巨噬细胞凋亡与动脉粥样硬化

细胞凋亡是动脉粥样硬化病变的主要特征之一,其中巨噬细胞凋亡贯穿动脉粥样硬化的整个过程,而在成熟病变中,大多数凋亡细胞是紧邻脂核的巨噬细胞。激活的巨噬细胞虽具有一些保护作用,但总的作用还是促进动脉粥样硬化损伤的启动和发展,巨噬细胞死亡可导致细胞外脂质核的发生和扩大,对斑块破裂及血栓形成有重要影响。因此,动脉粥样硬化病灶中巨噬细胞的丧失可预测斑块的稳定性。本文主要从巨噬细胞凋亡在动脉粥样硬化病变过程中的机制及重要作用,以及与其他造成斑块不稳定性相关因素之间的关系加以阐述,更进一步阐明动脉粥样硬化的发病机制,从而为探索新的有效的临床防治策略提供可靠的理论基础。     

动脉粥样硬化中巨噬细胞介导胞葬作用的研究进展

动脉粥样硬化斑块内累积的大量凋亡和坏死细胞是斑块增大、坏死核心形成及斑块破裂的主要原因。生理状态下,机体通过巨噬细胞等吞噬细胞介导的胞葬作用能及时吞噬和清除凋亡细胞。然而近年来研究表明,斑块内凋亡细胞的清除速度远远低于生理状态,其机制与巨噬细胞介导的胞葬功能障碍密切相关。本文综述了巨噬细胞介导的胞葬作用及其功能缺陷在动脉粥样硬化中的研究进展,期望为动脉粥样硬化性心血管疾病防治提供理论和实验基础。     

异鼠李素通过抑制泡沫细胞形成增加动脉粥样硬化斑块稳定性的机制研究

背景 泡沫细胞的形成是动脉粥样硬化重要的病理基础,其是由巨噬细胞吞噬大量胆固醇和三酰甘油后转化而来.因此,如何促进巨噬细胞的脂质代谢、抑制其转化为泡沫细胞是延缓动脉粥样硬化病情进展的关键.目的 分析异鼠李素通过抑制泡沫细胞形成增加动脉粥样硬化斑块稳定性的机制.方法 本实验时间为2020年8月至2021年10月.动物实验...     

动脉粥样硬化斑块中的细胞凋亡及Bax/Bc1-2的基因表达

目的 探讨细胞凋亡与Bax/Bc1-2基因表达的内在联系,以及该基因表达与动脉粥样硬化斑决稳定性的关系.方法 选取人体动脉内膜剥脱术标本13例,固定、脱钙、每隔4 mm连续取材153块,常规HE染色,将斑块分为稳定斑块组和不稳定斑块组.每组40块并进行免疫组织化学染色.通过图像分析系统对各阳性区域进行半定量分析.结果 不稳定斑块组和稳定斑块组caspase-3、Bax、Bc1-2阳性细胞面积百分比分别为27.4%和15.4%(P＜0.05)、20.9%和15.1%(P＜0.05)、5.9%和10.3%(P＜0.01);纤维帽中巨噬细胞的面积百分比分别为17.3%和9.8%(P＜0.01),而平滑肌细胞的面积百分比分别为9.8%和15.9%(P＜0.05).结论 不稳定斑决较稳定斑块炎性反应严重,细胞凋亡率较高,细胞凋亡在不稳定斑块形成中起一定作用,Bax/Bc1-2参与了斑块内的细胞凋亡,be1-2在抑制斑块进展方面可能起一定作用.     

巨噬细胞凋亡与易损斑块形成的关系研究进展

易损斑块形成是造成急性冠状动脉综合征最根本的病理基础。近年来研究表明,粥样斑块内泡沫细胞凋亡尤其巨噬细胞凋亡是导致易损斑块形成的重要原因。本文就巨噬细胞凋亡在易损斑块形成中的作用及其机制作一综述。     

葛根总黄酮对载脂蛋白E基因缺陷小鼠动脉粥样硬化病变内细胞凋亡及凋亡相关基因的影响

目的 探讨葛根总黄酮对载脂蛋白E基因缺陷（apoE-／-）小鼠主动脉窦动脉粥样硬化斑块抑制作用的分子机制。方法 采用电镜观察、缺口末端标记（TUNEL）法检测apoE-／-小鼠动脉粥样硬化斑块内的细胞凋亡。免疫组化方法检测平滑肌细胞、巨噬细胞及Caspase一3蛋白的表达。结果 电镜观察到凋亡细胞核形不规则,胞核内染色质浓集、边聚,附着在核膜周边,线粒体肿胀,内质网扩张,超微结构形态符合巨噬细胞早期凋亡,并可见典型凋亡小体形成。TUNEL结果表明,凋亡细胞主要分布在粥样斑块脂质核心处,模型组动脉粥样硬化斑块内凋亡细胞数较多,而葛根总黄酮干预组凋亡细胞数明显减少,葛根高、低剂量组细胞凋亡率明显低于模型组[分别为（0．38±0．17）ok,（1．95±1．02）％,（10．50±5．89）％,P〈0．01],葛根高剂量组细胞凋亡率明显低于葛根低剂量组。抗CD68抗体免疫组化染色证实在动脉粥样硬化斑块脂质坏死核心内细胞CD68强阳性表达。葛根高、低剂量治疗组Caspase-3蛋白免疫表达低于模型组,葛根高剂量治疗组低于葛根低剂量治疗组。结论 葛根总黄酮可能通过下调apoE-／-小鼠主动脉窦动脉粥样硬化病变内Caspases-3蛋白的表达,显著降低了动脉粥样硬化病变内巨噬细胞凋亡,从而抑制了动脉粥样硬化斑块的进展。     

巨噬细胞增殖和凋亡与动脉粥样硬化

动脉粥样硬化（As）是一种由动脉壁脂质沉积所引发的一种病理生理过程,与巨噬细胞介导的慢性炎性反应高度相关。As早期,巨噬细胞通过吞噬作用清除斑块中修饰脂蛋白、细胞碎片和死亡细胞,限制斑块生长。随着病程进展,斑块中巨噬细胞凋亡增多且清除功能下降,引起继发性细胞坏死和炎性反应,促成不稳定斑块形成。巨噬细胞增殖和凋亡与As发生发展密切相关。本文主要针对巨噬细胞增殖和凋亡对As发生发展的影响做一综述,为As防治提供理论依据。     

细胞凋亡蛋白bax和下肢动脉粥样硬化的关系

目的探讨细胞凋亡蛋白bax和下肢动脉粥样硬化的关系。方法收集正常对照组股动脉标本12例(正常对照组)。糖尿病及非糖尿病尸检病例的股动脉标本各8例分别为糖尿病组及非糖尿病组。将所有动脉标本每隔4 mm连续取材,常规病理学检查,并行免疫组织化学染色。结果正常股动脉内膜未发现bax的表达。动脉粥样硬化病变的脂纹中可见巨噬细胞bax的表达。但平滑肌细胞上未发现bax表达。在斑块中,bax在平滑肌细胞和巨噬细胞均有表达。和非糖尿病组比较,糖尿病组斑块中bax阳性的平滑肌细胞多,bax阳性的巨噬细胞少。结论细胞凋亡蛋白bax参与下肢动脉粥样硬化的形成。糖尿病可能通过影响斑块中bax的表达,使斑块不稳定。     

巨噬细胞凋亡与糖尿病动脉粥样硬化

在动脉粥样硬化性病变的进展过程中,一个关键的步骤就是易损斑块的形成.而巨噬细胞凋亡可促进斑块的进展,并与易损斑块形成密切相关.动脉粥样硬化性血管疾病是糖尿病主要并发症之一,因此总结与糖尿病相关的脂代谢紊乱、胰岛素抵抗、脂肪因子等巨噬细胞凋亡影响因素,并初步探讨其介导斑块内巨噬细胞凋亡的信号转导途径,对于防治糖尿病患者动脉粥样硬化具有重要意义.     

巨噬细胞自噬与动脉粥样硬化的关系及相关中药研究进展

自体吞噬(自噬)是由溶酶体介导的降解细胞质内受损的细胞器或蛋白质的代谢过程。适度的自噬对动脉粥样硬化具有保护作用,过度自噬会导致细胞死亡,不利于斑块的稳定性。巨噬细胞在动脉粥样硬化斑块进展中起重要作用,自噬是影响巨噬细胞在动脉粥样硬化中生存的分子细胞机制,直接影响动脉粥样硬化进程。本研究对自噬在动脉粥样硬化中的双重作用、巨噬细胞自噬对干预动脉粥样硬化的意义、中药对巨噬细胞自噬的影响及其在动脉粥样硬化防治中的潜在意义进行综述。     

Monoclonal antibodies against oxidized low-density lipoprotein bind to apoptotic cells and inhibit their phagocytosis by elicited macrophages: Evidence that oxidation-specific epitopes mediate macrophage recognition

Apoptosis is recognized as important for normal cellular homeostasis in multicellular organisms. Although there have been great advances in our knowledge of the molecular events regulating apoptosis, much less is known about the receptors on phagocytes responsible for apoptotic cell recognition and phagocytosis or the ligands on apoptotic cells mediating such recognition. The observations that apoptotic cells are under increased oxidative stress and that oxidized low-density lipoprotein (OxLDL) competes with apoptotic cells for macrophage binding suggested the hypothesis that both OxLDL and apoptotic cells share oxidatively modified moieties on their surfaces that serve as ligands for macrophage recognition. To test this hypothesis, we used murine monoclonal autoantibodies that bind to oxidation-specific epitopes on OxLDL. In particular, antibodies EO6 and EO3 recognize oxidized phospholipids, including 1-palmitoyl 2-(5-oxovaleroyl) phosphatidylcholine (POVPC), and antibodies EO12 and EO14 recognize malondialdehyde-lysine, as in malondialdehyde-LDL. Using FACS analysis, we demonstrated that each of these EO antibodies bound to apoptotic cells but not to normal cells, whereas control IgM antibodies did not. Confocal microscopy demonstrated cell-surface expression of the oxidation-specific epitopes on apoptotic cells. Furthermore, each of these antibodies inhibited the phagocytosis of apoptotic cells by elicited peritoneal macrophages, as did OxLDL. In addition, an adduct of POVPC with BSA also effectively prevented phagocytosis. These data demonstrate that apoptotic cells express oxidation-specific epitopes-including oxidized phospholipids-on their cell surface, and that these serve as ligands for recognition and phagocytosis by elicited macrophages.     

IL-10-producing macrophages preferentially clear early apoptotic cells

Efficient clearance of apoptotic cells seems to be a prerequisite to prevent the development of autoimmunity. Here we identify that macrophage colony-stimulating factor (M-CSF)-driven macrophages (M?2s) are potent phagocytes that have the unique capacity to preferentially bind and ingest early apoptotic cells. This macrophage subset has intrinsic anti-inflammatory properties, characterized by high interleukin-10 (IL-10) production in the absence of proinflammatory cytokines, such as IL-6 and tumor necrosis factor-alpha (TNF-alpha). Importantly, whereas the IL-6 and TNF-alpha production by granulocyte-macrophage (GM)-CSF-driven macrophages (M?1s) is inhibited upon uptake of apoptotic cells, the anti-inflammatory status of M?2 is retained during phagocytosis. M?2s were shown to use CD14 to tether apoptotic cells, whereas recognition of phosphatidylserine (PS) contributed to uptake of early apoptotic cells. M?2s showed more potent macropinocytosis compared with dendritic cells (DCs) and M?1s, and uptake of apoptotic cells was inhibited by a macropinocytosis inhibitor. Our studies suggest that, under steady-state conditions, IL-10-producing M?2s are prominently involved in the clearance of early apoptotic cells.     

Phagocytosis in atherosclerosis: Molecular mechanisms and implications for plaque progression and stability

Macrophages play a key role in atherosclerotic plaque destabilization and rupture. In this light, selective removal of macrophages may be beneficial for plaque stability. However, macrophages are phagocytic cells and thus have an important additional role in scavenging of modified lipoproteins, unwanted or dead cells and cellular debris via phagocytosis. The concept of phagocytosis as well as the underlying mechanisms is well defined but the effect of phagocytosis in terms of plaque stability remains poorly understood. Recent findings point towards a complex role of macrophage phagocytosis in atherogenesis. Macrophages are necessary for removal of apoptotic cells from plaques, but exert strong proatherogenic properties upon phagocytosis of lipoproteins, erythrocytes and platelets. Apart from heterophagy, autophagocytosis better known as autophagy may occur in advanced atherosclerotic plaques. Several lines of evidence indicate that autophagy is initiated in plaque smooth muscle cells as a result of cellular distress. Since autophagy is well recognized as a survival mechanism, autophagic smooth muscle cells in the fibrous cap may reflect an important feature underlying plaque stability. All together, phagocytosis is a crucial process involved in atherogenesis that may significantly affect the stability of the atherosclerotic plaque.     

Interaction of macrophages with apoptotic cells enhances HIV Type 1 replication through PGE2, PAF, and vitronectin receptor

Phagocytosis of apoptotic cells by macrophages increases secretion of soluble mediators and generates an antiinflammatory environment. We previously reported that phagocytosis of apoptotic cells by HIV-1-infected macrophages enhances viral replication, with the participation of the cytokine transforming growth factor- beta1 and an integrin receptor. Now, we describe the role of prostaglandin E2 (PGE2), platelet-activating factor (PAF), and the integrin alphaVbeta3 (vitronectin receptor, VnR) in this phenomenon. Exacerbation of HIV-1 growth induced by phagocytosis of apoptotic cells was inhibited when HIV-1-infected macrophages were treated with a cyclooxygenase 2 inhibitor, or with a PAF receptor antagonist (BN 52021) immediately after macrophage interaction with apoptotic cells. Treatment of HIV-1-infected macrophages with BN 52021 decreased viral replication, whereas addition of PGE2 or PAF to these cells enhanced viral replication. Monoclonal antibodies (MAbs) to VnR reduced the macrophage uptake of apoptotic cells, prevented the enhancement of HIV-1 growth upon the engulfment of apoptotic cells, and potently augmented viral replication in HIV-1-infected macrophages in the absence of apoptotic cells. In conclusion, PGE2 and PAF, and ligation of VnR as well, contribute to amplify viral growth in HIV-1-infected macrophages upon uptake of apoptotic cells.     

The role of the macrophage in apoptosis: hunter,gatherer, and regulator

Clearance of cellular corpses is a critical feature of apoptosis in vivo during development, tissue homeostasis, and resolution of inflammation. As the professional phagocytes of the body, macrophages play a key role in this process. By recognizing emerging signals using several different receptors, macrophages engulf apoptotic cells swiftly and efficiently. In addition, the binding of apoptotic cells profoundly down-regulates the ability of the macrophage to produce inflammatory mediators by inducing the release of antiinflammatory mediators. Finally, macrophages may actually induce cell death in specific cells during embryogenesis. Abnormalities of apoptotic cell clearance may contribute to the pathogenesis of chronic inflammatory diseases, including those of autoimmune etiology. It is also possible that certain malignant tumor cells co-opt the mechanisms for apoptotic cell clearance to avoid immune surveillance by subverting macrophage and dendritic cell responses.     

CX3CL1/fractalkine is released from apoptotic lymphocytes to stimulate macrophage chemotaxis

Cells undergoing apoptosis are efficiently located and engulfed by phagocytes. The mechanisms by which macrophages, the professional scavenging phagocytes of apoptotic cells, are attracted to sites of apoptosis are poorly defined. Here we show that CX3CL1/fractalkine, a chemokine and intercellular adhesion molecule, is released rapidly from apoptotic lymphocytes, via caspase- and Bcl-2-regulated mechanisms, to attract macrophages. Effective chemotaxis of macrophages to apoptotic lymphocytes is dependent on macrophage fractalkine receptor, CX3CR1. CX3CR1 deficiency caused diminished recruitment of macrophages to germinal centers of lymphoid follicles, sites of high-rate B-cell apoptosis. These results provide the first demonstration of chemokine/chemokine-receptor activity in the navigation of macrophages toward apoptotic cells and identify a mechanism by which macrophage infiltration of tissues containing apoptotic lymphocytes is achieved.     

Syntaxin-11 is expressed in primary human monocytes/macrophages and acts as a negative regulator of macrophage engulfment of apoptotic cells and IgG-opsonized target cells

Syntaxin-11 is a member of a family of membrane-trafficking proteins referred to as soluble N -ethylmaleimide-sensitive factor attachment protein receptors (SNAREs). Recent studies have shown that syntaxin-11 is expressed in natural killer cells and cytotoxic T cells and is likely to play a role in the granule exocytosis pathway. However, the biological role of syntaxin-11 in other immune cells has remained elusive. This study found that stimulation with interferon-γ upregulated syntaxin-11 expression in primary monocytes. Experiments using monocytes from patients with familial haemophagocytic lymphohistiocytosis harbouring mutations in the gene encoding syntaxin-11 ( STX11 ), or monocytes from healthy individuals in which syntaxin-11 was downregulated using specific short-interfering RNA, demonstrated that syntaxin-11 was not required for antibody-dependent cellular cytotoxicity. On the other hand, silencing of syntaxin-11 expression in primary macrophages enhanced the phagocytosis of apoptotic target cells with a concomitant increase in macrophage secretion of tumour necrosis factor-α. Moreover, Fcγ-receptor-mediated uptake of target cells was also enhanced following silencing of syntaxin-11 expression in macrophages. In addition, syntaxin-11 localized to the plasma membrane in macrophages ingesting apoptotic cell corpses. Syntaxin-11 thus appears to act as a negative regulator of human macrophage engulfment of apoptotic cells and IgG-opsonized red blood cells.     

Role for the class A macrophage scavenger receptor in the phagocytosis of apoptotic thymocytes in vitro.

Numerous immature thymocytes undergo apoptosis and are rapidly engulfed by phagocytic thymic macrophages. The macrophage surface receptors involved in apoptotic thymocyte recognition are unknown. We have examined the role of the class A macrophage scavenger receptor (SR-A) in the engulfment of apoptotic thymocytes. Uptake of steroid-treated apoptotic thymocytes by thymic and inflammatory-elicited SR-A positive macrophages is partially inhibited by an anti-SR-A mAb and more completely by a range of scavenger receptor ligands. Thymic macrophages from mice with targeted disruption of the SR-A gene show a 50% reduction in phagocytosis of apoptotic thymocytes in vitro. These data suggest that SR-A may play a role in the clearance of dying cells in the thymus.     

Low-dose azithromycin improves phagocytosis of bacteria by both alveolar and monocyte-derived macrophages in chronic obstructive pulmonary disease subjects

Background and objective: Chronic inflammation and reduced airways integrity in chronic obstructive pulmonary disease (COPD) potentially results from secondary necrosis as a result of impaired phagocytosis of apoptotic material by airway macrophages, and increased bacterial colonization. We have previously shown that administration of low‐dose azithromycin to subjects with COPD improved macrophage phagocytosis of apoptotic airway epithelial cells, reduced inflammation and increased expression of macrophage mannose receptor. Methods: We firstly investigated whether there were defects in the ability of both alveolar (AM) and monocyte‐derived macrophages (MDM) to phagocytose bacteria in COPD, as we have previously reported for phagocytosis of apoptotic cells. We then assessed the effects of administration of low‐dose azithromycin to COPD patients on the ability of AM and MDM to phagocytose bacteria. Azithromycin (250 mg orally daily for 5 days then 2× weekly (total 12 weeks)) was administered to 11 COPD subjects and phagocytosis of fluorescein isothiocyanate‐labelled Escherichia coli assessed by flow cytometry. Results: COPD subjects had a significant defect in the ability of both AM and MDM to phagocytose bacteria that was significantly improved by administration of low‐dose azithromycin Conclusions: The data provide further support for the long‐term use of low dose azithromycin as an attractive adjunct treatment option for COPD. Improved clearance of both apoptotic cells and bacteria in the airway may have a dual effect; reducing the risk of secondary necrosis and release of toxic cell contents that perpetuate inflammation as well as contributing to a reduction in the rate of exacerbations in COPD.