姜黄素对缺血再灌注损伤器官的保护作用

近年来姜黄素对局部缺血再灌注损伤（ I／R）的保护效应受到关注,姜黄素可通过抑制细胞凋亡、促新生神经细胞增殖、调控炎症因子表达、抑制脂质过氧化反应等多种机制减轻缺血再灌注器官的损伤,从而发挥对心、脑、肝、肺、肾等器官缺血再灌注损伤的保护作用。本文对姜黄素在缺血再灌注损伤的器官保护作用研究进行综述,为临床治疗局部缺血再灌注损伤提供理论依据,为研究寻找新的药物作用靶点提供新思路。     

乌司他丁对急性肺损伤的保护作用

乌司他丁是由Beuer和Reich于1909年在人类尿液中发现的广谱蛋白水解酶抑制剂（UTI）,同时乌司他丁还能抑制多种炎性反应介质的释放,从而保护机体重要器官的功能。近年来乌司他丁在急性肺损伤的治疗中得到了越来越广泛的临床应用,现将其化学性质、药理作用及肺保护机制做一简介。     

番茄红素对大鼠急性肺损伤的保护作用及机制研究

目的研究番茄红素(lycopene)对急性肺损伤(ALI)的保护作用并探讨其作用机制。方法采用酸吸入致大鼠ALI模型,测定ALI后6 h肺毛细血管通透性、肺湿干质量比(mW∶mD)、肺组织髓过氧化物酶(MPO)活性并观察6 h、7 d、14 d肺组织病理学改变,研究番茄红素的肺保护作用;通过测定ALI大鼠血浆TNFα、NO、MDA含量及肺组织羟脯氨酸(HYP)含量和SOD活性以及骨形态生发蛋白4(BMP 4)mRNA的表达,探讨番茄红素的肺保护机制。结果番茄红素明显减轻酸吸入致ALI早期肺毛细血管通透性和炎性细胞浸润及后期肺纤维化,降低血浆TNFα、NO、MDA及肺组织HYP含量,增加SOD活性,抑制因ALI诱导而上调的BMP 4 mRNA的表达。结论番茄红素对酸吸入致ALI具有明显的保护作用,其机制可能与抗氧化、抑制早期炎症因子及BMP 4基因表达有关。     

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。     

右美托咪定的器官保护作用研究进展

目的:了解α2肾上腺素能受体(α2受体)激动药右美托咪定(DEX)对机体各器官保护作用的研究进展。方法:通过查阅2008-2013年PubMed、Medline等数据库中有关DEX对脑、心、肺、肾等器官的保护作用的文献,并进行归纳和总结。结果:DEX激动α2受体后通过抗交感、抑制细胞炎症和凋亡、抑制氧化应激反应、激活细胞保护信号通路等多种途径对重要脏器如脑、心脏、肺脏和肾脏发挥保护作用。结论:DEX具有多器官保护作用,但尚需更多、更细致的研究以使其更安全、有效地应用于临床。     

七氟醚在体外循环中的肺保护作用

目的观察七氟醚对于心脏手术患者体外循环后导致肺损伤所起到的保护作用。方法对笔者所在科室2010年9月12日～2011年9月12日手术治疗的30例心脏瓣膜病患者临床资料进行回顾性分析。结果 3组患者比较,S组与S1组CPB时间均延长,入住ICU时间缩短。结论应用七氟醚进行预处理能够改善患者肺换气功能,并提高其肺顺应性,同时减轻其体外循环所引起的肺损伤;主要机制则可能同炎症因子抑制关系密切。     

人参皂苷Rg_1通过作用于炎性因子和糖皮质激素受体减少金葡菌对肺上皮细胞的损伤(英文)

本文旨在探讨人参皂苷Rg_1体外对金葡菌感染肺上皮细胞所致病变的作用及其可能的机制。实验采用体外大鼠原代肺上皮细胞感染模型。RT-PCR和Western blot方法观察肺细胞中integrinβ1,NF-κB和糖皮质激素受体(GR)等相关因子的表达。结果表明人参皂苷Rg_1可以明显抑制金葡菌感染后肺上皮细胞整合素integrinβ1的表达,下调炎性因子NF-κB,ICAM-1,TNF-α,IL-2和IL-6,上调GR的表达。人参皂苷Rg_1可以明显抑制金葡菌感染肺上皮细胞后的炎性因子,从而对肺脏起到一定的保护作用。     

甘草及甘草酸类成分抗病毒性肺炎的药理作用研究进展

甘草及甘草酸类成分有抗冠状病毒、流感病毒、呼吸道合胞病毒和人巨细胞病毒等呼吸道病毒的作用,其机制可能与抑制病毒的蛋白合成,导致病毒复制受阻;改善免疫调控,上调一氧化氮表达,抑制血小板聚集,抑制炎症反应,保护宿主有关。甘草及甘草酸类成分有止咳祛痰、平喘及肺保护和抗肺纤维化作用,其机制可能是通过上调过氧化物酶体增殖激活受体-γ（PPARγ）、血管紧张素转化酶2（ACE2）和IκB-α的表达,阻滞ERK/NF-κB信号通路,又能与高迁移率属蛋白B1（HMGB1）结合直接抑制HMGB1的化学趋化和促有丝分裂的活性,抑制炎性细胞因子表达、杯状细胞增生和黏蛋白过表达,以及上调水通道蛋白表达,减轻炎症反应;通过阻滞TLR-4/MyD88/NF-κB信号通路保护肺上皮细胞;通过阻滞IL-17/TGFβ1/Smad信号通路,抑制胶原合成和成纤维细胞增生,减轻肺纤维化形成;也可通过上调Smad7的表达,抑制气道重塑,改善肺功能。     

小檗碱治疗肺部感染的药理作用研究进展

肺部感染临床常以肺炎形式存出现,治疗核心为抗感染,但多数病原菌对传统药物具有较高的耐药性。小檗碱是从黄连中提取的活性成分,具有多种活性,可通过降低病原菌耐药性,阻止病原菌复制,减轻肺部炎症反应,调节免疫功能,抑制肺纤维化进程,保护血管内皮细胞以治疗肺部感染,减轻肺组织损伤。综述了小檗碱用于肺部感染治疗的药理作用研究进展,为小檗碱临床治疗肺部感染提供依据。     

1例吉非替尼致Ⅱ级骨髓抑制的病例报告及文献复习

分析1例EGFR基因突变肺腺癌患者因服用吉非替尼片导致Ⅱ级骨髓抑制的病例,提示临床警惕吉非替尼使用过程中可能出现的骨髓抑制风险,并通过复习相关文献,探讨吉非替尼可能引起的不良反应以及骨髓抑制的治疗方法,为临床用药安全提供参考。     

Endothelial pathomechanisms in acute lung injury

Acute lung injury (ALI) and its most severe extreme the acute respiratory distress syndrome (ARDS) refer to increased-permeability pulmonary edema caused by a variety of pulmonary or systemic insults. ALI and in particular ARDS, are usually accompanied by refractory hypoxemia and the need for mechanical ventilation. In most cases, an exaggerated inflammatory and pro-thrombotic reaction to an initial stimulus, such as systemic infection, elicits disruption of the alveolo-capillary membrane and vascular fluid leak. The pulmonary endothelium is a major metabolic organ promoting adequate pulmonary and systemic vascular homeostasis, and a main target of circulating cells and humoral mediators under injury; pulmonary endothelium is therefore critically involved in the pathogenesis of ALI. In this review we will discuss mechanisms of pulmonary endothelial dysfunction and edema generation in the lung with special emphasis on the interplay between the endothelium, the immune and hemostatic systems, and highlight how these principles apply in the context of defined disorders and specific insults implicated in ALI pathogenesis.     

Endothelial pathomechanisms in acute lung injury

Acute lung injury (ALI) and its most severe extreme the acute respiratory distress syndrome (ARDS) refer to increased-permeability pulmonary edema caused by a variety of pulmonary or systemic insults. ALI and in particular ARDS, are usually accompanied by refractory hypoxemia and the need for mechanical ventilation. In most cases, an exaggerated inflammatory and pro-thrombotic reaction to an initial stimulus, such as systemic infection, elicits disruption of the alveolo-capillary membrane and vascular fluid leak. The pulmonary endothelium is a major metabolic organ promoting adequate pulmonary and systemic vascular homeostasis, and a main target of circulating cells and humoral mediators under injury; pulmonary endothelium is therefore critically involved in the pathogenesis of ALI. In this review we will discuss mechanisms of pulmonary endothelial dysfunction and edema generation in the lung with special emphasis on the interplay between the endothelium, the immune and hemostatic systems, and highlight how these principles apply in the context of defined disorders and specific insults implicated in ALI pathogenesis.     

Preventive effect of tranilast on oleic acid-induced lung injury in guinea pigs

Acute respiratory distress syndrome or acute lung injury (ARDS)/(ALI) involve the severe lung injury with pulmonary vascular hyper-permeability and hypoxemia induced by inflammatory reactions. Since ARDS/ALI carries high mortality, the development of new drugs against ARDS/ALI is required. We examined the effect of tranilast, an anti-allergic drug, on vascular hyper-permeability in the lungs and airways, and on hypoxemia, in oleic acid (OA)-induced acute lung injury, an animal model of ARDS/ALI. The increase in pulmonary and airway vascular permeability and the decrease in partial oxygen pressure of arterial blood induced by an intravenous injection of OA were drastically ameliorated by the oral administration of tranilast in a dose-dependent manner. This is the first report to prove that tranilast prevents pulmonary and airway vascular permeability and hypoxemia induced by OA. These results suggest that tranilast may be a candidate drug for the treatment of ARDS/ALI.     

Emodin ameliorates acute lung injury induced by severe acute pancreatitis through the up‐regulated expressions of AQP1 and AQP5 in lung

The present study investigates the ameliorating effects of emodin on acute lung injury (ALI) induced by severe acute pancreatitis (SAP). An ALI rat model was constructed by sodium ursodeoxycholate and they were divided into four groups: SHAM, ALI, emodin and dexamethasone (DEX) (n=24 per group). Blood samples and lung tissues were collected 6, 12 and 24 hours after the induction of SAP‐associated ALI. Lung wet/dry ratio, blood gases, serum amylase and tumor necrosis factor‐α (TNF‐α) were measured at each time point. The expressions of AQP1 and AQP5 in lung tissue were detected by immunohistochemical staining, western blotting and real‐time PCR. As the results show, there were no statistical differences in the levels of serum amylase, lung wet/dry ratio, blood gases indexes, serum TNF‐α and pathological changes between emodin and DEX groups. However, significant differences were observed when compared with the ALI group. AQP1 and AQP5 expressions were significantly increased and lung oedemas were alleviated with the treatment of emodin and DEX. The expressions of AQP1 and AQP5 were significantly decreased in SAP‐associated ALI rats. Emodin up‐regulated the expression of AQP1 and AQP5, it could reduce pulmonary oedema and ameliorate SAP‐induced ALI. Regulations on AQP1 and AQP5 expression had a great value in clinical application.     

Increased expression of endothelial iNOS accounts for hyporesponsiveness of pulmonary artery to vasoconstrictors after paraquat poisoning

Paraquat is a toxic herbicide that induces severe acute lung injury (ALI) and pulmonary hypertension in humans. Although vascular disorders are present and contribute to increased mortality in ALI patients, there is little data available on vascular responsiveness after toxic exposure to paraquat. We aimed to evaluate the vascular response of isolated pulmonary arteries from rats treated with a dose of paraquat that induces ALI. Paraquat treatment did not modify the relaxant response of pulmonary artery to acetylcholine, but greatly reduced phenylephrine-induced contraction. Removal of the endothelium, inhibition of nitric oxide synthase (NOS) with L-NAME or selective inhibition of inducible NOS (iNOS) with L-NIL, restored contraction of vessels from paraquat poisoned rats to the same level as those not exposed to paraquat. The basal production of NO and expression of iNOS were increased in endothelium-intact but not in endothelium-denuded vessels from paraquat-poisoned rats. Expression of endothelial NOS was not modified. Our findings suggest that paraquat poisoning increases endothelial iNOS expression and basal NO production decreasing responsiveness of pulmonary artery to vasoconstrictors. Thus, our results do not support the hypothesis that pulmonary hypertension in paraquat-induced ALI is mediated by a reduction in endothelial NO production or increased contractility of pulmonary artery.     

急性肺损伤时间隙连接通道调控肺血管通透性的机制研究

目的探讨间隙连接通道(GJC)是否通过调节胞内钙离子浓度,进而调控肺血管通透性,最终导致急性肺损伤的发病。方法应用小口径步枪致伤制造急性肺损伤动物模型,检测肺含水量、伊文思蓝漏出率,并应用免疫组织化学方法检测肺血管内皮Cx40表达;培养肺微血管内皮细胞,分别给予达氏修正伊氏培养基(DMEM)、伤后动物血清和GJC通道阻滞剂,应用染料划痕实验检测GJC功能、伊文思蓝漏出实验检测单层内皮细胞通透性、Fluo-3AM钙离子荧光探针检测胞内钙离子浓度。结果动物实验中,伤后Cx40表达随时间延长逐渐降低,肺血管通透性则呈递增趋势,二者呈负相关(r=-0.934,P<0.05)。离体实验中,伤后动物血清降低GJC功能,Cx40表达降低,当应用通道阻断剂后,GJC功能和Cx40表达降低程度更甚;此时肺微血管内皮细胞单层通透性增加,胞内钙离子浓度增加,应用GJC通道阻断剂后,这种效应更加明显。结论肺血管内皮细胞GJC对肺血管通透性有调节作用,胸部枪弹伤后,肺血管内皮Cx40表达降低,引起GJC功能下降,导致胞内钙超载,最终导致肺血管通透性增加和急性肺损伤的发病。     

药物保护肺毛细血管内皮细胞 降低SARS发病率

急性呼吸窘迫综合征(ARDS)的致病因素很多，但最终均形成急性肺损伤(ALI)，主要由肺毛细血管内皮细胞损害所介导，虽采用医疗措施，包括吸氧及气管插管进行呼吸机呼吸等，病人死亡率仍高。传染性非典型肺炎(SARS)引起ALI时，出现肺动脉高压及肺纤维化，最终临床出现ARDS。ARDS的病理核心是肺毛细血管内皮细胞的损害，血管内皮细胞可作为治疗ARDS及SARS的靶点。SARS病毒感染后，引起细胞因子的释放，其中包括内皮素-1(ET-1)，ET-1可强烈收缩血管及致炎症反应。本文讨论在致病因子作用下，ET-1的增多与形成ARDS、败血症、休克的关系，致病机制包括ET-1诱导iNOS生成、使细胞膜Ca^2 内流增多、促使氧化应激而造成ALI。ET-1致肺损伤主要由于激活ETB受体，而ALI时肺内纤维化，ET-1亦起着重要的作用。过多的ET-1可使ARDS病人形成肺动脉高压，以ET-1及其所参与的SARS及ARDS发病的各个环节为靶点，应用抗病毒药、抑制炎症的糖皮质激素及阻断冠状病毒侵入细胞的大分子药物，使用内皮素受体拮抗剂和多离子通道阻断剂CPU86017，可阻断感染冠状病毒后形成肺损伤、肺纤维化、肺动脉痉挛及肺动脉高压等，有可能明显降低SARS及ARDS的发病率及致死率。     

Obeticholic acid alleviate lipopolysaccharide-induced acute lung injury via its anti-inflammatory effects in mice

Acute lung injury (ALI) is a common disease that may result in acute respiratory failure and death. However, there are still no effective treatments for ALI. Several studies have shown that farnesoid X receptor (FXR) has an anti-inflammatory effect. We investigated the effects of obeticholic acid (OCA), an agonist of FXR, on Lipopolysaccharide (LPS)-induced ALI in mice. Sixty male mice were randomly divided into six groups, and orally administered with or without OCA once daily for 3 consecutive days before LPS (1.0 mg/kg). Animals were sacrificed at 0 h, 2 h or 6 h after LPS. As expected, OCA enhanced pulmonary FXR activity. OCA prevented LPS-induced ALI. Additional experiment showed that OCA alleviated LPS-induced up-regulation of pulmonary pro-inflammatory and chemokine genes. Moreover, OCA also repressed LPS-induced the release of TNF-α and KC in serum and bronchoalveolar lavage fluid. In contrast, OCA further up-regulated LPS-induced the expression of Il-10, an anti-inflammatory cytokine. Further study showed that OCA inhibited LPS-evoked NF-κB signaling in the lungs. OCA attenuated LPS-induced ERK1/2, JNK, p38 and Akt phosphorylation in the lungs. Overall, these results suggest that OCA prevent LPS-induced ALI may be through enhancing pulmonary FXR activity and then blockading several inflammatory signaling pathways.