molecular weight antioxidant concentrations in lung, BALF and heart tissue. Wistar (normal) and JCR and SHHF (CVD) rats appeared to stand out as peculiar in terms of basal- or O₃-induced changes. Results elucidate interactions among antioxidants and air pollutants that could enhance understanding of cardiopulmonary disease.     

Clinical and pathological manifestations of cardiovascular disease in rat models: the influence of acute ozone exposure

Abstract

Rodent models of cardiovascular diseases (CVD) and metabolic disorders are used for examining susceptibility variations to environmental exposures. However, cross-model organ pathologies and clinical manifestations are often not compared. We hypothesized that genetic CVD rat models will exhibit baseline pathologies and will thus express varied lung response to acute ozone exposure. Male 12–14-week-old healthy Wistar Kyoto (WKY), Wistar (WIS), and Sprague–Dawley (SD) rats and CVD-compromised spontaneously hypertensive (SH), fawn-hooded hypertensive (FHH), stroke-prone SH (SHSP), obese SH heart-failure (SHHF), obese diabetic JCR (JCR) rats were exposed to 0.0, 0.25, 0.5, or 1.0?ppm ozone for 4?h and clinical biomarkers, and lung, heart and kidney pathologies were compared immediately following (0–h) or 20-h later. Strain differences were observed between air-exposed CVD-prone and WKY rats in clinical biomarkers and in kidney and heart pathology. Serum cholesterol was higher in air-exposed obese SHHF and JCR compared to other air-exposed strains. Ozone did not produce lesions in the heart or kidney. CVD-prone and SD rats demonstrated glomerulopathy and kidney inflammation (WKY?=?WIS?=?SH?<?SD?=?SHSP?<?SHHF?<?JCR?=?FHH) regardless of ozone. Cardiac myofiber degeneration was evident in SH, SHHF, and JCR, while only JCR tends to have inflammation in coronaries. Lung pathology in air-exposed rats was minimal in all strains except JCR. Ozone induced variable alveolar histiocytosis and bronchiolar inflammation; JCR and SHHF were less affected. This study provides a comparative account of the clinical manifestations of disease and early-life organ pathologies in several rat models of CVD and their differential susceptibility to lung injury from air pollutant exposure.     

Executive Summary: variation in susceptibility to ozone-induced health effects in rodent models of cardiometabolic disease

Abstract

Seven million premature deaths occur annually due to air pollution worldwide, of which ～80% are attributed to exacerbation of cardiovascular disease (CVD), necessitating greater attention to understanding the causes of susceptibility to air pollution in this sector of population. We used rat models of CVD with or without obesity and compared them to healthy strains to examine the risk factors of ozone-induced lung injury and inflammation. We examined functional, biochemical and molecular changes in several organs to evaluate how physiological factors as well as compensatory antioxidant reserves modulate processes by which ozone injury is influenced by underlying disease. In this study, we highlight key findings of this series of reports. We show that underlying cardiopulmonary insufficiency in genetically predisposed rats appears to increase the effective ozone dose; thus dosimetry is one factor contributing to exacerbated ozone effects. We further show that antioxidant reserve in airway lining fluid modulates ozone-induced damage such that strains with the least antioxidant reserve incur the greatest injury. And finally, we show that the inflammatory response to ozone is governed by a cluster of genes involved in regulating cytokine release, trafficking of inflammatory cells and processes related to cellular apoptosis and growth. All such processes are influenced not only by ozone dosimetry and the lung antioxidant milieu but also by the strain-specific genetic factors. In using a comprehensive systems biology research approach, our data reveal key risk factors for – and strategies to reduce risk of – air pollution mortality among those with CVD.     

Variability in ozone-induced pulmonary injury and inflammation in healthy and cardiovascular-compromised rat models

Abstract

The molecular bases for variability in air pollutant-induced pulmonary injury due to underlying cardiovascular (CVD) and/or metabolic diseases are unknown. We hypothesized that healthy and genetic CVD-prone rat models will exhibit exacerbated response to acute ozone exposure dependent on the type and severity of disease. Healthy male 12–14-week-old Wistar Kyoto (WKY), Wistar (WS) and Sprague Dawley (SD); and CVD-compromised spontaneously hypertensive (SH), Fawn-Hooded hypertensive (FHH), stroke-prone spontaneously hypertensive (SHSP), obese spontaneously hypertensive heart failure (SHHF) and obese JCR (JCR) rats were exposed to 0.0, 0.25, 0.5, or 1.0?ppm ozone for 4?h; pulmonary injury and inflammation were analyzed immediately following (0-h) or 20-h later. Baseline bronchoalveolar lavage fluid (BALF) protein was higher in CVD strains except for FHH when compared to healthy. Ozone-induced increases in protein and inflammation were concentration-dependent within each strain but the degree of response varied from strain to strain and with time. Among healthy rats, SD were least affected. Among CVD strains, lean rats were more susceptible to protein leakage from ozone than obese rats. Ozone caused least neutrophilic inflammation in SH and SHHF while SHSP and FHH were most affected. BALF neutrophils and protein were poorly correlated when considering the entire dataset (r?=?0.55). The baseline and ozone-induced increases in cytokine mRNA varied markedly between strains and did not correlate with inflammation. These data illustrate that the degree of ozone-induced lung injury/inflammation response is likely influenced by both genetic and physiological factors that govern the nature of cardiovascular compromise in CVD models.     

The use of plethysmography and oscillometry to compare long-acting bronchodilators in patients with COPD

Aims

Assessment of bronchodilator pharmacology in chronic obstructive pulmonary disease (COPD) may be improved by using more sensitive methods than spirometry, such as impulse oscillometry (IOS) and body plethysmography. We sought to compare salmeterol (S) and tiotropium (Tio) using these methods.

Methods

In this double-blind, randomized, four-way crossover study, 32 COPD patients received single doses of Tio (18 µg), S (50 and 100 µg) or placebo. Specific airway conductance (sGaw), forced expiratory volume in 1 s (FEV₁) and IOS were measured pre- and up to 26 h postdose. Comparisons between treatments were analysed by weighted means (WM) between 0 and 12 (WM 0–12 h) and 12–24 h (WM 12–24 h) postdose. Data are expressed as mean difference (or geometric ratio for nonparametric data) with 95% confidence intervals.

Results

Tio and S100 significantly improved FEV₁, sGaw and IOS parameters up to 26 h and S50 up to 16 h. WM analysis showed no difference between Tio and S100 in FEV₁ for 0–12 h or 12–24 h. Maximum mid-expiratory flow (−0.06; −0.11, −0.01) and R35 (0.02; 0.01, 0.03) demonstrated superiority of S100 compared with Tio for WM 0–12 h sGaw (1.12; 1.02, 1.23), R5 (−0.06; −0.09, −0.02), R15 (−0.03; −0.05, −0.01), and resonant frequency (RF) (−2.30; −3.83, −0.77) showed superiority of Tio compared with S100 for WM 12–24 h. At 26 h, sGaw, R5, R15, X5 and RF also showed superiority of Tio compared with S100.

Conclusions

sGaw and IOS parameters sensitively differentiated between the effects of Tio and S when FEV₁ measurements were similar. Clinical trials in patients with COPD should use IOS and sGaw to assess comprehensively bronchodilator pharmacology.

What is already known about this subject

• Forced expiratory voume in 1 s (FEV₁) is the standard measurement used to measure drug effects in chronic obstructive pulmonary disease (COPD) clinical trials.
• Having previously shown that specific airway conductance (sGaw) measured using body plethysmography and impulse oscillometry (IOS) are more sensitive than FEV₁ for assessing short-acting bronchodilator effects in patients with COPD, we conducted the first randomized, placebo-controlled study to compare long-acting bronchodilators in COPD patients using these techniques.

What this study adds

• sGaw and IOS sensitively differentiated between the effects of tiotropium and salmeterol when FEV₁ measurements were similar.
• sGaw and IOS measurements are better than FEV₁ for sensitively assessing bronchodilator pharmacology and differentiating between treatments in COPD clinical trials.

     

首发心血管疾病患者血脂水平与心血管疾病发病的相关性分析

目的探讨首发心血管疾病患者血脂水平与心血管疾病发病危险的相关性。方法选取2009年11月至2012年10月浙江省绍兴市人民医院心内科收治的首发心血管疾病患者210例作为观察组,以同期体检健康的志愿者150例作为对照组,采集2组受试者清晨空腹静脉血,检测总胆固醇、三酰甘油、高密度脂蛋白胆固醇（HDL-C）、低密度脂蛋白胆固醇（LDL-C）、载脂蛋白（apo）AI及apoB等血脂指标。结果观察组患者总胆固醇、三酰甘油、LDL-C及apoB分别为（6．1±0．3）、（1．9±0．8）、（3．9±1．5）、（1．4±0．7）mmol／L,对照组分别为（4．4±0．6）、（1．1±0．5）、（2．6±0．9）、（0．9±0．3）mmol／L,观察组各项指标均明显高于对照组（t=35．349、10．827、465、8．223,P〈0．05）,而观察组apoA1为（1．5±0．3）mmol／L,低于对照组的（1．9±0．2）mmol／L,差异有统计学意义（t=14．225,P〈0．05）;观察组和对照组受试者体重指数及HDL-C比较,差异均无统计学意义[（26±3）kg／m。比（26±4）kg／m。,（1．4±0．6）mmoL／L比（1．2±0．9）mmol／L]（t=1．748、1．556,均P〉0．05）。观察组210例患者中极高危50例、高危44例、中危64例、低危52例;总胆固醇、三酰甘油、LDL-C及apoB水平与心血管疾病发病的危险分级均呈显著正相关（r=0．786、0．753、0．663、0．900,均P〈0．05）,apoA1与心血管疾病发病的危险分级呈显著负相关（r=-0．691,P〈0．05）。结论首发心血管疾病患者血脂指标的联合检测可作为预测心血管事件发生的重要方法．     

Consumption of a high-fat diet does not potentiate the deleterious effects on lipid and protein levels and body development in rats subjected to maternal protein restriction

Maternal undernutrition may cause injuries in several organs of the offspring, as well as lead to diseases in adulthood. Obesity and/or the consumption of a high-fat diet may also induce metabolic and cardiorespiratory diseases. We hypothesized that the consumption of a post-weaning high-fat diet would potentiate the deleterious effects of maternal protein undernutrition. This study evaluated the effects of the association of a low-protein diet during gestation and lactation with a post-weaning high-fat diet on the biochemical and ventilatory parameters of rats. Male Wistar rats from mothers who received a low-protein (9% of protein) or normoprotein diet during pregnancy and lactation received a high-fat (32% of total kilocalories from lipids) or a normal fat diet after weaning. Mass gain and somatic growth of the offspring were monitored. Also examined were biochemical chemical parameters and respiratory frequency, tidal volume (volume of air displaced in each normal respiratory cycle when extra effort is not applied), and pulmonary ventilation. Offspring from undernourished mothers presented lower birth weight (P = .0225), which remained until the end of lactation (P < .01). The rats that consumed high-fat diet and had been submitted to maternal undernutrition presented higher tidal volume when compared to the ones that consumed control diet at the 21st day of life (P ˂ .05). At 30 and 90 days, no further ventilatory changes were observed. Our data show that the consumption of a high-fat diet post-weaning did not seem to potentiate the changes induced by maternal undernutrition.     

Application of quantitative structure activity relationship (QSAR) models to predict ozone toxicity in the lung

The sequence of events leading to ozone-induced airway inflammation is not well known. To elucidate the molecular and cellular events underlying ozone toxicity in the lung, we hypothesized that lipid ozonation products (LOPs) generated by the reaction of ozone with unsaturated fatty acids in the epithelial lining fluid and cell membranes play a key role in mediating ozone-induced airway inflammation. To test our hypothesis, we ozonized 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine (POPC) and generated LOPs. Confluent human bronchial epithelial cells were exposed to the derivatives of ozonized POPC-9-oxononanoyl, 9-hydroxy-9-hydroperoxynonanoyl, and 8-(5-octyl-1,2,4-trioxolan-3-yl-)octanoyl-at a concentration of 10 muM, and the activity of phospholipases A2 (PLA2), C (PLC), and D (PLD) was measured (1, 0.5, and 1 h, respectively). Quantitative structure-activity relationship (QSAR) models were utilized to predict the biological activity of LOPs in airway epithelial cells. The QSAR results showed a strong correlation between experimental and computed activity (r = 0.97, 0.98, 0.99, for PLA2, PLC, and PLD, respectively). The results indicate that QSAR models can be utilized to predict the biological activity of the various ozone-derived LOP species in the lung.     

Left ventricular gene expression profile of healthy and cardiovascular compromised rat models used in air pollution studies

Abstract

The link between pollutant exposure and cardiovascular disease (CVD) has prompted mechanistic research with animal models of CVD. We hypothesized that the cardiac gene expression patterns of healthy and genetically compromised, CVD-prone rat models, with or without metabolic impairment, will reveal underlying disease processes that facilitate understanding of the mechanisms of air pollution susceptibility differences. Left ventricular gene expression was examined using Affymetrix rat 230A-gene arrays in male, age-matched (12–14 weeks old) healthy Wistar Kyoto (WKY) and CV-compromised spontaneously hypertensive (SH), stroke-prone SH (SHSP), obese SH heart failure (SHHF) and obese insulin-resistant (JCR) rats. Principle component analysis separated strains in three clusters: (1) WKY, (2) JCR and (3) SH, SHSP and SHHF. Gene expression pattern in JCR differed from all other CVD strains. Both SHHF and JCR strains presented the most differentially expressed genes from WKY, but generally with opposing directional pattern suggesting that the CVD in these strains arise through different mechanisms. Hierarchical clustering of nuclear factor-kappaB target genes indicated varying degrees of, but similar directional changes, in SH, SHSP and SHHF relative to WKY rats, which may relate to the severity of their CVD. The JCR strain had less pronounced expressions of these genes suggesting milder cardiac disease. No unique expression pattern could be identified for genes implicated in stroke and heart failure in SHSP and SHHF rats, respectively. The data show that the CVD pathophysiological mechanisms differ in models with different genetic backgrounds, and therefore, the mechanisms by which air pollutants affect the cardiopulmonary system are likely to vary.     

老年性痴呆动物模型研究进展

老年性痴呆 (Alzheimersdisease,AD)是以老年斑和神经纤维缠结为特征的一种进行性、退行性神经系统疾病。AD动物模型的研究可大大促进AD病因、发病机制及药物筛选的研究 ,是深入开展AD研究的必要条件之一。损伤性、自然衰老动物和复合型动物模型能够复制出认知缺损等表现 ,但缺乏AD的特征性病变。SAM P/ 8是相对理想的模型。转基因小鼠是目前研究的热点 ,为在体研究AD的特定发病基因及其代谢产物提供了新的载体。随着AD治疗学由对症治疗转向对因治疗 ,AD模型也应顺应这一发展。     

心血管疾病患者参与临床决策倾向性的影响因素研究

目的 分析影响心血管疾病患者参与临床决策倾向性的因素.方法 抽取符合入选标准的心血管疾病患者258例,采用问卷调查方法,对患者的就医过程及对其临床决策倾向性的影响进行探讨.问卷调查的具体内容包括：①一般人口学资料;②疾病状况;③患者心理健康状况评估;④患者参与临床决策的意愿.结果 患者平均年龄（64±13）岁;男性占55.8%（144/258）,女性占44.2%（114/258）;88.0%（227/258）的患者可以报销医疗费用;82.2%的患者家庭月收入≥3 000元;89例（34.5%）患者在做临床决策时倾向于＆quot;医生根据医学知识做出决策＆quot;,61例（23.7%）患者在做临床决策时倾向于＆quot;医生在询问患者需求后做出决策＆quot;,94例（36.4%）患者倾向于＆quot;和医生共同做出决策＆quot;,14例（5.4%）患者倾向于＆quot;和医生讨论后自己做出决策＆quot;.无患者依据自己的知识独立做出决策.患者对医生的信任评分：最低7分,最高10分,平均（9.7±0.5）分;文化程度（OR=4.052,95%CI：1.800～9.126）是患者和医生做出共同决策的危险因素,对医生的信任评分（OR=0.071,95%CI：0.016～0.309）是患者和医生做出共同决策的保护因素.结论 心血管疾病患者对医生的信任度很高,患者的临床决策倾向性主要取决于患者对医生的信任程度.     

钠-葡萄糖共转运酶2抑制剂降低心血管和肾病风险

心血管疾病(Cardiovascular disease,CVD)是2型糖尿病(Type 2 diabetes mellitus,T2DM)患者发病和死亡的主要原因,因此,合理利用降糖药物积极进行糖尿病管理的同时,最大限度降低CVD不良结果风险是非常重要的.T2DM患者发生CVD的风险很高,而且糖尿病引发的糖尿病肾病使...     

护理干预对糖尿病肾病患者血液透析中并发心血管病的影响

目的：探讨护理干预对糖尿病肾病（DN）患者血液透析中并发心血管病的影响。方法行维持性血液透析的糖尿病肾病患者80例,随机分为对照组和观察组,每组40例,对照组进行常规护理,观察组在对照组基础上进行全面护理干预,比较两组患者的心血管并发症的发生率。结果对照组并发症发生率为95.0%,观察组并发症发生率为62.5%,两组比较差异具有统计学意义（P〈0.05）。结论综合全面的护理干预,能有效的降低糖尿病肾病患者血液透析中的心血管并发症的发病率,提高糖尿病肾病患者的生活质量,值得临床推广应用。     

乳果糖口服液治疗心血管疾病患者便秘的疗效观察

目的观察乳果糖口服液治疗心m管疾病患者便秘的疗效。方法收集心血管内科便秘患者120例,随机分为实验组与对照组各60例,对照组应用大黄苏打片,每次0．6～0．9g,每Et3次口服。同时应用果导片0．1～0．2g,晚睡前口服。实验组应用乳果糖口服液,1次15ml,每日3次口服。比较两组患者服药后排便的有效率。结果服药后,实验组排便有效率为96．67％（58／60）,明显高于对照组83．33％（50／60）,差异具有统计学意义（P〈0．05）。整个研究过程中,实验组无严重不良反应发生。结论乳果糖口服液治疗心血管疾病患者便秘的疗效满意,安全性高.     

超敏C-反应蛋白和胆固醇/高密度脂蛋白胆固醇比值联合测定在心血管疾病中的应用

目的 探讨超敏C-反应蛋白(hs-CRP)和胆固醇(TG/HDL-C)在心血管疾病中的应用.方法 超敏C-反应蛋白的测定采用胶乳比浊法,总胆固醇/高密度脂蛋白胆固醇的测定,分别采用氧化酶法和一步法.结果 hs-CRP、TC/HDL-C在高血压组、冠心病组(CAD)和急性心肌梗死组(AMI)与健康对照组比较,均显著升高(P<0.01).而且急性心肌梗死组显著高于冠心病组(P<0.01),冠心病组又高于高血压组(P<0.05).结论 hs-CRP浓度和心血管疾病及其病变程度明显相关,且联合检测hs-CRP和TC/HDL-C可提高心血管疾病的预测及危险程度的评估.     

循证护理在老年心血管疾病并发症中的应用研究

目的探讨循证护理在老年心血管疾病并发症中应用的意义。方法将医院收诊的老年心血管疾病患者随机分为对照组与观察组各120例。对照组予常规护理,观察组予循证护理。比较2组间住院时间、满意率及并发症发生率差异。结果观察组患者对疗效、医院环境、医护人员等满意率显著高于对照组;观察组住院时间显著低于对照组;观察组患者便秘、失眠、下肢静脉血栓、心理问题等并发症发生率均显著低于对照组,2组比较差异有统计学意义（P〈0．05）。结论循证护理能有效降低老年心血管疾病并发症的发生率,缩短其住院时间并提高患者的满意度。