Toluene diisocyanate enhances human bronchial epithelial cells' permeability partly through the vascular endothelial growth factor pathway

Background Toluene diisocyanate (TDI) is a recognized chemical asthmogen; yet, the mechanisms of its toxicity have not been elucidated.
Objective To investigate the influence of TDI on the permeability of human bronchial epithelial cell (HBE; HBE135-E6E7) monolayers in vitro , and the expression of vascular endothelial growth factor (VEGF) in these cells.
Methods TDI–human serum albumin (HSA) conjugates were prepared by a modification of Son's method. Fluorescein isothiocyanate-labelled dextran and transmission electron microscopy were used to evaluate the effects of TDI–HSA on HBE135-E6E7 permeability. RT-PCR and ELISA were used to evaluate VEGF gene expression and protein release from HBE135-E6E7 cells stimulated by TDI–HSA. A VEGF-neutralizing antibody was used in monolayer permeability experiments to determine the role of the VEGF pathway in this process.
Results TDI–HSA significantly increased the permeability coefficients of HBE135-E6E7 monolayers ( P <0.01). TDI–HSA treatment significantly increased the expression of VEGF165 and VEGF189 genes ( P <0.01). ELISA showed that TDI significantly induces VEGF release from HBE135-E6E7 cells. Cells treated with TDI–HSA and VEGF-neutralizing antibody had significantly lower permeability coefficients than cells treated with TDI–HSA only ( P <0.01), but still significantly higher than control cells ( P <0.01). Cells treated with TDI–HSA had fewer tight junctions (TJs) than control and HSA-treated cells, and addition of the anti-VEGF antibody did not restore the original number of TJs.
Conclusion TDI increases the permeability of HBE cell monolayers, partly through a VEGF-mediated pathway. This suggests the importance of VEGF in TDI-induced pulmonary diseases, but shows that other pathways may be involved in the pathogenic process.     

用组织多谱勒评价正常人左右心室壁的速度和加速度

目的:心脏多部位组织多普勒速度曲线同时显示技术是目前研究心室功能的新技术。方法:本研究运用组织多普勒技术,对31例正常人,在心尖四腔切面,在同一心动周期同时对心室及室间隔的9个观察点的心肌运动速度、加速度进行观察。结果:基底部的速度大于心室中部,中部大于心尖部。最快的速度出现于左心室舒张早期(10.36±3.54)cm／s,右心室的运动速度在等容收缩期、收缩期及舒张晚期均大于左心室。在收缩期和舒张早期,左右心室的速度达峰时间不同,左心室和室间隔在前,右心室在后。左心室在射血期和舒张早期加速度较右心室大,右心室在等容收缩期和舒张晚期的加速度较左室大,舒张早期左心室和室间隔的加速度大于右心室,舒张晚期是右心室和室间隔的加速度大于左心室。结论:组织多普勒是评价心室运动功能准确可靠的方法。     

Distribution and reactivity of inhaled 14C-labeled toluene diisocyanate (TDI) in rats

Inhalation exposure to toluene diisocyanate (TDI) can result in a variety of airway diseases. Concern has been expressed that a putative carcinogenic potential of TDI exists as a result of the formation of toluenediamine (TDA) by hydrolysis of the isocyanate in the body. Results from long-term bioassays (TDI inhalation versus gavage in rats and mice) are contradictory and discrepancies do exist concerning the interpretation of adverse effects. This study was performed to analyze the distribution and reactivity of radioactively-labeled TDI using vapor exposure in a rat model system. Rats were exposed to ¹⁴C-TDI vapors at concentrations ranging from 0.026 to 0.821 ppm for 4 h. All tissues examined showed detectable quantities of radioactivity, with the airways, gastrointestinal system and blood having the highest levels which increased with exposure concentration. The concentration of radioactivity in the bloodstream after exposure was linear with respect to dose. The majority (74 – 87%) of the label associated with the blood was recovered in the plasma, and of this, 97 – 100% of the ¹⁴C existed in the form of biomolecular conjugates. Analysis of stomach contents shows that the majority of the label is also associated with high (>10 kDa) molecular weight species. While a larger percentage (28%) of the label is found in the low molecular weight fraction relative to blood, this low molecular weight labeled material represents at least eight different components. Thus, over the vapor exposure concentrations and time tested, it appears that conjugation is the predominant reaction and that free TDA is not a primary in vivo reaction product under the conditions tested. Received: 7 December 1993/Accepted: 7 March 1994     

某小学集体发热与塑胶跑道相关性的调查

2006年5月17—30日,朝阳区某小学累计43人发热(发热定义为>37.2℃)。为了解小学集体发热的流行病学特征,探讨其可能的致病原因是否与聚氨酯塑胶跑道有关,我们对该学校集体发热情况进行了调查分析,现报道如下。1对象与方法1.1对象北京市朝阳区某小学校(以下称K小学)于2006年5月17—30日有发热症状的学生。1.2方法①通过现场流行病学调查并结合电话调查获取K小学集体发热患者43例相关的资料。②采用描述性流行病学方法分析病例的发病时间、地点和人群分布。③运用职业流行病学方法调查生产原料来源、工艺流程、接触时间以及作用方式等。2结果…     

组织多普勒显像评价心衰患者心肌运动

目的应用组织多普勒成像技术评价心力衰竭患者左室内心肌收缩和舒张运动的同步性情况。方法本研究共收入25例正常人和70例心力衰竭患者,心力衰竭患者又根据心电图QRS波群宽度分为三个亚组:窄QRS亚组(QRS宽度小于120ms)23例;QRS中度延长亚组(QRS宽度在120ms至150ms之间)26例;QRS重度延长亚组(QRS宽度大于150ms)21例。应用组织多普勒技术中的组织速度成像,测量左心室各节段长轴方向的收缩达峰时间(TS),舒张早期达峰时间(TE)。计算12节段TS和TE的标准差(TS-SD和TE-SD)和极差(TSmax-min和TEmax-min),评价左心室收缩舒张同步性。结果收缩期同步性指标TS-SD在对照组和心力衰竭三个亚组中分别为18.60(7.89)ms、27.02(11.16)ms、38.37(15.52)ms、47.28(19.06)ms,心力衰竭亚组与对照组相比均有统计学意义,P<0.05。舒张期同步性指标TE-SD在对照组和心力衰竭三个亚组中分别为19.53(6.4)ms、35.40(16.92)ms、45.66(21.22)ms、51.93(27.92)ms,心力衰竭亚组与对照组相比均有统计学意义,P<0.05。三组心力衰竭患者中收缩期收缩失同步的比率分别为39%、62%、76%,与正常对照组相比有明显统计学意义,P<0.001;三组心力衰竭患者中舒张失同步的比率分别为52%、69%、81%,与正常对照组相比有明显统计学意义,P<0.001。结论心力衰     

Upregulation of Cisd2 attenuates Alzheimer's-related neuronal loss in mice

CDGSH iron–sulfur domain-containing protein 2 (Cisd2), a protein that declines in an age-dependent manner, mediates lifespan in mammals. Cisd2 deficiency causes accelerated aging and shortened lifespan, whereas persistent expression of Cisd2 promotes longevity in mice. Alzheimer's disease (AD) is the most prevalent form of senile dementia and is without an effective therapeutic strategy. We investigated whether Cisd2 upregulation is able to ameliorate amyloid β (Aβ) toxicity and prevent neuronal loss using an AD mouse model. Our study makes three major discoveries. First, using the AD mouse model (APP/PS1 double transgenic mice), the dosage of Cisd2 appears to modulate the severity of AD phenotypes. Cisd2 overexpression (∼two-fold) significantly promoted survival and alleviated the pathological defects associated with AD. Conversely, Cisd2 deficiency accelerated AD pathogenesis. Secondly, Cisd2 overexpression protected against Aβ-mediated mitochondrial damage and attenuated loss of neurons and neuronal progenitor cells. Finally, an increase in Cisd2 shifted the expression profiles of a panel of genes that are dysregulated by AD toward the patterns observed in wild-type mice. These findings highlight Cisd2-based therapies as a potential disease-modifying strategy for AD. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

Childhood Obesity: Impact on Cardiac Geometry and Function

ObjectivesThe aim of our study was to assess geometric and functional changes of the heart in obese compared with nonobese children and adolescents.BackgroundObesity in children and adolescents has increased over the past decades and is considered a strong risk factor for future cardiovascular morbidity and mortality. Obesity has been associated with myocardial structural alterations that may influence cardiac mechanics.MethodsWe prospectively recruited 61 obese (13.5 ± 2.7 years of age, 46% male sex, SD score body mass index, 2.52 ± 0.60) and 40 nonobese (14.1 ± 2.8 years of age, 50% male sex, SD score body mass index, −0.33 ± 0.83) consecutive, nonselected Caucasian children and adolescents. A standardized 2-dimensional (2D) echocardiography and 2D speckle-tracking analysis was performed in all children. Furthermore, blood chemistry including lipid and glucose metabolism was assessed in all children.ResultsCompared with nonobese children, blood pressure, low-density lipoprotein cholesterol, and parameters of glucose metabolism were significantly increased in obese children, whereas high-density lipoprotein cholesterol was significantly lower. Compared with nonobese children, obese children were characterized by enlarged left- and right-sided cardiac chambers, thicker left ventricular walls, and, consequently, increased left ventricular mass. Despite a comparable left ventricular ejection fraction, decreased tissue Doppler–derived peak systolic velocity and regional basoseptal strain were found in obese children compared with nonobese children. Beyond that, 2D speckle tracking–derived longitudinal (−18.2 ± 2.0 vs. −20.5 ± 2.3, p < 0.001) and circumferential (−17.0 ± 2.7 vs. −19.5 ± 2.9, p < 0.001) strain of the left ventricle was reduced in obese children compared with nonobese children. Diastolic function was also impaired in obese compared with nonobese children. Both longitudinal strain and circumferential strain were independently associated with obesity.ConclusionsThe results of this study demonstrate that childhood obesity is associated with significant changes in myocardial geometry and function, indicating an early onset of potentially unfavorable alterations in the myocardium.     

Occupational asthma due to toluene diisocyanate among velcro-like tape manufacturers

During September-November, 1985, four employees of a factory were seen at the occupational clinic complaining of cough, shortness of breath, and wheezing. All four worked in the same area of the factory where an adhesive containing toluene diisocyanate (TDI) was applied to velcro-like tape during manufacturing. To confirm the diagnosis of TDI-induced asthma and determine the prevalence among workers, 38 workers were interviewed and examined (84%) in the factory. Air samples were also taken from several areas in the factory to determine the TDI concentration. For analysis, the factory was divided into three areas based on the concentration of TDI: low (0.012 +/- 0.002 ppm), medium (0.021 +/- 0.006 ppm), and high (0.047 +/- 0.054 ppm). The distribution of workers with symptoms of asthmatic bronchitis was highly associated with TDI concentration (p less than 0.001). After stopping work for a period of 10 days, workers in areas with a high concentration of TDI showed marked improvement in pulmonary function tests (PFTs). After isolation of the exposure site, improvement of the ventilation system, and substitution of the TDI with less volatile diphenylmethane diisocyanate (MDI), air concentration of isocyanates was usually below 0.007 ppm. Three of the four clinically overt asthma cases went back to work without any difficulty. The PFTs of affected workers showed a significant improvement 5 months later. We conclude that TDI was responsible for the occupational asthma among velcro-like tape manufacturers and that the TDI-induced impairment of pulmonary functions was at least partially reversible.     

An epidemiology study of lung function changes of toluene diisocyanate foam workers in the United Kingdom

Objective: To determine whether longitudinal declines in ventilatory capacity and the occurrence of respiratory symptoms in workers manufacturing polyurethane foam were related to toluene diisocyanate (TDI) exposure. Methods : A population of 780 workers in 12 United Kingdom factories was followed for 5 years. Modified United Kingdom Medical Research Council (MRC) respiratory questionnaires and three or more lung function measurements were completed for each subject. Mean TDI exposures for all jobs in which subjects were employed were assessed by personal monitoring (2294 measurements) and related to their occupational histories. Results : The United Kingdom 8-h and 15-min maximum exposure limits for TDI were exceeded in 4.7% and 19.0% of the samples taken, respectively. There was some increase in reported respiratory symptoms amongst exposed workers, but the annual declines of 1-s forced expiratory volume (FEV₁) and forced vital capacity (FVC) were not related to TDI exposure and were typical of those observed in other longitudinal populations. FEV₁ declines were smoking-related. Evidence was found suggesting that a small excess decline in FEV₁ and FVC occurred in the first few years of employment for workers not previously exposed to TDI. Conclusion: This study does not provide evidence that there is a TDI-related decline in FEV₁ and FVC in workers exposed to less than the United Kingdom 8-h occupational exposure limit of 5.8 ppb. Received: 21 February 1997 / Accepted: 10 July 1997