血管紧张素受体拮抗剂对SHR左室肥厚的影响

目的探讨血管紧张素Ⅱ受体（ＡＴＲ）拮抗剂在左室肥厚中的作用。方法自发性高血压大鼠（ＳＨＲ）分别接受ＴＣＶ－１１６（血管紧张素Ⅱ－１受体拮抗剂）、德那脯利（Ｄｅｌａｐｒｉｌ）及ＰＤ１２３３１９（血管紧张素Ⅱ－２受体拮抗剂）治疗３周,ＷＫＹ大鼠分别接受ＴＣＶ－１１６、Ｄｅｌａｐｒｉｌ治疗３周,分别与对照组比较收缩压及左室重量与体重比（ＬＶＷ／ＢＷ）。结果ＳＨＲ实验组：口服ＴＣＶ－１１６和Ｄｅｌａｐｒｉｌ分别使收缩压下降１８．５％和１９．０％,使ＬＶＷ／ＢＷ下降７．６％和８．３％;皮下注射ＰＤ１２３３１９对收缩压及ＬＶＷ／ＢＷ均无影响。ＷＫＹ实验组：口服ＴＣＶ－１１６和Ｄｅｌａｐｒｉｌ分别使收缩压下降１１．８％和１１．１％,对ＬＶＷ／ＢＷ无影响。结论血管紧张素Ⅱ－１型受体拮抗剂ＴＣＶ－１１６能逆转ＳＨＲ左室肥厚;血管紧张素Ⅱ－２型受体拮抗剂ＰＤ１２３３１９对ＳＨＲ左室肥厚无逆转作用。     

加味定喘汤对支气管哮喘模型小鼠的治疗作用研究

目的:探讨中药加味定喘汤对支气管哮喘小鼠的治疗作用及可能的机制。方法:30只BALB/c小鼠随机分为3组:正常对照组(A组)、哮喘模型组(B组)和加味定喘汤治疗组(C组)。A组和B组每只小鼠均予以20ml/kg体重生理盐水胃饲,C组每只小鼠予以20ml/kg体重加味定喘汤(每1ml相当于1g生药)胃饲,每天1次,7d后观察小鼠支气管肺泡灌洗液(BALF)中细胞总数、嗜酸性粒细胞(Eos)百分比及IL-4和IFN-γ含量的变化。结果:B组与A组比较,BALF中细胞总数、Eos百分比明显增多(P<0.05),IL-4含量明显升高(P<0.01),IFN-γ含量明显降低(P<0.05);C组与B组比较,细胞总数、Eos百分比明显降低(P<0.05),IL-4的含量明显降低(P<0.01),IFN-γ表达升高(P<0.05)。结论:加味定喘汤能降低支气管哮喘小鼠BALF细胞总数、Eos百分比和IL-4的含量,提高IFN-γ的分泌,对支气管哮喘有治疗作用。     

TOLL样受体4对哮喘气道平滑肌细胞分泌IL-5、IL-8的影响

目的探讨TOLL样受体4（TLR4）在哮喘气道炎症反应中的作用及机制。方法 建立哮喘大鼠模型,分离、培养其气道平滑肌细胞（ASMCs）,传至6代后随机分为转染组和对照组,转染组应用小分子RNA干扰技术、脂质体转染法进行小干扰RNA（siRNA）-TLR4转染,对照组为空白对照。培养24h后应用ELISA法检测两组细胞培养上清液中IL-5、IL-8水平,应用RT-PCR和Western-blot法检测细胞中TLR4 mRNA和蛋白表达水平。结果转染组IL-5、IL-8水平及TLR4 mRNA、蛋白表达水平均显著低于对照组（P均〈0.01）。结论TLR4可能通过促进ASMCs合成分泌IL-5、IL-8而加重哮喘气道炎症反应,此为临床靶向治疗提供了理论依据。     

联合应用IL-4突变体及抗IL-25抗体对哮喘小鼠炎性细胞及细胞因子水平的影响

目的探讨联合应用IL-4突变体及抗IL-25抗体对哮喘小鼠炎性细胞及细胞因子水平的影响。方法50只BALB/c小鼠随机分为对照组、哮喘组、IL-4突变体治疗组、抗IL-25抗体治疗组、联合IL-4突变体及抗IL-25抗体治疗组(简称联合治疗组)。哮喘组和治疗组用鸡卵蛋白(OVA)和氢氧化铝致敏,用OVA激发,建立小鼠哮喘模型,对照组用生理盐水代替,其中IL-4突变体治疗组、抗IL-25抗体治疗组及联合治疗组分别于诱发前30分钟给予腹腔注射相关抗体蛋白,对照组及哮喘组用生理盐水代替。细胞计数板测外周血炎性血细胞,ELISA双抗体夹心法测定各组血清细胞因子水平变化。结果与对照组比较,哮喘组炎性细胞数及IL-4、IL-25、IgE水平明显升高(P<0.05);联合治疗组可有效降低炎性细胞计数及IL-4、IL-25、IgE水平,与哮喘组比较差异有统计学意义(P<0.05);与单独治疗组相比,联合治疗组效果更明显(P<0.05)。结论联合应用IL-4突变体及抗IL-25抗体对支气管哮喘小鼠外周血炎性细胞有抑制作用,且可以降低IL-4、IL-25、IgE细胞因子水平,为治疗和缓解支气管哮喘提供一定的帮助。     

组胺H4受体在变态反应性炎症中的作用

组胺是变态反应性炎症的核心介质，组胺H1受体一直被认为是介导组胺引起变态反应性炎症的唯一介质。近年来研究发现组胺H4受体（histamine receptor，H4R）主要表达于免疫器官及免疫纽胞上，广泛参与变态反应性炎症的过程，并在其中起着重要作用。组胺H4受体的特异性拮抗剂与其有着极高的亲和力，并能有效发挥抗炎及免疫调节作用，可能成为一种新型的治疗变态反应性疾病的有效手段。     

Acute Effect of Inhaled Budesonide on Bronchial Inflammation in Asthmatic Rats

The aim of this study was to determine the level of asthma control and the concordance between physicians' and patients' opinions and the real patients' situation. A total of 777 subjects (55% female) with asthma were recruited. The study comprised a 4-week follow-up period, during which subjects completed a diary recording peak expiratory flow (PEF), symptoms, and use of rescue medication. At the end, both physicians and patients rated asthma control status. The level of control was evaluated using a composite measure. Agreement among subjective assessments of asthma control by patients and physicians and objective evaluation with the composite measure was assessed through kappa scores. A total of 518 (67%) patients had “not well-controlled asthma,” being the remaining “totally controlled” (8%) or “well-controlled” (25%). “Not well-controlled asthma” was more frequent in smokers (82%) than in ex-smokers (70%) or in non-smokers (62%; p = 0.0002). Kappa scores between patients' and physicians' opinions and the real patients' status were 0.02 (95% CI, 0.01–0.05) and 0.07 (95% CI, 0.03–0.09), respectively. In conclusion, current level of asthma control is suboptimal for a majority (67%) of patients in Spain. Besides, asthma control is worse in smokers. Neither patients' nor physicians' opinions agree with patients' real situation. Both patients and physicians accept as normal a suboptimal status of their disease.     

Cardioprotective Effect of Angiotensin n Receptor Antagonist on Perfused Ischemic Reperfusion Injury of Whole Isolated Rat Hearts

Objectives Investigated the cardioprotective and mechanisms of losartan on whole isolated ischemic reperfused rat heart. Methods Langendorff perfused systems was used to investigate losartan effect on whole isolated rat hearts in CPK, LDH, MDA, SOD, ang II and arrhythmia. Results Losartan decreased incidence of arrhythmia, improved atrial ventricular block recovery in reperfu-sion period, during ischemic period, CPK and LDH in I/R group increased significantly compared with control group, 51. 33±27. 02 vs 22. 42 ± 13. 33, 31. 80 ±4.56 vs 22. 28 ± 15. 96, respectively, but greatly decreased in losartan group compared with I/R group, 23. 90±21.74 vs 51. 33 ±27. 02 and 11. 50 ±13. 20 vs 31. 80 ±4. 56, respectively. During reperfusion period CPK, LDH increased significantly in I/R group compared with control group, 49. 11 ± 20. 63 vs 12. 14 ±5.92 and 28. 70±4. 69 vs 23. 10±21. 38, respectively, but decreased greatly in losartan group compared with I/R group, 39. 40 ± 9. 60 vs 49. 11 ± 20.63 an     

Soluble CD23 and Interleukin-1 Receptor Antagonist in Human Asthmatics Following Antigen Challenge

Two postulated intrinsic anti-inflammatory mechanisms in asthma include the low affinity IgE receptor, or CD23, and interleukin 1 receptor antagonist (IL-1ra). We investigated the role these mediators play in the asthmatic response by measuring local levels in human asthmatics before and after segmental allergen challenge and examined the effect of inhaled corticosteroids on soluble CD23 and IL-1ra levels. Ten subjects underwent bronchoscopy at baseline and 24 hours after antigen challenge. Prior to challenge and every 12 hours afterward subjects received beclomethasone 252 µg or placebo. Fluid was analyzed for sCD23 and IL-1ra using ELISA immunoassays. Eosinophil percentages significantly increased at 24 hours following antigen challenge. sCD23 levels were generally undetectable at baseline and increased significantly following antigen challenge. IL-1ra levels increased 28-fold in the late-phase response. Beclomethasone significantly reduced the late-phase eosinophil percentage at 24 hours compared with placebo but did not attenuate late-phase sCD23 or IL-1ra levels. Our data showed a significant rise in the levels of two mediators thought to play an important role in the attenuation of the asthmatic response. The finding that steroid treatment did not enhance these levels suggests that this may be an independent approach to asthma therapy that should be investigated.     

Protective effect of recombinant human IL-1Ra on CCl4-induced acute liver injury in mice

AIM: To evaluate the effects of positive regulation of recombinant human interleukin 1 receptor antagonist (rhIL-1Ra) on hepatic tissue recovery in acute liver injury in mice induced by carbon tetrachloride (CCl 4 ). METHODS: Acute liver damage was induced by injecting 8-wk-old mice with CCl 4 1 mL/kg (1:3 dilution in corn oil) intraperitoneally (ip). Survival after liver failure was assessed by injecting 8-wk-old mice with a lethal dose of CCl 4 2.6 mL/kg (1:1 dilution in corn oil) ip. Mice were subcutaneo...     

Leukotriene Receptor Antagonists: A Good Choice in the Treatment of Premenstrual Asthma?

The aim of this study was to investigate the effects of leukotriene receptor antagonists (LTRAs) on the premenstrual exacerbation of asthma (PMA). Twenty-four female patients with mild asthma were enrolled in the study. Patients were followed for three menstrual cycles and separated into two groups based on whether they exibit premenstrual worsening of asthma symptoms (n = 11) or not (n = 13). During the first month all were treated with only inhaled steroids (IS) (run-in period); during the second month they received IS plus placebo; and during the third month they were given IS plus montelukast. Furthermore, they were advised to use beta ₂ -agonists as needed. Peak expiratory flow rate (PEFR) and symptom scores were recorded during the 3 months. Pulmonary function tests (PFT) and the levels of oestrogen, progesterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were measured a week before the begining of the menstrual period. At the end of the 3-month period, it was observed that following therapy with montelukast, the patients with PMA showed significant improvement in PEFR variability and symptom scores when compared with the placebo group. Baseline FSH levels were higher, but FSH and other hormone levels and PFTs did not change in these groups. However, in the group without PMA there was no difference between the montelukast or placebo groups in PEFR variability, symptom scores, PFTs, and hormone levels. Based on the data in hand, it could be stated that LTRAs have ensured the control of symptoms and improved PEFR variability in patients with PMA by supressing inflammation. We are of the view that LTRAs would be a right choice in the treatment of patients with PMA.     

Clinical Implication of Protein Levels of IL-5 in Induced Sputum in Asthmatic Patients

To determine whether protein levels of interleukin-5 (IL-5) in induced sputum reflect the degree of eosinophilic inflammation, we evaluated the role of IL-5 on clinical characteristics in stable asthmatic patients. IL-5 level, differential eosinophil count, and level of eosinophil cationic protein (ECP) in induced sputum were all significantly higher for asthmatics than for normal controls. Both eosinophil counts and ECP levels in induced sputum were inversely correlated with the degree of airflow limitation (FEV₁/FVC). In addition, patients with measurable IL-5 in sputum had significantly more eosinophils, higher levels of ECP in sputum, and lower FEV₁ (percent predicted) than did patients with levels of IL-5 beneath the limit of detection. However, we found no significant difference in IL-5 levels between atopic and nonatopic asthmatics. IL-5 level in induced sputum is a good indicator of eosinophilic inflammation in atopic and nonatopic asthmatic patients.     

Angiotensin II Type 1 Receptor Antagonist Suppress Angiogenesis and Growth of Gastric Cancer Xenografts

Angiotensin II (Ang II) has been reported to promote tumor progression, tumor growth and angiogenesis in many cancers. We previously observed that angiotensin II type1 receptors (AT1R) were upregulated in human gastric cancer and may be involved in the progression of gastric cancer. We studied the effects of AT1R antagonist on angiogenesis and growth in gastric cancer xenografts to observe the mechanism action of AT1R in the gastric cancer. The results showed that the growth of gastric cancer cells was significantly suppressed by treatment with AT1R antagonist. In vivo, TCV-116, at doses of both 2 and 5 mg/kg/day, significantly suppressed tumor growth in mice (47.3 and 70.2%). Microvessel density was significantly decreased by TCV-116 (3.4 ± 0.9 and 2.8 ± 0.5 per field) compared with the control group (12.9 ± 1.1 per field), and VEGF expression was significantly suppressed by AT1R antagonist. These results demonstrate that AT1R plays an important role in the progression of gastric cancer. Suppression tumor angiogenesis could be one of the mechanisms by which AT1R antagonist suppresses the growth of gastric cancer. These findings also provide a theoretical basis for the future clinical application of AT1R antagonist against gastric cancer.     

精氨酸加压素受体拮抗剂在慢性心力衰竭伴发低钠血症应用进展

慢性心力衰竭是许多心血管疾病终末状态的表现,而低钠血症是慢性心力衰竭中最常见的电解质紊乱。大量循证医学证据表明低钠血症是慢性心力衰竭患者病死率及再次住院率的独立预测因子,而传统的治疗低钠血症的方法在慢性心力衰竭中应用效果不佳且不良反应较多。作为新一代的利尿剂,研究表明精氨酸加压素受体拮抗剂在纠正慢性心力衰竭患者的低钠血症中具有积极作用,现将对此进行综述。     

Association between the IL-4 promoter polymorphisms and asthma or severity of hyperresponsiveness in Taiwanese

BACKGROUND AND OBJECTIVES: Recent family-based studies have revealed a linkage between human chromosome 5q31 and asthma, elevated serum IgE levels and airway hyperresponsiveness (AHR). Among the candidate genes in this region is the gene encoding IL-4. This gene could be a candidate gene for asthma. The aim of this prospective case-control study was to assess the frequency of polymorphisms in the IL-4 gene promoter among asthmatic patients from Taiwan. METHODS: The study consisted of 167 patients with asthma and 111 healthy subjects. PCR amplification followed by Bsm F1 restriction digestion were used to assign genotypes at the IL-4 promoter C-589T locus. Pulmonary function tests, methacholine challenge tests, total IgE, specific IgE antibodies against common inhalant allergens and total eosinophil counts were assessed in asthmatic patients. RESULTS: The T allele frequency for the C-589T IL-4 gene promoter in asthma patients was higher than for normal subjects (P < 0.0001). The frequency discrepancy was found to be even higher for asthmatic patients with severe AHR (P < 0.05). There were no significant differences for the T allele frequency among asthmatic patients with the various other phenotypes such as high versus normal total eosinophil, high versus normal total IgE and high versus normal levels of specific IgE against mite, cockroach or cat dander, or dog dander. CONCLUSIONS: Polymorphism in the promoter of the IL-4 gene is associated with asthma and is a disease modifier in terms of the severity of AHR.     

血管紧张素Ⅱ受体拮抗剂在心房颤动防治中的研究进展

心房颤动是临床上最常见的心律失常之一,抗心律失常药物因效果不佳且不良反应多,使其在心房颤动的防治中应用有限。血管紧张素Ⅱ通过促进心房纤维化,缩短心房有效不应期,延长房室传导,诱导细胞内Ca^2＋超负荷及炎症反应等,促进心房的电重构及组织重构,从而在心房颤动的发生和维持中起积极作用。越来越多的研究表明血管紧张素Ⅱ受体拮抗剂在心房颤动的防治中具有广泛作用。     

CXCR4 Receptor Antagonist Blocks Cardiac Myocyte P38 MAP Kinase Phosphorylation by HIV gp120

The prognosis for patients with human immunodeficiency virus (HIV) infection has improved remarkably as a result of effective antiretroviral therapy. This has resulted in an increased awareness of cardiac complications from HIV infection, including cardiomyopathy and overt heart failure. Mechanisms responsible for HIV cardiomyopathy and heart failure are unknown, but may include direct effects of HIV proteins on the heart. We have previously reported that the HIV envelope glycoprotein, gp120, has a p38 MAP kinase-dependent negative inotropic effect on adult rat ventricular myocytes (ARVM). This signaling pathway presumably results from the binding of gp120 to a specific receptor on the surface of cardiac myocytes. HIV gp120 has been shown to bind to CD4, CXCR4, and CCR5 receptors on lymphocytes and macrophages. Accordingly, we sought to determine if HIV gp120 regulated its negative inotropic effect through activation of one of these binding sites on cardiac myocytes. AMD3100, a highly selective CXCR4 receptor antagonist, reversed HIV gp120-induced negative inotropic effect on ARVM. AMD3100 also blocked HIV gp120 phosphorylation of both p38 MAP kinase and Troponin I. The binding of gp120 to the CXCR4 receptor on ARVM was confirmed by co-immunoprecipitation. We conclude that the negative inotropic effect of HIV gp120 is mediated by a novel signaling pathway that begins with binding to a cardiac myocyte CXCR4 receptor, followed by phosphorylation of both p38 MAP kinase and Troponin I.     

Different Doses of Lipopolysaccharides Regulate the Lung Inflammation of Asthmatic Mice via TLR4 Pathway in Alveolar Macrophages

Allergic asthma is a complicated genetic disorder caused by interaction of the acquired and innate immune responses. Acquired immune responses to protein antigens could induce type 2 T lymphocyte-driven responses and result in atopic asthma. Recent studies demonstrated that endotoxin, LPS and air pollution-induced innate immunity induce asthma through Toll-like receptors (TLR). However, the definite mechanism of LPS-induced asthma is still not known. Here, we investigated the effects of different doses of LPS in a mouse model of allergic asthma to define the molecular mechanism of LPS-induced asthma. We found that low doses of LPS in OVA induced significant inflammatory infiltration in lung tissue of asthmatic mice. Histologic studies demonstrated that lungs of these asthmatic mice were characterized by the recruitment of both eosinophils and neutrophils, increased airway mucus secretion and the elevated levels of Th2 cytokines. A high dose of LPS in OVA can induce a Th1 associated response, histologically characterized by neutrophil recruitment, the absence of airway mucus secretion and an increase of IFN-γ production. Regardless of high or low dose of LPS, TLR4 in alveolar macrophages (AM) was up-regulated in lungs of asthmatic mice. Our data demonstrated that the dose of LPS exposure determines the type of inflammatory response and a low dose of LPS together with OVA augments the antigen-induced lung inflammation in asthma. This study demonstrates that the TLR4 signaling pathway plays a vital role in the development of asthma and indicates the tight connection between endotoxin exposure and asthma prevalence in the clinic.     

Ramatroban (BAY u 3405): A Novel Dual Antagonist of TXA2 Receptor and CRTh2, a Newly Identified Prostaglandin D2 Receptor

It is known that thromboxane A₂ (TXA₂) contributes to various diseases such as bronchial asthma, ischemic heart disease, cerebrovascular disorders and allergic rhinitis. A number of TXA₂ synthase inhibitors and TXA₂ receptor (TP receptor) antagonists have been developed to treat these diseases. Ramatroban (BAY u 3405) was developed as a potent TP receptor antagonist with excellent efficacy against allergic rhinitis in many animal models and patients. Recent studies also revealed that ramatroban can block the newly identified PGD₂ receptor, chemoattractant receptor‐homologous molecule expressed on Th2 cells (CRTh2). PGD₂ induces migration and degranulation of eosinophils through CRTh2 and contributes to late‐phase inflammation and cell damage. Accordingly, it was considered that ramatroban suppresses the late‐phase inflammation via TP receptor and CRTh2 blockade. In terms of the efficacy on vascular systems, it was revealed that ramatroban can suppress the expression of monocyte chemoattractant protein‐1 (MCP‐1) and adhesion molecules in endothelial cells and prevent exacerbation of inflammation by blocking these responses. According to our recent studies in hypercholesterolemic rabbits ramatroban prevents macrophage infiltration through MCP‐1 downregulation and neointimal formation after balloon injury and attenuates vascular response to acetylcholine. Therefore, ramatroban may be beneficial in the treatment of atherosclerosis.     

Effect of Suplatast Tosilate on Airway Hyperresponsiveness and Inflammation in Asthma Patients

Because eosinophilic airway inflammation is a characteristic of bronchial asthma, the treatment of such inflammation is important in the management of this disease. Suplatast tosilate is a novel anti-asthma drug that suppresses eosinophil proliferation and infiltration through selective inhibition of Th2 cytokine synthesis.

We investigated the effect of oral suplatast tosilate therapy in patients with mild and moderate asthma.

Twenty-eight asthma patients were randomized into two groups with or without suplatast tosilate treatment (100 mg t.i.d. for 28 days). We examined the blood eosinophil counts, eosinophilic cationic protein level, sputum eosinophil count, exhaled nitric oxide level, and airway responsiveness before and after treatment.

In patients treated with suplatast tosilate, the eosinophil count in the blood and sputum was significantly decreased after treatment, while there was no such change in the patients without suplatast treatment. The exhaled nitric oxide level and airway responsiveness (measured using an Astograph) were also decreased after treatment with suplatast tosilate, while there were no significant changes in patients without suplatast tosilate.

These results strongly suggest that oral administration of suplatast tosilate suppresses airway hyperresponsiveness in asthma patients by reducing eosinophilic inflammation in the airways.     

Effect of Suplatast Tosilate on Airway Hyperresponsiveness and Inflammation in Asthma Patients

Because eosinophilic airway inflammation is a characteristic of bronchial asthma, the treatment of such inflammation is important in the management of this disease. Suplatast tosilate is a novel anti-asthma drug that suppresses eosinophil proliferation and infiltration through selective inhibition of Th2 cytokine synthesis.

We investigated the effect of oral suplatast tosilate therapy in patients with mild and moderate asthma.

Twenty-eight asthma patients were randomized into two groups with or without suplatast tosilate treatment (100 mg t.i.d. for 28 days). We examined the blood eosinophil counts, eosinophilic cationic protein level, sputum eosinophil count, exhaled nitric oxide level, and airway responsiveness before and after treatment.

In patients treated with suplatast tosilate, the eosinophil count in the blood and sputum was significantly decreased after treatment, while there was no such change in the patients without suplatast treatment. The exhaled nitric oxide level and airway responsiveness (measured using an Astograph) were also decreased after treatment with suplatast tosilate, while there were no significant changes in patients without suplatast tosilate.

These results strongly suggest that oral administration of suplatast tosilate suppresses airway hyperresponsiveness in asthma patients by reducing eosinophilic inflammation in the airways.