心肌纤维化与肾素血管紧张素醛固酮系统

心肌纤维化可分为反应性纤维化和修复性纤维化。本文综述了循环RAS系统与心肌组织RAS系统机与心肌纤维化的关系及心肌纤维化的最新研究进展。     

自发性高血压大鼠左室心肌纤维化与黄连清降合剂的干预效应

目的:观察清热解毒复方(黄连清降合剂)抑制自发性高血压大鼠心肌纤维化的作用,并探讨其作用机制。方法:实验于2005-01/12在山东中医药大学细胞分子生物学实验室完成。①实验分组:将自发性高血压大鼠30只随机分为4组,即模型对照组6只、牛黄降压丸组8只、卡托普利组8只、黄连清降合剂组8只,并设Wistar大鼠8只作为正常对照组。②实验方法:牛黄降压丸组、卡托普利组、黄连清降合剂组分别给于牛黄降压丸混悬液、卡托普利混悬液、黄连清降合剂混悬液10mL/kg体质量,分别相当于0.75g牛黄降压丸/(kg·d)、35mg卡托普利/(kg·d)、22g中药生药/(kg·d)(均相当于临床用量的14倍量),灌服10mL/kg体质量;正常对照组和模型对照组给等量的生理盐水,不给任何药物。根据每周的体质量变化调整给药量。1次/d,每周用药6d,连续用药8周。③实验评估:采用套尾法测定各组大鼠清醒状态下尾动脉收缩压;采用苦味酸-天狼猩红染色法标记心肌胶原分布,并测定心肌胶原容积分数和血管周围胶原面积/管腔面积比;采用免疫组化法测定心肌Ⅰ、Ⅲ型胶原的表达;采用放射免疫分析法测定心肌血管紧张素Ⅱ的含量。结果:清热解毒复方(黄连清降合剂)能够降低自发性高血压大鼠清醒状态下尾动脉收缩压,而且无反弹和快速耐受性,能够减轻心肌间质和心肌内血管周围胶原纤维的沉积,能够降低心肌胶原容积分数和血管周围胶原面积/管腔面积比,能够降低心肌组织Ⅰ、Ⅲ型胶原的蛋白表达,能够降低心肌组织血管紧张素Ⅱ的含量,各指标效应与卡托普利组相近,均明显优于模型对照组(P<0.05)。结论:清热解毒复方(黄连清降合剂)具有良好的抗高血压心肌纤维化的作用,其机制与降低心肌组织血管紧张素Ⅱ的含量、抑制肾素-血管紧张素-醛固酮系统活性有关。     

微血管炎症及心肌纤维化指标在早期川崎病诊断中的临床意义

目的 探讨微血管炎症及心肌纤维化指标[金属蛋白酶1组织抑制剂（TIMP-1）、半乳糖凝集素-3(Gal-3)、转化生长因子-β(TGF-β)、脂质运载蛋白2(Lcn2)]在川崎病（KD）诊断中的意义。方法 选取2020年1月-2022年1月唐山市妇幼保健院KD患儿100例,分别在KD急性期与亚急性期抽取所有患儿血液样本测定相关生化指标（TIMP-1、Gal-3、TGF-β、Lcn2）水平,超声检测冠状动脉内径D值、心肌灌注状态。统计KD患儿不同时期、不同冠状动脉内径、不同心肌灌注情况者相关生化指标（TIMP-1、Gal-3、TGF-β、Lcn2）水平。结果 KD急性期患者TIMP-1、Gal-3、TGF-β、Lcn2水平高于亚急性期,差异有统计学意义（P<0.05）;100例KD患儿中,冠状动脉内径异常者36例（CAL组）、无冠状动脉内径异常者64例（NCAL组）,CAL组TIMP-1水平低于NCAL组,Gal-3、TGF-β、Lcn2水平高于NCAL组,差异有统计学意义（P<0.05）;本组100例KD患儿中,心肌灌注异常者38例（异常组）、心肌灌注正常者62例（正常组）...     

高血压心肌纤维化的发病机制：成纤维细胞在血管紧张素Ⅱ刺激下单核细胞趋化蛋白-1的表达状况

目的：研究成年大鼠心脏成纤维细胞(cardiac fibroblasts，CFs)在血管紧张素Ⅱ刺激下单核细胞趋化蛋白-1(monocyte chemotaxia protein-1，MCP-1)表达情况，探讨高血压合并心脏损害的可能机制，方法：成年大鼠CFs体外培养，在不同浓度血管紧张素Ⅱ不同作用时间刺激下，应用免疫蛋白印迹法和ELISA法分别测定细胞中和培养上清中MCP-1的含量。结果：①在细胞内和培养上清中均有MCP-1表达。②随着血管紧张素Ⅱ、刺激浓度的增加和刺激时间的延长，细胞内和上清中MCP-1的表达量也逐渐增加。在1&;#215;10^-11，1&;#215;10^-9，1&;#215;10^-8，1&;#215;10^-7，1&;#215;10^-6mol／L的血管紧张素Ⅱ作用下，上清中MCP-1的含量分别为(1．60&;#177;0．21)，(3．18&;#177;0．15)．(4．70&;#177;0．22)，(9．18&;#177;0．52)，(8．75&;#177;0．42)μg／L，与对照组(1．13&;#177;0．09)μg／L比较，除1&;#215;10^-11mol／L组外，差异均有显著性意义(t=26．21-39．67．P均&;lt;0．05)。③在1&;#215;10^-7mol／L的血管紧张素Ⅱ作用下，3，6，12和24h MCP-1的表达量分别为(2．13&;#177;0．31)，(3．25&;#177;0．20)．(5．28&;#177;0．50)和(9．18&;#177;0.52)μg／L，与空白对照组(1.13&;#177;0．09)μg／L比较差异均有显著性意义(t=6.93～34．11，P均&;lt;0．05)。结论：成年大鼠CFs的MCP-1的表达对血管紧张素Ⅱ的刺激有浓度和时间依赖性。CFs的MCP-1的表达可能参与高血压时心肌内的炎性反应和心肌纤维化。     

血浆和心肌组织血管紧张素Ⅱ水平对肺动脉高压患者左室心肌细胞凋亡和间质纤维化程度的不同影响

目的:分析血浆和心肌局部组织血管紧张素Ⅱ水平对肺动脉高压患者左室心肌细胞凋亡和间质纤维化程度的不同影响及与肺动脉压力的相关关系。方法:纳入南方医科大学儿科中心和解放军第四○一医院2003-10/2005-08住院期间死亡的先天性心脏病患儿为观察对象,生前均经临床、X射线胸片和多普勒超声心动图确诊是否合并肺动脉高压,按确诊死亡原因分组,先天性心脏病合并肺动脉高压组(n=10),单纯先天性心脏病组(n=4),对照组(n=2意外交通事故死亡行尸检的婴儿)。采用心肌细胞原位末端标记与半定量分析、免疫组织化学检测3组尸体的心肌细胞凋亡和间质纤维化的程度及用放射免疫法和HPLC-RIA法检测心肌和血浆血管紧张素Ⅱ含量。结果:①先天性心脏病合并肺动脉高压组的左室心肌细胞凋亡指数高于先天性心脏病组和正常对照组(25.0±6.0,18.0±4.0,1±0.1,P<0.05~0.01)。先天性心脏病合并肺动脉高压组心肌细胞凋亡小体的数量少于单纯先天性心脏病组。先天性心脏病合并肺动脉高压患儿血浆、心肌血管紧张素Ⅱ水平与心肌细胞凋亡指数均呈显著相关性[(221.0±24.5),(91.0±19.3)μg/L,(25.0±6.0)%;r=0.522,0.4131,P<0.01,0.05]。②单纯先天性心脏病组左室心肌组织Ⅲ型胶原蛋白呈阳性表达,先天性心脏病合并肺动脉高压组左室心肌组织Ⅲ型胶原蛋白表达呈强阳性,两组比较差异有显著性意义(P<0.05)。Ⅲ型胶原蛋白主要在细胞间质表达,呈黄色片状颗粒。先天性心脏病合并肺动脉高压组血浆、心肌血管紧张素Ⅱ水平与心肌Ⅲ型胶原蛋白表达量均呈相关关系[(221.0±24.5)μg/L,(91.0±19.3),0.334±0.04,r=0.422,P<0.05,0.01]。③血浆血管紧张素Ⅱ与肺动脉压无相关关系[(221.0±24.5)μg/L,(58.87±38.39)mmHg(1mmHg=0.133kPa),r=0.22,P>0.05]。结论:心肌组织型血管紧张素Ⅱ在心肌纤维化过程中发挥了重要作用,而血浆血管紧张素Ⅱ对心肌细胞凋亡的作用显的更加重要。     

血管紧张素-(1-7)对压力负荷增高大鼠心肌胶原网络重塑的影响

目的　探讨血管紧张素 ( 17)〔Ang ( 17)〕对压力负荷增高大鼠心肌胶原网络重塑的影响。方法　腹主动脉缩窄术制备压力负荷增高大鼠模型 ,75只 SD大鼠随机分为假手术组、模型组、Ang ( 17)治疗组 ( 2 5 μg· kg- 1· h- 1 ,持续静脉给药 )。各组分别于术后 1周和 4周处死部分大鼠 ,检测左心室质量 /体质量比以及心肌胶原容积分数 ,并采用逆转录聚合酶链反应检测左心室心肌 、 型胶原 m RNA的表达水平。结果　与假手术组比较 ,模型组和 Ang ( 17)治疗组术后 1周 、 型胶原 m RNA表达均明显增高 ,Ang ( 17)治疗组增高的幅度明显低于模型组 ;模型组和 Ang ( 17)治疗组术后 4周的左心室质量 /体质量比、心肌胶原容积分数均高于假手术组 ,但 Ang ( 17)治疗组上述指标低于模型组。结论　给予外源性Ang ( 17)能减轻压力负荷增高所致的心肌胶原网络重塑。     

大鼠颅脑损伤后心肌损害及血浆和心肌血管紧张素的变化

背景：颅脑损伤可以引起一系列的内脏并发症，其中心血管并发症日益引起人们的重视。目的：探讨颅脑损伤所致循环和心脏局部血管紧张素Ⅱ及心脏局部血管紧张素Ⅱ1型受体水平的变化。设计：随机对照动物实验。单位：首都医科大学附属北京天坛医院和首都医科大学基础医学院。材料：实验于2003／2004在首都医科大学中心实验室和北京天坛医院中心实验室进行。健康雌性Wistar大鼠40只，随机分为颅脑损伤组和对照组两组，每组20只。方法：颅脑损伤组用局部重物撞击法建立大鼠颅脑损伤模型，对照组不打击。在撞击即时点后24h取材，每组10只用于血管紧张素Ⅱ及其1型受体检测，另外10只用于心肌病例形态观察。主要观察指标：①用均相竞争放免法测定血浆血管紧张素Ⅱ水平。②采用免疫组织化学方法检测心肌血管紧张素Ⅱ及其1型受体的表达。③采用酶反应速率法测定血清肌酸磷酸激酶同工酶活性。④苏木精-伊红染色，光镜，透射电镜观察大鼠心肌超微结构等病理形态学改变。结果：40只大鼠进入结果分析。①血浆血管紧张素Ⅱ水平：颅脑损伤组明显高于对照组[（965．52&;#177;176．71），（485．03&;#177;86．13）ng／L，P〈0．05]。②血清肌酸磷酸激酶同工酶活性：颅脑损伤组显著高于对照组[（12．77&;#177;4．07），（3．49&;#177;1．55）μkat／L，P〈0．05]。③心肌血管紧张素Ⅱ及其1型受体的表达：颅脑损伤组的阳性反应物面积与灰度值均高于对照组（P〈0．05）。④苏木精-伊红染色颅脑损伤组心肌细胞胞浆强嗜酸性染色。明显的胞质皱缩，肌纤维断裂、减少或消失，可见心肌局灶性水样变性、溶解或坏死。超微结构的病理观察均见心肌病理损害。结论：大鼠颅脑损伤可导致心肌损害的发生，血管紧张素系统变化可能是其因素之一。     

保心合剂对缺血性心肌病心衰患者炎症指标及心肌纤维化指标的影响

目的:观察保心合剂对缺血性心肌病心衰患者炎症指标及心肌纤维化指标的影响.方法:选择符合标准的100例在我院心内科住院的缺血性心肌病心衰患者,随机分为对照组和治疗组,每组各50例,对照组采用常规西医治疗,治疗组在此基础上加用保心合计治疗,2组均治疗12d,观察治疗前后2组患者中医症候积分、炎症及心肌纤维化指标.结果:与对照组比较,治疗组中医症候积分明显降低,炎症指标(IL-1β、TNF-α、IL-6和CRP)及心肌纤维化指标(sST2和Gal-3)较对照组同期明显改善.结论 对于缺血性心肌病心衰患者联合运用保心合剂治疗,能改善缺血性心肌病心衰患者的中医症候积分,能降低其炎症因子IL-1β、TNF-α、IL-6和CRP水平,降低纤维化因子sST2和Gal-3水平.     

细胞因子在腹膜纤维化中的作用

腹膜透析是终未期肾脏病的有效治疗方法之一,长期的连续不卧床腹膜透析患者,腹膜会有大量的细胞外基质沉积和新生血管形成即发生了腹膜纤维化,将导致超滤衰竭.细胞因子在腹膜纤维化中起了重要作用.转化生长因子可引起腹膜间皮细胞向成纤维细胞转分化,间皮细胞的转分化是腹膜纤维化的重要机制;血管内皮生长因子是引起腹膜新生血管形成的重要因子;炎症因子、血管紧张素II在腹膜纤维化中亦起一定作用.     

大鼠颅脑损伤后心肌损害及血浆和心肌血管紧张素的变化

背景颅脑损伤可以引起一系列的内脏并发症,其中心血管并发症日益引起人们的重视.目的探讨颅脑损伤所致循环和心脏局部血管紧张素Ⅱ及心脏局部血管紧张素Ⅱ1型受体水平的变化.设计随机对照动物实验.单位首都医科大学附属北京天坛医院和首都医科大学基础医学院.材料实验于2003/2004在首都医科大学中心实验室和北京天坛医院中心实验室进行.健康雌性Wistar大鼠40只,随机分为颅脑损伤组和对照组两组,每组20只.方法颅脑损伤组用局部重物撞击法建立大鼠颅脑损伤模型,对照组不打击.在撞击即时点后24 h取材,每组10只用于血管紧张素Ⅱ及其1型受体检测,另外10只用于心肌病例形态观察.主要观察指标①用均相竞争放免法测定血浆血管紧张素Ⅱ水平.②采用免疫组织化学方法检测心肌血管紧张素Ⅱ及其1型受体的表达.③采用酶反应速率法测定血清肌酸磷酸激酶同工酶活性.④苏木精-伊红染色,光镜,透射电镜观察大鼠心肌超微结构等病理形态学改变.结果40只大鼠进入结果分析.①血浆血管紧张素Ⅱ水平颅脑损伤组明显高于对照组[(965.52±176.71),(485.03±86.13)ng/L,P＜0.05].②血清肌酸磷酸激酶同工酶活性颅脑损伤组显著高于对照组[(12.77±4.07),(3.49±1.55)μkat/L,P＜0.05].③心肌血管紧张素Ⅱ及其1型受体的表达颅脑损伤组的阳性反应物面积与灰度值均高于对照组(P＜0.05).④苏木精-伊红染色颅脑损伤组心肌细胞胞浆强嗜酸性染色,明显的胞质皱缩,肌纤维断裂、减少或消失,可见心肌局灶性水样变性、溶解或坏死.超微结构的病理观察均见心肌病理损害.结论大鼠颅脑损伤可导致心肌损害的发生,血管紧张素系统变化可能是其因素之一.     

慢性肝病肝纤维化进程的现今认识

肝纤维化是肝脏对各种原因所致损伤的愈合反应,表现为肝内结缔组织增生与沉积。过去曾把肝结缔组织视为一种隋性物质,而纤维化或瘢痕化形成是一被动性静止状态,类似于皮肤创伤后的瘢痕形成。现知肝结缔组织由胶原、非胶原基质蛋白及有关细胞组成,前两者作为细胞外基质(ECM)在支     

Myocardial fibrosis in desmin-related hypertrophic cardiomyopathy

Desmin-related myopathy (DRM) is known to cause different types of cardiomyopathy. Late gadolinium enhancement cardiovascular magnetic resonance (CMR) has been shown to identify fibrosis in ischemic and non-ischemic cardiomyopathies. We present a rare case of desmin-related hypertrophic cardiomyopathy, CMR revealed fibrosis in the lateral wall of the left ventricle. CMR is superior to conventional echocardiography for the detection of myocardial fibrosis in desmin-related cardiomyopathy, which may be useful to detect early cardiac involvement and predict the patient prognosis.     

The prognosis of the outcome of the inflammatory process in chronic bronchitis]

The authors relate the data on the leading part fibrosoformation plays in the disease outcome in patients with certain pulmonary chronic illnesses. The levels of free and bound hydroxyproline and hyaluronidase activity served as diagnostic criteria for processes of fibrosoformation. Based on the data obtained a method of predicting chronic bronchitis (CB) was devised. Thus, the two-fold rise of hyaluronidase activity as compared to normal and the index of fibrosing (the ratio of free to bound hydroxyproline) exceeding 1 suggest an unfavourable course of CB accompanied by the enhancement of fibrosoformation. Meanwhile if hyaluronidase activity increases 2-fold and more and the index of fibrosing is less than 1, the prognosis of inflammatory process may be favourable. Based on the clinical data, the significance of prognosis was proved in 93% of cases.     

A clinical inflammatory syndrome attributable to aerosolized lipid-DNA administration in cystic fibrosis

Immunologic reactivity to lipid-DNA conjugates has traditionally been viewed as less of an issue than with viral vectors. We performed a dose escalation safety trial of aerosolized cystic fibrosis transmembrane conductance regulator (CFTR) cDNA to the lower airways of eight adult cystic fibrosis patients, and monitored expression by RT-PCR. The cDNA was complexed to a cationic lipid amphiphile (GL-67) consisting of a cholesterol anchor linked to a spermine head group. CFTR transgene was detected in three patients at 2-7 days after gene administration. Four of the eight patients developed a pronounced clinical syndrome of fever (maximum of 103.3EF), myalgias, and arthralgia beginning within 6 hr of gene administration. Serum IL-6 but not levels of IL-8, IL-1, TNF-alpha, or IFN-gamma became elevated within 1-3 hr of gene administration. No antibodies to the cationic liposome or plasmid DNA were detected. We found that plasmid DNA by itself elicited minimal proliferation of peripheral blood mononuclear cells taken from study patients, but led to brisk immune cell proliferation when complexed to a cationic lipid. Lipid and DNA were synergistic in causing this response. Cellular proliferation was also seen with eukaryotic DNA, suggesting that at least part of the immunologic response to lipid-DNA conjugates is independent of unmethylated (E. coli-derived) CpG sequences that have previously been associated with innate inflammatory changes in the lung.     

Induced sputum in cystic fibrosis: within-week reproducibility of inflammatory markers

Analysis of induced sputum has provided significant insight into the inflammatory response in chronic respiratory diseases such as asthma. The thick, tenacious nature of cystic fibrosis (CF) sputum presents certain challenges to such evaluation. We describe the development of a methodology to assess CF sputum, and the within-week reproducibility (to limit the possibility of any change in clinical status) of cellular and inflammatory markers. METHODS: Seventeen young adults [9 males, 8 females, mean age 24 (5), median (quartile range) years, percentage of predicted FEV(1) = 64.0 (18.0%)] with CF underwent sputum inductions on the Monday and Thursday of the same week. Patients were pretreated with 400 microg salbutamol and subsequently inhaled 5% saline via a breath enhanced nebulizer. Every 3-min nebulization was interrupted to allow for expectoration of sputum into a polypropylene pot. Sputum samples were dispersed with a solution of dithiothreitol (DTT) and deoxyribonuclease to allow for analysis of total cell count (TCC) and percentage neutrophils (%Neut). Measurement of tumor necrosis factor-alpha (TNF-alpha), interleukin-8 (IL-8), and neutrophil elastase was performed on samples dispersed with DTT alone. RESULTS: There were no significant differences between the measurements taken in the same week. Values for Day 1 versus Day 2 were as follows: TCC 20.8 (6.4) vs. 17.6 (2.5) x 10(6) cells/ml; %Neut: 94.1 (0.0) vs. 95.4 (0.5) %; TNF-alpha 7.5 (26.0) vs. 21.0 (44.0) pg/ml; IL-8 610.0 (422.0) vs. 524.0 (587.0) ng/ml and neutrophil elastase 110.0 (19.75) vs. 49.75 (60.75) microM. High intraclass correlation coefficients (ICC) for TCC, %Neut, TNF-alpha IL-8 and neutrophil elastase were found (ICC = 0.76, 0.82, 0.93, 0.82, 0.74, respectively). CONCLUSIONS: The method developed here for the analysis of CF sputum shows good reproducibility and can be used to evaluate therapeutic interventions in patients with cystic fibrosis.     

Possibilities of bronchoscopy in evaluating the activity of the inflammatory process in chronic bronchitis patients

Interrelationships between the intensity of signs of endobronchitis and indices of the activity of an inflammatory process were studied in bronchoscopic and biochemical investigation of patients with chronic bronchitis. With an increase in the activity of an inflammatory process certain regularities of change in a bronchoscopic picture were noted. The author showed linear relationship and significant correlation between the signs of endobronchitis assessed by a qualitative-quantitative analysis, and biochemical indices of the activity of an inflammatory process. The established relationships raised the potentialities of bronchoscopy in assessment of the activity of an inflammatory process in patients with chronic bronchitis creating the necessary prerequisites for pathogenetically substantiated treatment taking account of a differentiated approach to the intensity of endobronchial signs of disease.