T淋巴细胞与高血压肾损伤的研究进展

近年来,免疫机制特别是T淋巴细胞参与的免疫反应在高血压肾损伤中备受关注.高血压期间新抗原产生、共刺激信号、交感神经兴奋和高浓度盐可激活T淋巴细胞,被激活的T淋巴细胞不仅通过引起炎症反应导致肾损伤,还可以通过促进氧化应激、影响水盐代谢、激活肾素-血管紧张素系统(renin-angiotensin system,RAS)导...     

一氧化氮和动脉粥样硬化

动脉粥样硬化是脂蛋白、单核细胞、巨噬细胞、T淋巴细胞与血管壁内皮细胞相互作用而导致的慢性炎症反应。这个炎症的过程由脂质浸润开始,涉及氧化应激反应,最终导致复杂的病理损伤和斑块的形成,斑块突出入血管,破裂形成血栓而导致急性的心肌梗塞或中风。激活内皮源性的一氧化氮合成酶而生成的一氧化氮（NO）能够预防动脉粥样硬化,并对不周发展阶段的动脉粥样硬化的病理形成均有改善和逆转作用。其生成的NO能抗氧化、清除自由基、抑制低密度脂蛋自在血管壁被氧化,防止氧化低密度脂蛋白（oxLDL）的产生,而影响脂质浸润;能抑制NFKB的激活和核内迁移,阻抑激活的内皮细胞表达黏附分子,减少嗜中性粒细胞和单核细胞的黏附和活化,减少血管壁的炎症反应;能抑制血小板黏附、聚集,抑制凝血酶诱导的血小板活性因子的表达以减少血栓形成;能阻止凋亡,保持内皮细胞的完整性;还能有效地抑制血管平滑肌细胞增殖、迁移和细胞外基质的合成,对动脉粥样硬化病理形成和发展具有阻抑作用。     

T淋巴细胞与血管紧张素Ⅱ的升压作用

血管紧张素(angiotensin,Ang)Ⅱ诱导水钠潴留及血管损害导致血压升高部分依赖于T淋巴细胞的活动.AngⅡ通过1-磷酸鞘氨醇(sphingosine-1-phosphate,S1P)通路促进T淋巴细胞组织浸润,且AngⅡ可促进T淋巴细胞炎症因子释放及自身RAS激活,而T淋巴细胞的活动可正反馈式导致AngⅡ水平...     

星形胶质细胞在阿尔茨海默病中的功能变化及分子机制

星形胶质细胞在脑内数量最多,分布最广,对神经元有营养支持的作用,并且能够调控神经元的活性。越来越多的证据表明星形胶质细胞激活参与阿尔茨海默病(Alzheimer's disease,AD)的发生和发展。在AD病理情况下,星形胶质细胞在多种因子如β淀粉样蛋白(beta-amyloid,Aβ)和促炎细胞因子的作用下被激活,激活的星形胶质细胞进一步释放一氧化氮(Nitric oxide,NO)和多种炎性因子增强炎症级联反应。功能失常的星形胶质细胞会促进Aβ的产生,减弱对Aβ的摄取和清除,导致Aβ聚集沉积形成老年斑。激活的星形胶质细胞释放的炎症因子还能显著增加神经元内tau蛋白的异常过度磷酸化,产生神经纤维缠结。本文对星形胶质细胞在AD中参与神经变性的功能变化和分子机制进行总结,为星形胶质细胞作为靶点预防及治疗AD提供一定的理论依据。     

NKT细胞在动脉粥样硬化中的作用

然杀伤T细胞（natural killer T cell,NKT细胞）是一种特殊的淋巴细胞亚群,具有部分T细胞和NK细胞的特征。与这些细胞不同的是,NKT细胞不仅能够识别醣脂类抗原,还在激活后产生促炎症因子和抗炎症因子。由于这些特性,NKT细胞在炎症和免疫方面的研究越来越热。动脉粥样硬化是一种受免疫调节的炎性疾病,因此对NKT细胞在该疾病中作用的研究也逐渐开展起来。     

NKT 细胞在动脉粥样硬化中的作用*

然杀伤T细胞(natural killer T cell,NKT细胞)是一种特殊的淋巴细胞亚群,具有部分T细胞和NK细胞的特征。与这些细胞不同的是,NKT细胞不仅能够识别醣脂类抗原,还在激活后产生促炎症因子和抗炎症因子。由于这些特性,NKT细胞在炎症和免疫方面的研究越来越热。动脉粥样硬化是一种受免疫调节的炎性疾病,因此对NKT细胞在该疾病中作用的研究也逐渐开展起来。     

微小RNAs在心力衰竭炎症机制中作用的研究进展

微小RNA是一组高度保守的长度约22个核苷酸非编码RNA,通过靶定相应的互补序列导致信使RNA的沉默,下调或者抑制翻译以调节基因和蛋白的表达。心力衰竭进程中存在慢性炎症激活和microRNA的异常表达,其中TLR4通路和NF-κB通路被广泛研究和认同,炎症因子如IL-1、IL-6、TNF-α参与心力衰竭的炎症激活过程,并且可以通过多种通路导致心肌细胞肥大,纤维化及凋亡,炎症因子激活、炎症通路中间因子及疾病进展形成复杂的病理网络,最终导致心肌功能紊乱和减退;microRNA可通过部分结合mRNA靶定部分在转录水平上抑制蛋白合成,参与心力衰竭炎症通路的整个过程,这一调节机制在心肌肥大、心力衰竭等多种心脏疾病中的作用逐渐被阐明。本文旨在总结微小RNAs在心力衰竭炎症机制中作用的研究进展,寻找微小RNA与心力衰竭中炎症激活过程的联系。     

基质金属蛋白酶在心肌缺血再灌注损伤中的作用

肌缺血再灌注损伤是指缺血心肌组织在恢复血流供给后,其细胞代谢功能障碍及结构破坏反而加重的现象,主要表现在心肌收缩与舒张功能障碍、血管内皮功能障碍、微循环血流紊乱、细胞代谢失调、电解质平衡紊乱、细胞凋亡与坏死等,并伴随着氧自由基的大量产生和毒性损伤以及炎症反应的激活,是一个极其复杂的病理过程。基质金属蛋白酶（MMPs）及其组织抑制物（TIMPs）是心肌组织中多种细胞分泌的内源性细胞因子,其作用涵盖了细胞外基质降解、炎症反应激活、调节血管功能、影响细胞凋亡与存活等众多病理生理过程,而这些过程均在心肌缺血再灌注损伤中发挥着重要的作用。     

基质金属蛋白酶在心肌缺血再灌注损伤中的作用

肌缺血再灌注损伤是指缺血心肌组织在恢复血流供给后,其细胞代谢功能障碍及结构破坏反而加重的现象,主要表现在心肌收缩与舒张功能障碍、血管内皮功能障碍、微循环血流紊乱、细胞代谢失调、电解质平衡紊乱、细胞凋亡与坏死等,并伴随着氧自由基的大量产生和毒性损伤以及炎症反应的激活,是一个极其复杂的病理过程。基质金属蛋白酶(MMPs)及其组织抑制物(TIMPs)是心肌组织中多种细胞分泌的内源性细胞因子,其作用涵盖了细胞外基质降解、炎症反应激活、调节血管功能、影响细胞凋亡与存活等众多病理生理过程,而这些过程均在心肌缺血再灌注损伤中发挥着重要的作用。     

Th17/Treg失衡与肝脏免疫病理反应的研究进展

Th17细胞及Th17/Treg失衡在炎症反应、组织损伤及纤维化形成中发挥了重要作用,与多种疾病的发生发展密切相关。前炎性细胞因子可诱导T细胞分化为Th17,使Th17/Treg失衡,导致IL-17、IL-6、趋化因子等促炎性细胞因子大量分泌并有效介导中性粒细胞动员与兴奋,使得机体产生炎症反应与免疫病理反应。就Th17/Treg细胞及其失衡在肝脏免疫病理反应中的研究进展进行了综述。     

Role of vascular smooth muscle cell in the inflammation of atherosclerosis

Atherosclerosis is a pathologic process occurring within the artery, in which many cell types, including T cell, macrophages, endothelial cells, and smooth muscle cells, interact, and cause chronic inflammation, in response to various inner- or outer-cellular stimuli. Atherosclerosis is characterized by a complex interaction of inflammation, lipid deposition, vascular smooth muscle cell proliferation, endothelial dysfunction, and extracellular matrix remodeling, which will result in the formation of an intimal plaque. Although the regulation and function of vascular smooth muscle cells are important in the progression of atherosclerosis, the roles of smooth muscle cells in regulating vascular inflammation are rarely focused upon, compared to those of endothelial cells or inflammatory cells. Therefore, in this review, we will discuss here how smooth muscle cells contribute or regulate the inflammatory reaction in the progression of atherosclerosis, especially in the context of the activation of various membrane receptors, and how they may regulate vascular inflammation. [BMB Reports 2014; 47(1): 1-7]     

Endothelial connexin-integrin crosstalk in vascular inflammation

Cardiovascular diseases including blood vessel disorders represent a major cause of death globally. The essential roles played by local and systemic vascular inflammation in the pathogenesis of cardiovascular diseases have been increasingly recognized. Vascular inflammation triggers the aberrant activation of endothelial cells, which leads to the functional and structural abnormalities in vascular vessels. In addition to humoral mediators such as pro-inflammatory cytokines and prostaglandins, the alteration of physical and mechanical microenvironment – including vascular stiffness and shear stress – modify the gene expression profiles and metabolic profiles of endothelial cells via mechano-transduction pathways, thereby contributing to the pathogenesis of vessel disorders. Notably, connexins and integrins crosstalk each other in response to the mechanical stress, and, thereby, play an important role in regulating the mechano-transduction of endothelial cells. Here, we provide an overview on how the inter-play between connexins and integrins in endothelial cells unfold during the mechano-transduction in vascular inflammation.     

Ezrin-Radixin-Moesin-binding Phosphoprotein 50 (EBP50) and Nuclear Factor-κB (NF-κB): A FEED-FORWARD LOOP FOR SYSTEMIC AND VASCULAR INFLAMMATION*

The interaction between vascular cells and macrophages is critical during vascular remodeling. Here we report that the scaffolding protein, ezrin-binding phosphoprotein 50 (EBP50), is a central regulator of macrophage and vascular smooth muscle cells (VSMC) function. EBP50 is up-regulated in intimal VSMC following endoluminal injury and promotes neointima formation. However, the mechanisms underlying these effects are not fully understood. Because of the fundamental role that inflammation plays in vascular diseases, we hypothesized that EBP50 mediates macrophage activation and the response of vessels to inflammation. Indeed, EBP50 expression increased in primary macrophages and VSMC, and in the aorta of mice, upon treatment with LPS or TNFα. This increase was nuclear factor-κB (NF-κB)-dependent. Conversely, activation of NF-κB was impaired in EBP50-null VSMC and macrophages. We found that inflammatory stimuli promote the formation of an EBP50-PKCζ complex at the cell membrane that induces NF-κB signaling. Macrophage activation and vascular inflammation after acute LPS treatment were reduced in EBP50-null cells and mice as compared with WT. Furthermore, macrophage recruitment to vascular lesions was significantly reduced in EBP50 knock-out mice. Thus, EBP50 and NF-κB participate in a feed-forward loop leading to increased macrophage activation and enhanced response of vascular cells to inflammation.     

Mineralocorticoid receptor: a critical player in vascular remodeling

Vascular remodeling is a pathological condition with structural changes of blood vessels. Both inside-out and outside-in hypothesis have been put forward to describe mechanisms of vascular remodeling. An integrated model of these two hypotheses emphasizes the importance of immune cells such as monocytes/macrophages, T cells, and dendritic cells. These immune cells are at the center stage to orchestrate cellular proliferation, migration, and interactions of themselves and other vascular cells including endothelial cells (ECs), vascular smooth muscle cells (VSMCs), and fibroblasts. These changes on vascular wall lead to inflammation and oxidative stress that are largely responsible for vascular remodeling. Mineralocorticoid receptor (MR) is a classic nuclear receptor. MR agonist promotes inflammation and oxidative stress and therefore exacerbates vascular remodeling. Conversely, MR antagonists have the opposite effects. MR has direct roles on vascular cells through non-genomic or genomic actions to modulate inflammation and oxidative stress. Recent studies using genetic mouse models have revealed that MR in myeloid cells, VSMCs and ECs all contribute to vascular remodeling. In conclusion, data in the past years have demonstrated that MR is a critical control point in modulating vascular remodeling. Studies will continue to provide evidence with more detailed mechanisms to support this notion.     

Increased retinoid signaling in vascular smooth muscle cells by proinflammatory cytokines

Retinoids have been shown to modulate inflammation and the immune response in many cell types including macrophages, endothelial cells, and vascular smooth muscle cells. However, present knowledge of whether inflammatory mediators modulate vitamin A status in these cells is limited. To identify the role of inflammation on retinoid metabolism in vascular smooth muscle cells, the cells were exposed to a combination of proinflammatory cytokines: interleukin-1beta, interferon-gamma, and lipopolysaccharides. Without stimulation with proinflammatory cytokines, vascular smooth muscle cells expressed retinol dehydrogenases-2 and 5 mRNA detected by RT-PCR. Stimulation with the combination of cytokines induced a substantial increase of retinol dehydrogenase-5 mRNA. This was associated with increased production of ligands for retinoic acid receptors, when assayed in a retinoic acid receptor-dependent luciferase reporter system. Our results demonstrate that inflammatory mediators activate the retinoid metabolic pathway in vascular smooth muscle cells, which potentially may modulate the inflammatory response in the vascular wall.     

Vascular endothelial growth factor (VEGF) induces remodeling and enhances TH2-mediated sensitization and inflammation in the lung

Exaggerated levels of VEGF (vascular endothelial growth factor) are present in persons with asthma, but the role(s) of VEGF in normal and asthmatic lungs has not been defined. We generated lung-targeted VEGF(165) transgenic mice and evaluated the role of VEGF in T-helper type 2 cell (T(H)2)-mediated inflammation. In these mice, VEGF induced, through IL-13-dependent and -independent pathways, an asthma-like phenotype with inflammation, parenchymal and vascular remodeling, edema, mucus metaplasia, myocyte hyperplasia and airway hyper-responsiveness. VEGF also enhanced respiratory antigen sensitization and T(H)2 inflammation and increased the number of activated DC2 dendritic cells. In antigen-induced inflammation, VEGF was produced by epithelial cells and preferentially by T(H)2 versus T(H)1 cells. In this setting, it had a critical role in T(H)2 inflammation, cytokine production and physiologic dysregulation. Thus, VEGF is a mediator of vascular and extravascular remodeling and inflammation that enhances antigen sensitization and is crucial in adaptive T(H)2 inflammation. VEGF regulation may be therapeutic in asthma and other T(H)2 disorders.     

Interleukin-32β Propagates Vascular Inflammation and Exacerbates Sepsis in a Mouse Model

Background

Inflammation is associated with most diseases, which makes understanding the mechanisms of inflammation vitally important.

Methodology/Principal Findings

Here, we demonstrate a critical function of interleukin-32β (IL-32β) in vascular inflammation. IL-32β is present in tissues from humans, but is absent in rodents. We found that the gene is highly expressed in endothelial cells. Three isoforms of IL-32, named IL-32α, β, and ε, were cloned from human endothelial cells, with IL-32β being the major isoform. Pro-inflammatory cytokines (TNFα and IL-1β) induced IL-32β expression through NF-κB. Conversely, IL-32β propagated vascular inflammation via induction of vascular cell adhesion molecules and inflammatory cytokines. Accordingly, IL-32β increased adhesion of inflammatory cells to activated endothelial cells, a paramount process in inflammation. These results illustrate a positive feedback regulation that intensifies and prolongs inflammation. Importantly, endothelial/hematopoietic expression of IL-32β in transgenic mice elevated inflammation and worsened sepsis. This was demonstrated by significant elevation of leukocyte infiltration and serum levels of TNFα and IL-1β, increased vascular permeability and lung damage, and accelerated animal death. Together, our results reveal an important function of IL-32 in vascular inflammation and sepsis development.

Conclusions/Significance

Our results reveal an important function of IL-32 in vascular inflammation and sepsis development.     

Anti-inflammatory and anti-atherogenic properties of adiponectin

Obesity-related disorders, such as insulin resistance, hypertension and atherosclerosis, are associated with chronic inflammation. Adiponectin is an adipocyte-derived secreted factor that is down-regulated in obese states. Adiponectin exerts the protective actions on obesity-linked diseases, such as insulin resistance and atherosclerosis by attenuating chronic inflammation in its target organs. Adiponectin also exerts the salutary effects on vascular disorders by directly acting on vascular component cells including endothelial cells, smooth muscle cells and macrophages. This review will focus on the role of adiponectin in control of inflammatory responses and atherogenic processes.     

Neurogenic inflammation, vascular permeability, and mast cells. II. Additional evidence indicating that mast cells are not involved in neurogenic inflammation.

Activation of cutaneous sensory nerves induces vasodilatation and vascular permeability, i.e., neurogenic inflammation. We examined the histology and possible mast cell involvement in cutaneous neurogenic inflammation induced by electrical nerve stimulation (ENS). Three lines of evidence indicated that mast cells were not involved in rodent cutaneous neurogenic inflammation induced by electrical stimulation of the saphenous nerve. 1) Most mast cells (86.5% of all mast cells in the dorsal skin of the paw) were found in the deep dermis, whereas vessels developing increased vascular permeability after nerve stimulation (visualized with the supravital dye Monastral blue B, a macro-molecular tracer) were localized predominantly in the superficial dermis. By contrast, i.v. substance P, which also causes increased cutaneous vascular permeability, predominantly caused deeper vessels to leak. As analyzed by electron microscopy, the vessels that developed permeability in response to nerve stimulation, and were thereby stained with Monastral blue B, were found to be exclusively postcapillary venules. 2) Disodium cromoglycate (DSCG), a mast cell stabilizing compound, inhibited the cutaneous vascular permeability induced by intradermal injections of anti-IgE in a dose-dependent manner. By contrast, vascular permeability induced by ENS was not influenced by disodium cromoglycate treatment. 3) ENS and i.v. substance P both induced cutaneous vascular permeability in mast cell-deficient W/Wv mice, despite the fact that their skin contained only 4.7% of the mast cells present in their normal +/+ litter mates. The magnitude of ENS-induced vascular permeability responses in W/Wv mice were similar to control +/+ and BALB/c mice. This study supports our earlier observations suggesting that mast cell activation is not essential for the initial, vascular permeability phase of neurogenic inflammation in rodent skin.