抑制肾素-血管紧张素系统治疗降低2型糖尿病发病率的作用机制

激活的肾素-血管紧张素系统(RAS)通过改变血流动力学、增加细胞纤维化和凋亡、调节多种基冈表达、加重炎症反应及氧化应激,使胰岛形态和功能受损,并致胰岛素抵抗甚至2型糖尿病.血管紧张素转化酶抑制剂(ACEI)和血管紧张素Ⅱ受体阻断剂(ARB)可改善胰岛β细胞功能和胰岛素抵抗.本文简述抑制RAS治疗降低2型糖尿病发病率的作...     

mTOR信号通路在特发性肺纤维化中的作用研究进展

特发性肺纤维化(IPF)是一种病因不明的纤维化性间充质性肺疾病,多发于中老年人,且死亡率高。哺乳动物西罗莫司(雷帕霉素)靶点蛋白(mTOR)信号通路在机体生长、代谢和存活方面起着核心调控作用。在IPF疾病进程中,mTOR信号通过调控多种细胞功能缓解肺纤维化。抑制mTOR信号可诱导肺泡上皮自噬,抑制上皮细胞损伤、凋亡和炎症反应以保护上皮细胞;同时抑制成纤维细胞增殖和活化,促进成纤维细胞凋亡,抑制胶原合成和分泌;抑制mTOR信号还可抑制上皮间充质转化和肺部纤维化因子的释放,抑制纤维化进程。以mTOR为靶点治疗IPF在临床上也具有一定可行性,目前以mTOR为靶点的临床在研药物有西罗莫司、奥米帕西(omipalisib)和HEC-68498。本文综述mTOR信号通路在IPF中的研究进展,为进一步研究mTOR在肺纤维化发病机制和治疗中的作用提供支持。     

支气管肺泡灌洗液中的炎症细胞和细胞因子与肺纤维化

肺纤维化是以慢性进行性弥漫性肺间质纤维化为特点的间质性肺疾病。大量的临床与实验研究证实,在肺纤维化的形成过程中,支气管肺泡灌洗液（BALF）中的炎症细胞、细胞因子、蛋白和酶异常增多。这些炎症细胞、细胞因子和肺组织细胞之间的相互作用,在肺纤维化的形成过程中具有重要作用。     

血管紧张素Ⅱ与肺纤维化

肾素一血管紧张素系统(RAS)目前被认为是存在于心、肾、脑和肺等组织局部的内分泌系统之一，其中血管紧张素Ⅱ(AngⅡ)为该系统的主要效应分子。近年来研究发现AngⅡ不仅参与心肌重塑、肾硬化等发生发展过程，而且可能通过刺激细胞增殖、趋化炎性细胞等作用，参与肺纤维化的发生发展过程，且血管紧张素Ⅱ与肺纤维化的关系已引起广泛关注，本文将其最近的相关研究进展作一综述。     

三甲胺-N-氧化物协同RAS诱导动脉粥样硬化发展机制研究

目的 探究三甲胺-N-氧化物(TMAO)与肾素-血管紧张素系统(RAS)在人脐静脉内皮细胞(HUVECs)炎症中的关系及作用机制。方法 采用分子克隆技术，构建血管紧张素Ⅱ(AngⅡ)过表达和敲减的HUVECs; TMAO干预上述HUVECs后，检测细胞中炎症因子及细胞增殖、迁移、血管形成能力，并分析细胞中RAS重要组分的表达水平。结果 成功构建了AngⅡ过表达和敲减的HUVECs; AngⅡ过表达促进TMAO调节HUVECs炎症，抑制HUVECs增殖，抑制HUVECs迁移能力，抑制HUVECs血管形成，促进细胞中RAS组分AGT、ACE、AngⅡ、ATR的表达；敲减AngⅡ抑制TMAO调节HUVECs炎症，促进HUVECs增殖，促进HUVECs迁移能力，促进HUVECs细胞的血管形成，抑制细胞中RAS组分AGT、ACE、AngⅡ、ATR的表达。结论 TMAO能够协同RAS诱导HUVECs炎症。     

地塞米松对肺纤维化大鼠肺单核细胞趋化蛋白-1基因表达的影响

目的　研究地塞米松 (Dxs)对肺纤维化大鼠肺单核细胞趋化蛋白 1(MCP 1)mRNA表达的影响 ,阐明糖皮质激素治疗肺纤维化疾病的分子机制。方法　气管内滴注博莱霉素致大鼠肺纤维化模型 ,不同浓度的地塞米松处理后 ,观察肺组织的病理学变化和计数 5× 5mm高倍视野内炎症细胞数目 ;RT PCR方法检测肺组织MCP 1mRNA表达水平。结果　地塞米松减少了肺组织炎症细胞的聚集 ,延缓了肺纤维化的形成过程 ,并抑制了MCP 1mRNA的表达 ,呈现一定的剂量依赖效应趋势。结论　地塞米松治疗肺纤维化疾病的分子机制与抑制肺MCP 1基因表达有关     

肺泡灌洗液中的炎症细胞、细胞因子与肺纤维化

肺纤维化是以慢性进行性弥漫性肺间质纤维化为特点的间质性肺疾病.大量的临床与实验研究证实,在肺纤维化的形成过程中,支气管肺泡灌洗液（BALF）中的炎症细胞、细胞因子、蛋白和酶异常增多,它们与肺组织细胞之间的相互作用,在肺纤维化的形成过程中具有重要作用.     

特发性肺纤维化的炎症机制和新型分子靶标

目的研究肺泡巨噬细胞参与调控特发性肺纤维化的作用特点及关键药物作用靶标。方法在Akt2和PKC-δ基因敲除小鼠上,采用博来霉素诱导的特发性肺纤维化模型,比较敲除小鼠和野生型小鼠肺纤维化和肺部炎症变化情况,检测肺部炎症因子产生和炎性细胞浸润。利用巨噬细胞过继转移和细胞因子回复实验,考察巨噬细胞调控特发性肺纤维化的作用。体外分离小鼠骨髓来源巨噬细胞,比较巨噬细胞极化情况和信号通路变化。结果与野生型小鼠相比,PKC-δ基因敲除小鼠肺纤维化和炎症反应增强,与此相反,Akt2基因敲除小鼠肺纤维化和炎症反应减弱。Akt2和PKC-δ基因从正负2个方向调控巨噬细胞极化,进而影响肺部炎症微环境变化,调控肺纤维化进程。结论在特发性肺纤维化的炎性环境中,Akt2和PKC-δ基因从正反2条信号调控肺泡巨噬细胞的极化,通过影响肺部炎症微环境调节纤维化进程。提示PKC-δ和Akt2基因是治疗特发性肺纤维化的潜在药物作用靶标。     

抗肺纤维化药物的研究进展

肺间质纤维化的形成中有炎症免疫反应参与,糖皮质激素和免疫抑制药是传统治疗肺纤维化的药物. 近年来,新型的抗肺纤维化药物一直是药学研究的重要课题,也取得很大进展. 该文从细胞因子相关药物、抗氧化剂、基质金属蛋白酶抑制药、成纤维化细胞抑制剂、花生四烯酸代谢调节剂、中药提取物等方面进行论述新型抗肺纤维化药物的研究进展.     

二甲双胍干预肺纤维化发病机制的研究进展

肺纤维化是一种慢性、进行性和不可逆的呼吸系统疾病，其特征是细胞外基质过度沉积导致炎症和广泛的肺重塑。目前尚无有效的治疗方法。多项研究表明二甲双胍是一种具有抗纤维化潜力的经典抗血糖药物。但目前关于二甲双胍发挥抗纤维化作用的具体机制尚未达成共识，本文就近几年来二甲双胍在肺纤维化领域的研究进展进行综述，主要从IGF-1/IGF-1R/PI3K信号、AMPK/mTOR信号、TGF-β/Smad信号通路以及干预肌成纤维细胞增殖和凋亡、改善氧化应激、抑制上皮间质转化及转谷氨酰胺酶2多种途径展开讨论，以期未来能够更深入和全面地理解二甲双胍抗纤维化机制与临床应用范围，为肺纤维化治疗提供新的思路。     

Attenuation of bleomycin-induced pulmonary fibrosis by intratracheal administration of antisense oligonucleotides against angiotensinogen mRNA

Apoptosis of alveolar epithelial cells (AECs) is believed to be critical for the development of bleomycin (BLEO)-induced pulmonary fibrosis. Previous studies showed that apoptosis of alveolar epithelial cells in response to BLEO could be abrogated by antisense oligonucleotides against angiotensinogen (AGT) mRNA and requires angiotensin II (ANG II) synthesis de novo [17]. In this study we hypothesized that blockade of local pulmonary ANG II synthesis by intratracheal (I.T.) administration of antisense oligonucleotides against AGT mRNA might attenuate BLEO-induced apoptosis of AECs and prevent pulmonary fibrosis. In a BLEO-induced rat model of lung fibrosis, endogenous lung AGT was upregulated in vivo as early as 3 hours after BLEO instillation, as detected by RT-PCR, in situ hybridization and immunohistochemistry. AGT mRNA and angiotensin peptides were localized in type II alveolar epithelial cells and also colocalized with alpha-smooth muscle actin (alpha-SMA), a marker of myofibroblasts. Tagged antisense administered I.T. was specifically accumulated by the lung relative to liver and kidney, and localized primarily in the epithelium of airways and cells within alveolar walls. The intratracheal AGT antisense reduced BLEO-induced pulmonary fibrosis measured by lung hydroxyproline assay, decreased lung AGT and active caspase-3 proteins, and reduced the number of apoptotic epithelial cells but had no effect on the serum ANG II concentration. These data are consistent with the hypothesis that lung-derived AGT and local pulmonary ANG II are required for BLEO-induced pulmonary fibrosis, and suggest the possibility of antisense-based manipulation of the local angiotensin system as a potential treatment of fibrotic lung diseases.     

lncRNA NEAT1通过靶向抑制miR-29a促进低氧低糖诱导的肺纤维化进程的机制研究

目的 探究lncRNA NEAT1通过负调控miR-29a促进低氧低糖诱导的肺纤维化进程的机制.方法 收集健康者和缺血再灌注引起急性肺损伤患者的血清样本,通过qRT-PCR检测血清样本中NEAT1与miR-29a的表达.构建肺纤维化细胞模型和动物模型,进行离体和在体的RNA干扰,通过显微镜观察细胞的形态学改变,Hoec...     

Apoptosis as a therapeutic target for the treatment of lung disease

It has been speculated that the destruction of lung tissue, associated with several acute and chronic diseases, is in part mediated through apoptosis or programmed cell death. Thus, it has been shown that both increased endothelial/epithelial cell apoptosis and decreased cell death of inflammatory cells are associated with acute lung injury/acute respiratory distress syndrome, chronic obstructive pulmonary disease, asthma and pulmonary fibrosis. In the light of these observations, it might be possible to use apoptosis modulation as a novel therapeutic approach to the treatment of lung disease.     

灯盏花素对实验性肺纤维化大鼠的干预作用

目的探讨灯盏花素对博莱霉素致肺纤维化大鼠肺组织细胞凋亡、Fas/FasL表达以及氧自由基的影响。方法48只大鼠随机分为对照组(16只)、模型组(16只)以及灯盏花素组(16只),气管内注入博莱霉素复制大鼠肺纤维化模型,次日灯盏花素组每日腹腔内注射灯盏花素注射液10mg.kg-1,于d7及d28每组分别处死8只大鼠,运用流式细胞仪测定肺纤维化大鼠肺组织细胞凋亡率、Fas/FasL表达,用TAB法测定肺组织匀浆丙二醛含量以及肺组织匀浆羟脯氨酸含量。结果炎症期和纤维化期大鼠肺组织细胞凋亡率增加,Fas/FasL表达增多,丙二醛及羟脯氨酸含量增高(P<0.01),而灯盏花素能明显降低肺组织的凋亡率,降低丙二醛及羟脯氨酸含量,下调Fas/Fasl的阳性表达。结论灯盏花素能减慢肺间质纤维化的进程,对肺间质纤维化有一定的保护作用。     

The pulmonary renin-angiotensin system

The circulating renin-angiotensin system (RAS) has a well-described role in circulatory homeostasis. Recently, local tissue-based RAS have also been described which appear to play a key role in the injury/repair response. The expression of RAS components and the elevation of angiotensin converting enzyme in a number of interstitial lung diseases suggests the existence of a pulmonary RAS and that angiotensin II could mediate, at least in part, the response to lung injury. Activation of a local RAS within the pulmonary circulation and lung parenchyma could influence the pathogenesis of lung injury via a number of mechanisms including an increase in vascular permeability, vascular tone and fibroblast activity, and by reducing alveolar epithelial cell survival. The ability of both ACE inhibitors and angiotensin II receptor antagonists to attenuate experimental lung injury further supports a role for RAS activation and suggests these agents may be useful in the treatment of diffuse parenchymal lung disease. However, further studies are required to delineate the cell types responsible for RAS component expression in the lung and also to identify the key effector molecules of this system. The presence of common polymorphisms in RAS genes and their study in relation to specific physiological phenotypes will aid both our understanding of the role of RAS in the lung and also aid the targeting of future therapies.     

Ethanol and Vitamin D Receptor in T Cell Apoptosis

Ethanol has been demonstrated to cause T cell apoptosis. In the present study, we evaluated the role of VDR and the renin angiotensin system (RAS) in oxidative stress-induced T cell apoptosis. Ethanol-treated human T cells displayed down regulation of vitamin D receptor (VDR) and the activation of the RAS in the form of enhanced T cell renin expression and angiotensin II (Ang II) production. The silencing of VDR with siRNA displayed the activation of the RAS, and activation of the VDR resulted in the down regulation of the RAS. It suggested that ethanol-induced T cell RAS activation was dependent on the VDR status. T cell ROS generation by ethanol was found to be dose dependent. Conversely, ethanol-induced ROS generation was inhibited if VDR was activated or Ang II was blocked by an angiotensin II type 1 (AT1) receptor blocker (Losartan). Furthermore, it was observed that ethanol not only induced double strand breaks in T cells but also attenuated DNA repair response, whereas, VDR activation inhibited ethanol-induced double strand breaks and also enhanced DNA repairs. Since free radical scavengers inhibited ethanol-induced DNA damage, it would indicate that ethanol-induced DNA damage was mediated through ROS generation. These findings indicated that ethanol-induced T cell apoptosis was mediated through ROS generation in response to ethanol-induced down regulation of VDR and associated activation of the RAS.     

Induction of pulmonary fibrosis by methotrexate treatment in mice lung in vivo and in vitro

Methotrexate (MTX) has been used as the first-line disease-modifying antirheumatic drug (DMARD) in patients with early progressive rheumatoid arthritis (RA). Several severe side effects such as myelosuppression, hepato-, nephro-, and pulmonary toxicities have been reported. However, the pathogenic mechanism of MTX-induced pulmonary fibrosis is still unknown. Here, we evaluated the morphological and biological changes of the pulmonary fibrosis in mice treated with MTX. Three, four and five weeks after consecutive administration of MTX (3 mg/kg/day), hydroxyproline content in the lung tissues increased significantly to about 2 times higher that of the control level. This result closely reflected to the results of hematoxylin and eosin (HE) and Azan stains. Immunohistochemical analysis revealed that MTX treatment resulted in a decrease of alveolar epithelial cells and an increase of fibroblast cells in the mouse lung tissues. When we examined the effects of MTX on primary mouse alveolar epithelial cell (MAEC) and mouse lung fibroblast (MLF) survival in vitro, the efficiency of MTX-induced cytotoxicity and apoptosis in MAEC was more sensitive than MLF cells. Thus, our results indicate that the administration of MTX by an oral route could induce a fibrotic response with cell dysfunction of the alveolar epithelium by which MTX-induced apoptosis. Our results thus suggest that MTX could induce alveolar epithelial cell injury and resulted in the loss of integrity of the alveolar-capillary barrier basement membranes followed by the recruitment and proliferation of myofibroblasts with the deposition of collagens.     

环孢霉素A慢性肾毒性机制研究进展

慢性肾毒性是环孢霉素A(CsA)的主要副作用。细胞外基质沉积 ,肾小管萎缩 ,肾小球入球动脉透明样变是其主要特点。该文论述了CsA可以直接刺激肾脏细胞合成细胞外基质 ,引起细胞凋亡外 ,还能通过促进肾小球旁细胞合成肾素 ,激活肾素血管紧张素系统 ,使AngⅡ增加 ;AT1受体下调。而AngⅡ可以促进骨桥蛋白、TGF β表达。它们共同参与了肾间质纤维化形成。     

Lovastatin overcomes gefitinib resistance in human non-small cell lung cancer cells with <Emphasis Type="Italic">K-Ras</Emphasis> mutations

Lovastatin is a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor. Its inhibitory action on HMG-CoA reductase leads to depletion of isoprenoids, which inhibits post-translational modification of RAS. In this study, we investigated the effect of combining lovastatin with gefitinib on gefitinib-resistant human non-small cell lung cancer (NSCLC) cell lines with K-Ras mutations. Antitumor effects were measured by growth inhibition and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Effects on apoptosis were determined by flow cytometry, DNA fragmentation, and immunoblots. Protein levels of RAS, AKT/pAKT, and RAF/ERK1/2 in cancer cells were analyzed by immunoblot. Compared with gefitinib alone, a combination of gefitinib with lovastatin showed significantly enhanced cell growth inhibition and cytotoxicity in gefitinib-resistant A549 and NCI-H460 human NSCLC cells. In addition, lovastatin combination treatment significantly increased gefitinib-related apoptosis, as determined by fluorescence microscopy and flow cytometric analysis. These effects correlated with up-regulation of cleaved caspase-3, poly (ADP-ribose) polymerase (PARP), and Bax and down-regulation of Bcl-2. The combination of lovastatin and gefitinib effectively down-regulated RAS protein and suppressed the phosphorylation of RAF, ERK1/2, AKT, and EGFR in both cell lines. Taken together, these results suggest lovastatin can overcome gefitinib resistance, in NSCLC cells with K-Ras mutations, by down regulation of RAS protein, which leads to inhibition of both RAF/ERK and AKT pathways.     

肝纤维化中肾素-血管紧张素的作用研究进展

在肝损伤中,肝星状细胞是公认的主要细胞外基质生成细胞,导致肝纤维发生有很多关键因素。在这些因素中,肾素-血管紧张素系统起着重要的作用。已发现的ACE-AngⅡ-AT1R受体轴具有致肝纤维化的作用,ACE2-Ang(1-7)-Mas受体轴具有抗肝纤维化的作用,两者相互作用调节肝纤维化的进程。该文旨在对近几年这方面的研究做一综述。