他汀类药物在支气管哮喘治疗中的作用

支气管哮喘是一种气道慢性炎症性疾病.他汀类药物是临床最常用的调脂药物.大量研究显示,他汀类药物具有降脂之外的抑制炎症、抑制平滑肌细胞增生和免疫调节等作用.该文就他汀类药物在支气管哮喘治疗中可能的作用机制研究进展作一综述.     

他汀类药物在支气管哮喘治疗中的作用

支气管哮喘是一种气道慢性炎症性疾病.他汀类药物是临床最常用的调脂药物.大量研究显示,他汀类药物具有降脂之外的抑制炎症、抑制平滑肌细胞增生和免疫调节等作用.该文就他汀类药物在支气管哮喘治疗中可能的作用机制研究进展作一综述.     

他汀类药物非调脂作用及其机制(续9-2)

5 改善心肌重构 他汀类药物可通过下调血管紧张素(ANG)Ⅱ受体-1,抑制ANGⅡ介导的心肌肥厚和纤维化,并能阻断包括下调RHO家族小GTP结合蛋白活性在内、并与心肌肥厚相关的多种细胞内信号通路[9].另外他汀类药物还能减轻心肌间质纤维化.一方面,他汀类药物直接抑制Ⅰ型、Ⅲ型胶原合成及其mRNA的表达;另一方面,他汀类药物通过调节基质金属蛋白酶及其抑制物活性来改善心肌间质的重构.     

他汀类药物的降脂外效应研究进展

大量研究证实他汀类药物除有降低血清胆固醇水平作用外,还有多重心血管保护作用.本文从内皮功能改善、抗炎、抗纤维化及心肌保护作用等方面介绍他汀类的降脂外效应.     

他汀类药物抗乳腺癌作用的研究进展

他汀类药物是一种3-羟基-3-甲戊二酸单酰辅酶A还原酶抑制剂,通过抑制胆固醇生物合成中的这一限速步骤,在心血管事件的一级和二级预防中起重要作用.近年来,国内外多项研究表明,他汀类药物不仅具有降脂作用,而且还对肿瘤细胞具有抑制增殖,促进凋亡,抑制肿瘤新生血管,降低肿瘤细胞转移,增强化疗活性等作用.现就他汀类药物抗乳腺癌的...     

从循征医学看老年心血管病药物治疗进展(下)

三、老年冠状动脉粥样硬化性心脏病(冠心病)的药物治疗 1.他汀类药物:对这类药物的药理研究发现它除了良好的降胆固醇、甘油三酯的作用外,还具有重要的非调脂作用,如抑制炎症、稳定斑块,改善内皮功能,抗血小板聚集、改善血流状态,抑制平滑肌细胞增殖等作用.因而他汀类药物在临床得到广泛的应用.甚至有人认为它所带来的贡献可以与20世纪40年代青霉素所带来的贡献相媲美.因此,他汀类药物成为目前研究的热点和重点.     

辛伐他汀对60例非缺血性心脏病心功能及心律失常的影响

辛伐他汀在血管治疗领域的降脂稳定斑块作用以及改善内皮功能、抑制平滑肌细胞增殖、抑制血小板功能、抑制血管的炎症反应等均得到临床证实[1,2],但对于他汀类药物治疗非缺血性心脏病并发心衰的观察较少,本研究主要观察他汀类药物在非缺血性心脏病并发心力衰竭治疗中对心功能、心律失常以及C反应蛋白(CRP)的影响,从而探讨他汀类药物对非缺血性心脏病的治疗作用.     

他汀类药物在慢性心力衰竭治疗中的影响及研究进展

大量研究显示,他汀类药物还具有降脂之外的抑制炎症作用、抗心室重塑、改善神经体液调节、抗心律失常、改善血管内皮功能、抗氧化等作用.现对他汀类药物治疗心力衰竭的临床依据和可能机制做一综述.     

他汀类药物非降脂作用研究新进展

他汀类药物非降脂作用目前受到越来越多人的注意。它包括改善内皮功能,增加内皮源性一氧化氮(NO)的生物利用度,抗氧化,抗炎,稳定粥样斑块,促进血管再生,抑制免疫反应,抑制心肌肥厚和纤维化,保护肾功能等作用。它在心血管疾病的防治中占有重要地位。其机制目前尚不十分清楚。本文概述他汀类药物非降脂的研究进展。     

他汀类药物在心脑血管病防治中的地位

他汀类药物具有多向性作用,如改善血管内皮功能、抑制平滑肌细胞增殖、抑制血小板聚集、抗炎作用和稳定斑块作用等.常用于心脑血管病一级、二级预防及治疗,本文拟就他汀类药物多向性作用的机制及临床应用综述如下.     

Comparative gene expression profiling in three primary human cell lines after treatment with a novel inhibitor of Rho kinase or atorvastatin

Inhibitors of Rho kinase (ROCK) are a relatively new class of drugs with potential benefits in oncology, neurology, and fibrotic and cardiovascular diseases. ROCK inhibitors modulate many cellular functions, some of which are similar to the pleiotropic effects of statins, suggesting additive or synergistic properties. Studies to date have used compounds that inhibit both isoforms of ROCK, ROCK1 and ROCK2. This study was designed to compare gene expression profiles of atorvastatin with the newly developed ROCK2 inhibitor SLx-2119 in primary cultures of normal human endothelial cells, smooth muscle cells, and fibroblasts. Cells were treated with each compound for 24 h, after which total RNA was isolated and genome-wide gene-expression profiles were obtained with Illumina arrays. Because of the known effect of statins on the actin cytoskeleton and on connective tissue growth factor, a prominent growth factor involved in tissue fibrosis, the effects of SLx-2119 and atorvastatin on the actin cytoskeleton and connective tissue growth factor mRNA were also examined in cultures of smooth muscle cells with a fibrotic phenotype, isolated from biopsies of human intestine with radiation-induced fibrosis. Although SLx-2119 and atorvastatin affected expression of genes belonging to the same biological processes, individual genes were mostly different, consistent with synergistic or additive properties. Both SLx-2119 and atorvastatin reduced connective tissue growth factor mRNA and remodeled the actin cytoskeleton in fibrosis-derived smooth muscle cells, suggesting that both compounds have antifibrotic properties. These results form the basis for further studies to assess the possible therapeutic benefit of combined treatments.     

Use of tacrolimus, a potent antifibrotic agent, in bleomycin-induced lung fibrosis.

Idiopathic pulmonary fibrosis has a poor prognosis and few efficacious treatments. The immunosuppressant cyclosporin A has been shown to inhibit tumour growth factor (TGF)-beta-induced collagen deposition in vitro, and is widely used in Japan as a potent antifibrotic agent. Tacrolimus (FK506) is another attractive immunosuppressant, which may be useful in the treatment of pulmonary fibrosis. The aim of the present study was to elucidate the antifibrotic effect of FK506. The inhibitory effect of FK506 on collagen synthesis in cultured lung fibroblastic cells, TIG-3-20, and its antifibrotic effect on bleomycin (BLM)-induced pulmonary fibrosis in mice was investigated. FK506 inhibited TGF-beta-induced collagen synthesis, and suppressed the expression of TGF-beta type I receptor (TbetaR-I) in TIG-3-20 cells. Consistent with the in vitro findings, FK506 treatment starting on day 6 attenuated BLM-induced pulmonary fibrosis, in part, via reduced TbetaR-I expression. FK506 treatment in the acute BLM injury phase unexpectedly increased pro-inflammatory cytokine levels in bronchoalveolar lavage fluid and enhanced lung injury, resulting in poor survival. In conclusion, the present results suggest that FK506 has a potent antifibrotic effect and may be useful for the treatment of pulmonary fibrosis, although its use in the acute inflammatory phase may exacerbate lung injury.     

Pitavastatin inhibits hepatic steatosis and fibrosis in non‐alcoholic steatohepatitis model rats

Aim: Non‐alcoholic steatohepatitis (NASH) may progress to liver cirrhosis, and NASH patients with liver cirrhosis are at risk of developing hepatocellular carcinoma. Statins, 3‐hydroxy‐3‐methyglutaryl‐coenzyme A reductase inhibitors, are well known to reduce low‐density lipoprotein cholesterol and reduce the incidence of coronary heart disease and other major vascular events by anti‐inflammatory and antifibrotic effects, and antiproliferative properties in colorectal cancers have also been reported. Recently, statins have been reported to improve hepatic steatosis; however, the effect on fibrosis is controversial. Methods: The effects of pitavastatin (one of the strongest statins) were examined using a choline‐deficient L‐amino acid‐defined (CDAA) diet liver fibrosis model. Results: Pitavastatin significantly attenuated increases in serum aspartate aminotransferase, alanine aminotransferase, hepatic steatosis, oxidative stress, pre‐neoplastic lesions (glutathione S‐transferase placental form‐positive lesions), expression of cytokines, such as tumor necrosis factor‐α and transforming growth factor‐β1, and the expression of tissue inhibitor of metalloproteinase‐1, tissue inhibitor of metalloproteinase‐2 and type I procollagen genes followed by attenuating fibrosis of the liver of CDAA‐fed rats. Conclusion: These results indicate that pitavastatin may inhibit steatosis, hepatic fibrosis and carcinogenesis in rat model of NASH.     

牛磺酸对四氯化碳诱导大鼠肝纤维化的抑制作用

目的研究牛磺酸的体内抗肝纤维化作用。方法用四氯化碳（ＣＣｌ４）复制大鼠肝纤维化模型;造模开始或造模６周后给予牛磺酸;实验结束后分别测定肝功能、纤维化指标（透明质酸和层粘连素）、肝羟脯氨酸及Ⅰ、Ⅲ型前胶原ｍＲＮＡ含量,并作肝病理检查。结果牛磺酸可显著减轻ＣＣｌ４肝纤维化程度,能明显降低肝羟脯氨酸和Ⅰ、Ⅲ型前胶原ｍＲＮＡ含量,降低血清透明质酸和层粘连素水平,改善肝功能,组织学检查亦显示具有抗肝纤维化作用。结论牛磺酸在体内具有抗肝纤维化的作用,可望用于肝纤维化的防治。     

Pleiotropic effects of statins in the diseases of the liver

Statins are a class of molecules that inhibit HMG Co A reductase. They are usually prescribed as a lipid lowering medication. However, there is accumulating evidence that statins have multiple secondary effects both related and unrelated to their lipid-lowering effect. This narrative review of the literature aims to provide the reader with information from clinical studies related to the effect of statin and statins' potential use in patients with liver diseases. In patients with advanced liver disease due to any etiology, statins exhibit an antifibrotic effect possibly through the prevention of hepatic sinusoidal microthrombosis. Two randomized controlled trials confirmed that statins decrease hepatic vein pressure gradient in patients with portal hypertension and improve the survival of patients after variceal bleeding. Lower rates of infections were observed in patients with cirrhosis who received statin treatment. Statins decrease the risk of hepatocellular carcinoma(HCC) in patients with advanced liver disease in general but particularly in patients with chronic hepatitis B and C. Statins in patients with chronic hepatitis C likely increase the virological response to the treatment with pegylated interferon and ribavirin and have the potential to decrease the rate of fibrosis. Finally, data from randomized controlled trials also confirmed that the addition of statin prolongs the survival of patients with advanced HCC even more than sorafenib. Statins are a very promising group of drugs especially in patients with liver disease, where therapeutic options can often be limited. Some indications, such as the prevention of re-bleeding from esophageal varices and the palliative treatment of HCC have been proven through randomized controlled trials, while additional indications still need to be confirmed through prospective studies.     

Antifibrotic Therapies: Will We Ever Get There?

Progressive hepatic fibrosis is the final common pathway for most chronic liver injuries, leading to cirrhosis with risk of liver failure and hepatocellular carcinoma. It is now recognized that fibrosis is a dynamic process, and may be reversible prior to the establishment of advanced architectural changes to the liver. The most effective antifibrotic strategy is to cure the underlying disease process before advanced fibrosis has developed. Unfortunately, this is often not possible, and specific antifibrotic therapies are needed. Advances in the understanding of the pathogenesis of liver fibrosis have identified several potential novel therapeutic targets, but unfortunately clinical development has been disappointing. One major limitation has been the often prolonged natural history of fibrosis compared to experimental models, and difficulties in accurate noninvasive fibrosis assessment, thus making clinical trial design difficult. In this review, we highlight the most promising current antifibrotic strategies.     

Impact of angiotensin-converting enzyme inhibitors and statins on survival in idiopathic pulmonary fibrosis

STUDY OBJECTIVES: To assess the clinical relevance of angiotensin-converting enzyme inhibitors (ACEI) and 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitors (statins) in the context of idiopathic pulmonary fibrosis (IPF). BACKGROUND: IPF is a progressive interstitial lung disease for which there is no effective treatment. ACEI and statins have been shown to possess antifibrotic properties in experimental models in vitro and in vivo. DESIGN, SETTING, AND PATIENTS: Retrospective review of the effects of ACEI and statins on survival of 478 patients with IPF seen at Mayo Clinic Rochester from 1994 through 1996. Fifty-two patients (11%) were receiving ACEI, 35 patients (7%) were receiving statins, and 5 patients (1%) patients were receiving both at their initial visit. RESULTS: For subjects receiving ACEI, the median survival from the index visit was 2.2 years, compared to 2.9 years for subjects not receiving ACEI (p = 0.088). The median survival was 2.9 years if patients were receiving statins or not (p = 0.573). There was also no significant difference in survival between patients with IPF receiving either ACEI or statins vs those receiving neither at the index visit (2.5 years vs 3 years, respectively; p = 0.066). After adjusting for age, gender, recommended IPF treatment, smoking status, prior oxygen use, FVC, diffusion capacity for carbon monoxide, coronary artery disease, congestive heart failure, diabetes mellitus, and hypertension, there were no differences in survival between those subjects receiving either ACEI, statins, or both vs neither. CONCLUSIONS: These data do not suggest a beneficial effect of ACEI and/or statins on survival in patients with IPF.     

Fadrozole reverses cardiac fibrosis in spontaneously hypertensive heart failure rats: discordant enantioselectivity versus reduction of plasma aldosterone

Reversal of cardiac fibrosis is a major determinant of the salutary effects of mineralocorticoid receptor antagonists in heart failure. Recently, R-fadrozole was coined as an aldosterone biosynthesis inhibitor, offering an appealing alternative to mineralocorticoid receptor antagonists to block aldosterone action. The present study aimed to evaluate the effects of R- and S-fadrozole on plasma aldosterone and urinary aldosterone excretion rate and to compare their effectiveness vs. the mineralocorticoid receptor antagonist potassium canrenoate to reverse established cardiac fibrosis. Male lean spontaneously hypertensive heart failure (SHHF) rats (40 wk) were treated for 8 wk by sc infusions of low (0.24 mg/kg.d) or high (1.2 mg/kg.d) doses of R- or S-fadrozole or by potassium canrenoate via drinking water (7.5 mg/kg.d). At the high dose, plasma aldosterone levels were decreased similarly by R- and S-fadrozole, whereas urinary aldosterone excretion rate was reduced only by S-fadrozole. In contrast, whereas at the high dose, R-fadrozole effectively reversed preexistent left ventricular interstitial fibrosis by 50% (vs. 42% for canrenoate), S-fadrozole was devoid of an antifibrotic effect. The low doses of the fadrozole enantiomers did not change cardiac fibrosis or plasma aldosterone but similarly reduced urinary aldosterone excretion rate. In conclusion, R-fadrozole may possess considerable therapeutic merit because of its potent antifibrotic actions in the heart. However, the observed discordance between the aldosterone-lowering and antifibrotic effects of the fadrozole enantiomers raises some doubt about the mechanism by which R-fadrozole diminishes cardiac collagen and about the generality of the concept of lowering aldosterone levels to treat the diseased heart.     

Do the pleiotropic effects of statins have a clinical significance?

The effectiveness of statins in the treatment of hypercholesterolaemia and the reduction in cardiovascular risk have now been clearly demonstrated. While their beneficial effects on the reduction of atherosclerosis and its clinical manifestations occur mainly due to the reduction in LDL-cholesterol, some pleiotropic actions which are independent of LDL-cholesterol have frequently been put forward in recent years. In effect, an improvement in endothelial function (increased vasodilatation in particular), an in vitro reduction in smooth muscle cell proliferation, a reduction in thrombosis, promotion of fibrinolysis and positive effects on atheromatous plaque stabilisation have been observed. Elsewhere, some anti-oxidant and anti-inflammatory properties have been attributed to statins. However, many of the described 'pleiotropic' effects are not due to the direct action of statins, but occur with the reduction in LDL-cholesterol. Furthermore, certain in vitro effects only occur at much higher than therapeutic doses. These considerations have therefore caused doubt about the clinical significance of the statins' pleiotropic effects. Finally, analysis of the results of human clinical trials on statins have proved that their effectiveness relies on the reduction in LDL-cholesterol and that the pleiotropic effects do not actually have a clinical implication.     

Digital quantification of fibrosis in liver biopsy sections: description of a new method by Photoshop software

BACKGROUND: The precise quantification of fibrous tissue in liver biopsy sections is extremely important in the classification, diagnosis and grading of chronic liver disease, as well as in evaluating the response to antifibrotic therapy. Because the recently described methods of digital image analysis of fibrosis in liver biopsy sections have major flaws, including the use of out-dated techniques in image processing, inadequate precision and inability to detect and quantify perisinusoidal fibrosis, we developed a new technique in computerized image analysis of liver biopsy sections based on Adobe Photoshop software. METHODS: We prepared an experimental model of liver fibrosis involving treatment of rats with oral CCl4 for 6 weeks. After staining liver sections with Masson's trichrome, a series of computer operations were performed including (i) reconstitution of seamless widefield images from a number of acquired fields of liver sections; (ii) image size and solution adjustment; (iii) color correction; (iv) digital selection of a specified color range representing all fibrous tissue in the image and; (v) extraction and calculation. RESULTS: This technique is fully computerized with no manual interference at any step, and thus could be very reliable for objectively quantifying any pattern of fibrosis in liver biopsy sections and in assessing the response to antifibrotic therapy. It could also be a valuable tool in the precise assessment of antifibrotic therapy to other tissue regardless of the pattern of tissue or fibrosis.