细胞骨架与机械应力在机械通气相关性肺损伤中的病理生理作用

背景 机械通气相关性肺损伤(ventilator induced lung injury,VILI)是机械通气治疗中常见的严重并发症,过度牵拉引起的细胞机械应力是由细胞骨架以及细胞-期胞间和细胞-细胞外基质的相互作用调节完成. 目的 探讨细胞骨架在VILI中的病理生理机制,丰富和完善VILI理论. 内容 描述了机械通气刺激被转化为细胞内的生理信号,从而诱导细胞活化、增加肺血管通透性导致肺损伤.对细胞骨架与机械应力在VILI中的病理生理作用进行详尽的阐述. 趋向 关于细胞骨架及其相关结构在VILI的病理生理变化中作用的体外研究已广泛开展,但体内VILI模型较少,需进一步的研究.     

机械通气肺生物性损伤机制及防治

正机械通气是运用肌松药全麻患者维持生命的必要手段,同时作为呼吸支持治疗的重要措施,挽救了无数呼吸功能严重受损的患者。然而,机械通气作为一种损伤因素可导致或加重肺损伤,即机械通气肺损伤(ventilator-induced lung injury,VILI)[1]。VILI是一种肺部弥漫性肺泡-血管膜损伤和通透性增加综合征,包括气压伤、容积伤、肺萎缩伤和生物伤四类。气压伤、容积伤、肺萎缩伤在临床呼吸机的运用中比     

全身麻醉期间肺保护通气策略研究进展

背景 机械通气保障全身麻醉手术患者的呼吸和气体交换,但也可能诱发机械通气相关性肺损伤(ventilation induced-lung injury,VILI).随着对VILI发病机制的不断探索,能在一定程度上减轻VILI损伤程度的肺保护性通气策略的研究也越来越深入.目的 就全身麻醉期间肺保护通气策略的研究进展予以综述.内容 综述肺保护机械通气策略、低潮气量通气、复合适当呼气末正压通气(positive end expiratory pressure,PEEP)、肺复张策略(recruiting maneuvers,RM)、控制平台压及FiO2等相关进展与争议.趋向 肺保护性机械通气相关研究已取得一定进展,在全身麻醉过程中采取适当的、个体化的通气策略有待进一步研究.     

老年患者呼吸机相关性肺损伤及全麻术中保护性肺通气策略的应用

机械通气可造成呼吸机引起的肺损伤(ventilator-induced lung injury,VILI),由于老年患者常合并呼吸功能减退,所以全麻期间更易引起VILI,现就全身麻醉下老年患者机械通气引起的肺损伤的发生机制以及相关保护性肺通气策略及应用的研究进展作一综述.     

机械通气致肺水肿损伤机制的研究进展

背景 机械通气致肺损伤(ventilator induced lung injury,VILI)的机制研究众多,传统认为生物学损伤为主要机制,机械性损伤为触发因素.VILI的致死因素之一就是肺水肿的发生发展或以全身炎症反应综合征及多器官功能衰竭而终结. 目的 探讨肺水肿发生的机械损伤机制及其干预措施. 内容 现就生物学损伤及机械性损伤致VILI肺水肿的发生机制的最新研究作一综述,以期预防肺水肿的发生,为临床麻醉及重症监护过程中VILI致肺水肿的发生奠定理论基础. 趋向 机械性损伤触发肺水肿的发生,做为机械通气诱发肺损伤的特殊感受器,研究综述了机械力直接损伤、瞬时感受电位(transient receptor potential,TRP)超家族介导机械刺激诱发神经源性炎症反应(neurogenic inflammation,NI)在肺水肿的发生中所起的闸门作用,阻断早期肺损伤的诱发因素对于围术期肺保护具有重要意义.     

Talin及Integrin/FAK信号通路与肝癌

肿瘤细胞黏附能力的改变是肿瘤细胞侵袭和转移的起始;整合素(integrin)是细胞表面重要的黏附分子受体,介导许多信号通路的发生,包括Integrin/黏着斑激酶(focal adhesion kinase,FAK)信号通路,直接或间接地影响肿瘤复发和转移,其中Integrin/FAK信号转导通路,在Integrin介导的肝癌黏附转移信号转导通路中起着至关重要的作用.踝蛋白(Talin)是第一个被证实的Integrin活化蛋白,是黏着斑(focal adhesion plaque,FAP)结构的重要组成部分.本文就Talin结构、功能、与Integrin/FAK信号通路的相互作用及其与肝癌及其他肿瘤的关系作一综述.     

Talin及Integrin/FAK信号通路与肝癌

肿瘤细胞黏附能力的改变是肿瘤细胞侵袭和转移的起始;整合素(integrin)是细胞表面重要的黏附分子受体,介导许多信号通路的发生,包括Integrin/黏着斑激酶(focal adhesion kinase,FAK)信号通路,直接或间接地影响肿瘤复发和转移,其中Integrin/FAK信号转导通路,在Integrin介导的肝癌黏附转移信号转导通路中起着至关重要的作用.踝蛋白(Talin)是第一个被证实的Integrin活化蛋白,是黏着斑(focal adhesion plaque,FAP)结构的重要组成部分.本文就Talin结构、功能、与Integrin/FAK信号通路的相互作用及其与肝癌及其他肿瘤的关系作一综述.     

Talin及Integrin/FAK信号通路与肝癌

肿瘤细胞黏附能力的改变是肿瘤细胞侵袭和转移的起始;整合素(integrin)是细胞表面重要的黏附分子受体,介导许多信号通路的发生,包括Integrin/黏着斑激酶(focal adhesion kinase,FAK)信号通路,直接或间接地影响肿瘤复发和转移,其中Integrin/FAK信号转导通路,在Integrin介导的肝癌黏附转移信号转导通路中起着至关重要的作用.踝蛋白(Talin)是第一个被证实的Integrin活化蛋白,是黏着斑(focal adhesion plaque,FAP)结构的重要组成部分.本文就Talin结构、功能、与Integrin/FAK信号通路的相互作用及其与肝癌及其他肿瘤的关系作一综述.     

机械通气诱发肺纤维化机制的研究进展

机械通气使用不当可引起或加重肺损伤, 称为呼吸机所致肺损伤(ventilator-induced lung injury, VILI), 机械通气导致的肺纤维化则是VILI中非常严重的一种。文章综述机械通气引起肺纤维化的可能机制, 肺泡上皮细胞及肺血管内皮细胞转化为间充质细胞, 巨噬细胞极化及肥大细胞产生胶原、类胰蛋白酶等, 都参与机械通气诱发的肺纤维化;汇总了NOD样受体热蛋白结构域相关蛋白3(NOD-like receptor thermal protein domain associated protein 3, NLRP3)炎症小体、透明质酸(hyaluronic acid, HA)、中期因子(midkine, MK)、转化生长因子β(transforming growth factor-β, TGF-β)等细胞因子及Wnt等信号通路在机械通气肺纤维化中发挥的作用。文章多方面探索机械通气诱发肺纤维化的机制, 为早期诊断及防治提供新思路。     

呼吸机所致肺损伤的炎症机制与治疗进展

呼吸机所致肺损伤(ventilator-induced lung,VILI)的发生机制目前尚不清楚。最近提出的生物伤(biotrauma)概念,认为机械通气引起的牵张可使炎性反应上调,引起肺组织甚至是全身器官的损伤。肺保护性通气和免疫调节治疗可在一定程度上减轻VILI。     

Steen solution protects pulmonary microvascular endothelial cells and preserves endothelial barrier after lipopolysaccharide-induced injury

ObjectivesAcute respiratory distress syndrome represents the devastating result of acute lung injury, with high mortality. Limited methods are available for rehabilitation of lungs affected by acute respiratory distress syndrome. Our laboratory has demonstrated rehabilitation of sepsis-injured lungs via normothermic ex vivo and in vivo perfusion with Steen solution (Steen). However, mechanisms responsible for the protective effects of Steen remain unclear. This study tests the hypothesis that Steen directly attenuates pulmonary endothelial barrier dysfunction and inflammation induced by lipopolysaccharide.MethodsPrimary pulmonary microvascular endothelial cells were exposed to lipopolysaccharide for 4 hours and then recovered for 8 hours in complete media (Media), Steen, or Steen followed by complete media (Steen/Media). Oxidative stress, chemokines, permeability, interendothelial junction proteins, and toll-like receptor 4-mediated pathways were assessed in pulmonary microvascular endothelial cells using standard methods.ResultsLipopolysaccharide treatment of pulmonary microvascular endothelial cells and recovery in Media significantly induced reactive oxygen species, lipid peroxidation, expression of chemokines (eg, chemokine [C-X-C motif] ligand 1 and C-C motif chemokine ligand 2) and cell adhesion molecules (P-selectin, E-selectin, and vascular cell adhesion molecule 1), permeability, neutrophil transmigration, p38 mitogen-activated protein kinase and nuclear factor kappa B signaling, and decreased expression of tight and adherens junction proteins (zonula occludens-1, zonula occludens-2, and vascular endothelial-cadherin). All of these inflammatory pathways were significantly attenuated after recovery of pulmonary microvascular endothelial cells in Steen or Steen/Media.ConclusionsSteen solution preserves pulmonary endothelial barrier function after lipopolysaccharide exposure by promoting an anti-inflammatory environment via attenuation of oxidative stress, toll-like receptor 4-mediated signaling, and conservation of interendothelial junctions. These protective mechanisms offer insight into the advancement of methods for in vivo lung perfusion with Steen for the treatment of severe acute respiratory distress syndrome.     

黏附分子与心肺转流术肺损伤

急性肺损伤是心肺转流术(cardiopulmonary by-pass,CPB)后最常见的并发症,其中白细胞在肺内的“扣留”起到了主要作用,而细胞黏附分子参与了白细胞渗出及活化的各个环节。现就有关黏附分子与CPB肺损伤关系的研究作以下综述,并探讨目前抗黏附分子在这领域的应用,旨在进一步揭示C     

Sphingosine 1-Phosphate Inhibits Ischemia Reperfusion Injury Following Experimental Lung Transplantation

Ischemia reperfusion (I/R) injury following lung transplantation is exacerbated by the destruction of the endothelial cell barrier leading to pulmonary edema and dysregulated activated lymphocyte migration. Sphingosine 1-phosphate (S1P), a G-coupled protein receptor (GPCR) agonist, has been previously shown to promote endothelial cell tight junction formation and prevent monocyte chemotaxis. We asked if S1P treatment could improve pulmonary function and attenuate I/R injury following syngeneic rat lung transplantation. In comparison to vehicle-treated recipients, S1P administered before reperfusion significantly improved recipient oxygenation following transplantation. Improved graft function was associated with reduced inflammatory signaling pathway activation along with attenuated intragraft levels of MIP-2, TNF-alpha and IL-1beta. Moreover, S1P-treated recipients had significantly less apoptotic endothelial cells, pulmonary edema and graft accumulation of neutrophils than did vehicle-treated recipients. Thus our data show that S1P improves lung tissue homeostasis following reperfusion by enhancing endothelial barrier function and blunting monocytic graft infiltration and inflammation.     

Ventilator-induced lung injury and sepsis: two sides of the same coin?

Unequivocal evidence from both experimental and clinical research has shown that mechanical ventilation can damage the lungs and initiate an inflammatory response, possibly contributing to extrapulmonary organ dysfunction. This type of injury, referred to as ventilator-induced lung injury (VILI), resembles the syndromes of acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS). VILI can trigger a complex array of inflammatory mediators, resulting in a local and systemic inflammatory response. Substances produced in the lungs can be translocated into the systemic circulation as a result of injury to the pulmonary epithelium and to the capillary endothelium. This type of injury forms the basis for the use of low tidal volumes (5-7 mL/kg of predicted body weight) during mechanical ventilation of patients with ALI/ARDS. The recognition of VILI has prompted a number of investigators to suggest that ALI/ARDS may be, in part, a product of our efforts to mechanically ventilate patients rather than the progression of the underlying disease. On the other hand, current scientific evidence supports a link between VILI and the development of extrapulmonary organ dysfunction, similar to how most severe cases of sepsis are clinically manifested. In addition, functional genomics approaches using a gene array methodology to measure lung gene expression have identified differential patterns of gene expression in animal models of VILI, similar to those gene pathways activated during experimental and clinical sepsis. In this line of thought, we hypothesize that injurious mechanical ventilation could be responsible for the perpetuation and worsening of sepsis in some patients and for the development of a sepsis-like syndrome in others.     

机械通气肺损伤的基本机制

机械通气肺损伤发生机制复杂,临床表现多样,日益受到重视.其基本机制为对肺组织过度牵拉的机械因素和机械力学诱导的肺脏局部细胞因子和炎症介质的释放.不适当的机械通气除可造成气压损伤、容积损伤和肺不张损伤等机械性损伤外,其最后的共同途径可能是激活细胞内信号转导通路和加重炎症介质介导的肺局部炎症反应,即机械伤转化为生物伤.现就其发生机制、防治对策等方面的研究作一简要综述.     

Protein kinase cβ phosphorylates occludin regulating tight junction trafficking in vascular endothelial growth factor-induced permeability in vivo

Vascular endothelial growth factor (VEGF)-induced breakdown of the blood-retinal barrier requires protein kinase C (PKC)β activation. However, the molecular mechanisms related to this process remain poorly understood. In this study, the role of occludin phosphorylation and ubiquitination downstream of PKCβ activation in tight junction (TJ) trafficking and endothelial permeability was investigated. Treatment of bovine retinal endothelial cells and intravitreal injection of PKCβ inhibitors as well as expression of dominant-negative kinase was used to determine the contribution of PKCβ to endothelial permeability and occludin phosphorylation at Ser490 detected with a site-specific antibody. In vitro kinase assay was used to demonstrate direct occludin phosphorylation by PKCβ. Ubiquitination was measured by immunoblotting after occludin immunoprecipitation. Confocal microscopy revealed organization of TJ proteins. The results reveal that inhibition of VEGF-induced PKCβ activation blocks occludin Ser490 phosphorylation, ubiquitination, and TJ trafficking in retinal vascular endothelial cells both in vitro and in vivo and prevents VEGF-stimulated vascular permeability. Occludin Ser490 is a direct target of PKCβ, and mutating Ser490 to Ala (S490A) blocks permeability downstream of PKCβ. Therefore, PKCβ activation phosphorylates occludin on Ser490, leading to ubiquitination required for VEGF-induced permeability. These data demonstrate a novel mechanism for PKCβ targeted inhibitors in regulating vascular permeability.     

Changes in gap junctional connexin isoforms during prostate cancer progression

BACKGROUND: Connexins have their traditional function as part of gap junction (GJ) structures, but have recently been shown to have GJ-independent roles. Although GJs and their connexin subunits are thought to be down-regulated in cancer, depending on the connexin examined, many times the expression level is preserved or even increased. This is further apparent by the importance of GJs in "bystander effects" of radiation and viral targeting treatments. METHODS: We surveyed connexin isoforms in prostate cancer cell lines and tissue with RT-PCR and immunohistochemistry. Upon modulating GJ function, we observed prostate epithelial cell behaviors. RESULTS: Advanced cells within PC-3 and LNCaP prostate cancer progression models exhibit elevated connexin 26 (Cx26) levels-a trend validated in clinical samples. When GJs were inhibited, adhesion was not affected, but invasion and migration were strikingly decreased. A link between the expression of Cx26 and integrin adhesion-linked functions are suggested by Cx26's direct interaction with focal adhesion kinase (FAK). CONCLUSIONS: These results suggest a novel mechanism for adhesion regulation by a GJ-independent Cx26 function that correlates with prostate disease progression. The increased Cx26 expression during prostate cancer progression plays a role in adhesion regulation possibly through its interaction with FAK.     

FAK和VEGF在直肠癌中的表达及其相互关系的研究

目的：检测粘着斑激酶（FAK）和血管内皮生长因子（VEGF）在直肠癌中的表达及其与侵袭和转移的关系，探讨二者的相关性。方法：采用免疫组织化学SABC法，观察86例直肠癌及30例非直肠癌组织中FAK和VEGF的表达情况。结果：FAKVEGF在直肠癌中的阳性率分别为80％和59％。在非直肠癌组织中的阳性表达率分别为10％和13％。FAKF和VEGF在侵及浆膜层直肠癌病例中的表达明显高于未侵五2浆膜层者，二者之间差异性有统计学意义（P〈0．05）；有淋巴结转移组与无淋巴结转移组比较差异有统计学意义（P〈0．05），FAK与VEGF阳性表达呈正相关（p〈0．01）。结论：FAK、VEGF在直肠癌的侵袭和转移中起重要作用，二者在直肠癌中表达升高可以作为预测直肠癌侵袭和转移的指标     

Heparin-binding EGF-like growth factor (HB-EGF) promotes cell migration and adhesion via focal adhesion kinase

Background

Cell migration and adhesion are essential in intestinal epithelial wound healing and recovery from injury. Focal adhesion kinase (FAK) plays an important role in cell–extracellular matrix signal transduction. We have previously shown that heparin-binding EGF-like growth factor (HB-EGF) promotes intestinal epithelial cell (IEC) migration and adhesion in vitro. The present study was designed to determine whether FAK is involved in HB-EGF–induced IEC migration and adhesion.

Materials and methods

A scrape wound healing model of rat IECs was used to examine the effect of HB-EGF on FAK-dependent cell migration in vitro. Immunofluorescence and Western blot analyses were performed to evaluate the effect of HB-EGF on the expression of phosphorylated FAK (p-FAK). Cell adhesion assays were performed to determine the role of FAK in HB-EGF–induced cell adhesion on fibronectin (FN).

Results

HB-EGF significantly increased healing after scrape wounding, an effect that was reversed in the presence of an FAK inhibitor 14 (both with P < 0.05). HB-EGF increased p-FAK expression and induced p-FAK redistribution and actin reorganization in migrating rat IECs. Cell adhesion and spreading on FN were significantly increased by HB-EGF (P < 0.05). FAK inhibitor 14 significantly inhibited both intrinsic and HB-EGF–induced cell adhesion and spreading on FN (both with P < 0.05).

Conclusions

FAK phosphorylation and FAK-mediated signal transduction play essential roles in HB-EGF–mediated IEC migration and adhesion.     

设置最佳呼气末正压的临床应用进展

术后肺部并发症（PPCs）是全身麻醉后常见的并发症。俯卧位手术围术期呼吸管理复杂且机械通气导致的呼吸机相关肺损伤（VILI）发生率高。肺保护性通气策略（LPVS）不仅可以降低围术期VILI发生率,还可以预防PPCs,改善预后。相较于固定的呼气末正压（PEEP）值,基于患者个体差异设置最佳PEEP更具有优势及和应用前景,是肺保护通气最有效的措施之一。本文对LPVS与最佳PEEP的可行性以及设置最佳PEEP的临床应用进行综述,以期为全身麻醉尤其是俯卧位手术患者提供更好的肺保护,减少术后肺部并发症的发生。