淋巴管:干预动脉粥样硬化发生发展的潜在途径

动脉粥样硬化是一种慢性炎症性疾病,是血管壁对各种损伤的异常反应。虽然影响动脉粥样硬化的因素很多,但淋巴管在动脉粥样硬化中的作用一直被忽视。传统上认为淋巴管是将间质液回流至血液循环的通道。在早期的研究中,发现动脉粥样硬化周围存在大量淋巴管,但两者之间的关系一直不清楚。近期研究发现淋巴管不仅参与动脉炎症的起始和消退,在胆固醇逆转运中也发挥着积极作用。此外,改善淋巴功能或促进局部淋巴管生成似乎可以减轻动脉粥样硬化的进展。因此,研究淋巴管与动脉粥样硬化的关系对干预动脉粥样硬化的发生发展具有重要意义。文章介绍了淋巴管与动脉粥样硬化发生发展相关的炎症、胆固醇逆转运以及免疫等因素的关系,以期为动脉粥样硬化干预策略的研究提供新的视角。     

肝脏淋巴管新生在肝纤维化进展中的作用

肝纤维化可进展为肝硬化、终末期肝病而导致预后不良。除与病理性血管生成和肝血窦重塑相关外,肝脏淋巴管新生在肝纤维化的进展中也起重要作用。简述了淋巴管标志物及其在肝脏中的表达,叙述了淋巴管新生在肝纤维化中的作用,归纳了肝脏巨噬细胞即Kupffer细胞和淋巴管内皮细胞在肝脏淋巴管新生中的作用,提出淋巴管新生可能成为干预肝纤维化的潜在靶点,对早期治疗及逆转肝纤维化、预防肝硬化及终末期肝病的发生具有重要作用。     

淋巴管与消化系恶性肿瘤相关研究

肿瘤淋巴管形成与抑制在消化系恶性肿瘤转移中的作用逐渐受到重视,阻断淋巴管生成是抑制肿瘤淋巴道转移的有效途径,有关恶性肿瘤淋巴管生成机制的研究不断深入。此文综述了肿瘤淋巴管内皮细胞的分子标志物及针对上述靶点的抗肿瘤淋巴管生成的治疗方法。     

淋巴管新生与肿瘤淋巴道转移的相关性

在实体恶性肿瘤中,淋巴道是肿瘤细胞转移的主要途径,淋巴管生成在肿瘤的淋巴转移过程中起重要作用。随着淋巴管内皮特异标记物和淋巴管生长因子的发现,肿瘤诱发淋巴管生成的分子机制和以抑制肿瘤淋巴管生成作为抗肿瘤转移靶点的研究引起临床关注。现将淋巴管生成于肿瘤淋巴道转移相关性的研究进展综述如下。     

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。     

肿瘤淋巴管生成的调控

侵袭和转移是恶性肿瘤的基本特征,淋巴管是恶性肿瘤侵袭转移到局部淋巴结或远处器官的主要途径之一.近年来,越来越多的研究表明肿瘤中存在活跃的淋巴管生成,新生的淋巴管对肿瘤的转移起着重要作用.淋巴管的生成是一个由多种因子参与的复杂过程,除趋化因子、黏附分子和细胞外基质等作用外,淋巴管内皮细胞特异性转录因子和受体等发挥着关键性作用.明确淋巴管生成的调控机制对肿瘤的治疗有重要意义.     

神经导向因子Netrin-1调节单核巨噬细胞迁移与动脉粥样斑块关系的研究进展

动脉粥样硬化是动脉壁的一种慢性炎症性疾病,单核巨噬细胞在其发生发展中起着关键作用。动脉粥样斑块中单核巨噬细胞迁移能力受损,滞留于斑块内,增加了斑块不稳定性,加速动脉粥样硬化病变的进展。目前研究表明动脉粥样斑块中巨噬细胞分泌的神经导向因子Netrin-1通过与巨噬细胞表面相应受体结合,可以抑制巨噬细胞迁出斑块,促进动脉粥样硬化的进展。但在动脉粥样硬化形成初期,血管内皮细胞表达的Netrin-1却被发现对动脉粥样硬化起到保护作用。     

Src调控动脉粥样硬化斑块中巨噬细胞脂质累积的机制研究

目的:探究Src对动脉粥样硬化斑块中巨噬细胞脂质累积的调控机制。方法:取发生动脉粥样硬化的股动脉(病变组)与正常乳内动脉(对照组)组织,免疫组织化学法检测组织中磷酸化Src表达水平。采用Src干扰小RNA(siRNA)转染和Src蛋白激酶特异性抑制剂PP2处理巨噬细胞,通过油红O染色及比色法测定其胞内脂质含量,探究Src对巨噬细胞脂质累积的作用机制。通过构建C57BL/6小鼠动脉粥样硬化模型,进一步确定Src在动脉粥样硬化过程中的重要作用。结果:与正常对照相比较,动脉粥样硬化斑块中磷酸化Src表达量明显升高(P<0.05),且与CD68阳性细胞(巨噬细胞)共定位良好;降低Src表达水平和活性后,氧化低密度脂蛋白(oxLDL)诱导的巨噬细胞内脂质累积减少(P<0.05)。结论:Src可能通过介导巨噬细胞脂质累积调控动脉粥样硬化斑块的形成。     

结直肠癌淋巴管生成与淋巴结转移相关检测的临床研究进展

结直肠癌是人类常见的可经淋巴道转移的恶性肿瘤,其淋巴管生成与转移过程中牵涉了多种生物标志物表达水平的改变,检测这些相关生物标志物可为结直肠癌的诊断、治疗和预后情况提供重大参考价值．本文主要综述近年来与结直肠癌淋巴管生成与淋巴结转移相关检测的临床研究进展．     

消化道肿瘤淋巴管生成的临床研究进展

肿瘤淋巴管生成与淋巴转移的关系是近年肿瘤转移机制的一大研究热点 ,此文简要综述近年消化道恶性肿瘤淋巴管生成与淋巴管分布、临床病理指标及预后、生存等的关系。     

VEGF Pathways in the Lymphatics of Healthy and Diseased Heart

Cardiac lymphatic system is a rare focus of the modern cardiovascular research. Nevertheless, the growing body of evidence is depicting lymphatic endothelium as an important functional unit in healthy and diseased myocardium. Since the discovery of angiogenic VEGF‐A in 1983 and lymphangiogenic VEGF‐C in 1997, an increasing amount of knowledge has accumulated on the essential roles of VEGF ligands and receptors in physiological and pathological angiogenesis and lymphangiogenesis. Tissue adaptation to several stimuli such as hypoxia, pathogen invasion, degenerative process and inflammation often involves coordinated changes in both blood and lymphatic vessels. As lymphatic vessels are involved in the initiation and resolution of inflammation and regulation of tissue edema, VEGF family members may have important roles in myocardial lymphatics in healthy and in cardiac disease. We will review the properties of VEGF ligands and receptors concentrating on their lymphatic vessel effects first in normal myocardium and then in cardiac disease.     

Lymphatic biology and the microcirculation: past, present and future

Because of the role that lymphatics have in fluid and macromolecular exchange, lymphatic function has been tightly tied to the study of the microcirculation for decades. Despite this, our understanding of many basic tenets of lymphatic function is far behind that of the blood vascular system. This is in part due to the difficulty inherent in working in small, thin-walled, clear lymphatic vessels and the relative lack of lymphatic specific molecular/cellular markers. The application of cellular and molecular tools to the field of lymphatic biology has recently produced some significant developments in lymphatic endothelial cell biology. These have propelled our understanding of lymphangiogenesis and related fields forward. Whereas the use of some of these techniques in lymphatic muscle biology has somewhat lagged behind those in the endothelium, recent developments in lymphatic muscle contractile and electrical physiology have also led to advances in our understanding of lymphatic transport function, particularly in the regulation of the intrinsic lymph pump. However, much work remains to be done. This paper reviews significant developments in lymphatic biology and discusses areas where further development of lymphatic biology via classical, cellular, and molecular approaches is needed to significantly advance our understanding of lymphatic physiology.     

Engineered models of the lymphatic vascular system: Past,present, and future

The lymphatic vascular system is crucial for optimizing body fluid level, regulating immune function, and transporting lipid. Relative to the experimental models to investigate blood vasculature, there are significantly fewer tools to explore lymphatics. Although in vivo studies have contributed to major discoveries in the field, finding and characterizing lymphatic specific markers has opened the door to isolating lymphatic vessels and cells for building ex vivo and in vitro platforms. These preparations have enabled the study and analysis of lymphatic vasculature in various physiological and pathophysiological conditions leading to a better understanding of cellular expressions and signaling. In this review, a broad range of ex vivo and in vitro engineered models are highlighted and categorized based on the major lymphatic function they model including contractile function, inflammation, drainage and immune regulation, lymphangiogenesis, and tumor-lymphatic interactions. Then, the novel 3D engineered tissues are introduced consisting of acellularized scaffolds and hydrogels to form vessels and cellular structures close to in vivo morphology. This paper also compares traditional in vitro methods with recent technologies and elaborates on the inherent advantages and limitations of each preparation by critically discussing simplest to most complex tissue-cellular structures. It concludes with an outlook of the lymphatic vasculature models and the possible future direction of contemporary tools, such as organ-on-chips.     

淋巴管生成的分子机制与恶性肿瘤的转移

长期以来一直认为淋巴管是恶性肿瘤转移的有效途径;但是,关于淋巴管内皮细胞的特异性标记物缺乏一致的资料,而且,恶性肿瘤内是否存在新生淋巴管也一直有争议。直到最近,发现了新的淋巴管内皮细胞标记物,在肿瘤的动物模型以及人类肿瘤中均发现了新生淋巴管,对于VEGF-C、D／VEGFR-3信号途径的深入了解,因此淋巴管生成在肿瘤转移中的相关研究得以深入进行。越来越多的研究资料表明,淋巴管生成同肿瘤的转移播散、肿瘤患者的预后等直接相关。现将淋巴管生成的分子机制以及其与肿瘤转移的相关研究进展综述。     

Investigating lymphangiogenesis in vitro and in vivo using engineered human lymphatic vessel networks

The lymphatic system is involved in various biological processes, including fluid transport from the interstitium into the venous circulation, lipid absorption, and immune cell trafficking. Despite its critical role in homeostasis, lymphangiogenesis (lymphatic vessel formation) is less widely studied than its counterpart, angiogenesis (blood vessel formation). Although the incorporation of lymphatic vasculature in engineered tissues or organoids would enable more precise mimicry of native tissue, few studies have focused on creating engineered tissues containing lymphatic vessels. Here, we populated thick collagen sheets with human lymphatic endothelial cells, combined with supporting cells and blood endothelial cells, and examined lymphangiogenesis within the resulting constructs. Our model required just a few days to develop a functional lymphatic vessel network, in contrast to other reported models requiring several weeks. Coculture of lymphatic endothelial cells with the appropriate supporting cells and intact PDGFR-β signaling proved essential for the lymphangiogenesis process. Additionally, subjecting the constructs to cyclic stretch enabled the creation of complex muscle tissue aligned with the lymphatic and blood vessel networks, more precisely biomimicking native tissue. Interestingly, the response of developing lymphatic vessels to tensile forces was different from that of blood vessels; while blood vessels oriented perpendicularly to the stretch direction, lymphatic vessels mostly oriented in parallel to the stretch direction. Implantation of the engineered lymphatic constructs into a mouse abdominal wall muscle resulted in anastomosis between host and implant lymphatic vasculatures, demonstrating the engineered construct''s potential functionality in vivo. Overall, this model provides a potential platform for investigating lymphangiogenesis and lymphatic disease mechanisms.

The lymphatic and blood vascular systems are two distinct vessel network systems that work in synchrony to maintain tissue homeostasis. Blood vessels transport oxygen and nutrients around the body, while lymphatic vessels collect leaked fluid and macromolecules from the interstitial space and return them to the blood circulation, maintaining interstitial fluid homeostasis (1). Furthermore, the lymphatic system plays a central role in immune responses, inflammation regulation, and lipid absorption (2). While many in vitro models have been created to study angiogenesis, fewer attempts have been made to engineer an in vitro platform to study lymphangiogenesis. Such engineered models are critical for both fundamental research and the development of clinically implantable tissue to treat various diseases involving the lymphatic system. One such disease is lymphedema, a chronic condition that affects 200 million people worldwide (3). Lymphedema is characterized by tissue swelling resulting from a compromised lymphatic system. The condition is mainly caused by complications during cancer treatment but may also develop due to genetic disorders. The condition is progressive and incurable, with a high risk of infection. Implantation of engineered lymphatic tissue can serve as a treatment for such disease (4).Lymph flow is primarily driven by pressures generated by lymphatic contractions of the smooth muscle cells surrounding the vessels (5). Impaired contractility thus reduces lymph flow and may cause lymphedema. Previous computational studies have investigated the correlation between lymphatic vessel contractility and mechanical stimulation, such as mechanical loading, pressure gradients, and shear stress amplitudes (6, 7). Furthermore, studies have investigated lymphatic vessel capacity to distend under mechanical loading conditions. In addition, the microenvironment composition has been shown to play an important role in enabling lymphatic vessel functionality (4).Thus far, several groups have been able to engineer lymphatic tissues. Marino et al. created dermo-epidermal skin grafts with lymphatic and blood vessels embedded in a fibrin-collagen gel (8). Others created a lymphatic vessel network within multilayered fibroblast sheets (9, 10). Another study demonstrated that different hydrogel compositions are required for the optimal growth and development of blood and lymphatic endothelial cells (BECs and LECs, respectively) (11). However, no studies have investigated the influence of the supporting cells, the secreted extracellular matrix (ECM), and the mechanical environment on the forming lymphatic vessels. Since lymphatic pathologies are known to correlate with mechanically impaired lymphatic vessels (4), it is important to create lymphatic models with a biomimetic microenvironment.In this study, lymphatic vessel networks were engineered to investigate fundamental questions concerning lymphangiogenesis, including the influence of different supporting cells on the formation of lymphatic vessels and the role of PDGFR-β, an important receptor associated with support cells recruitment, in vessel formation. In addition, a complex tissue designed to better mimic native tissue was generated and lymphatic and blood vessel development along with muscle formation were monitored. In addition, the impact of the application of cyclic stretch on the organization and alignment of lymphatic-blood-vessel-muscle tissue was assessed. Finally, the penetration and anastomosis of the engineered lymphatic vessels were monitored following their implantation into mice.     

Modeling lymphangiogenesis: Pairing in vitro and in vivo metrics

Lymphangiogenesis is the mechanism by which the lymphatic system develops and expands new vessels facilitating fluid drainage and immune cell trafficking. Models to study lymphangiogenesis are necessary for a better understanding of the underlying mechanisms and to identify or test new therapeutic agents that target lymphangiogenesis. Across the lymphatic literature, multiple models have been developed to study lymphangiogenesis in vitro and in vivo. In vitro, lymphangiogenesis can be modeled with varying complexity, from monolayers to hydrogels to explants, with common metrics for characterizing proliferation, migration, and sprouting of lymphatic endothelial cells (LECs) and vessels. In comparison, in vivo models of lymphangiogenesis often use genetically modified zebrafish and mice, with in situ mouse models in the ear, cornea, hind leg, and tail. In vivo metrics, such as activation of LECs, number of new lymphatic vessels, and sprouting, mirror those most used in vitro, with the addition of lymphatic vessel hyperplasia and drainage. The impacts of lymphangiogenesis vary by context of tissue and pathology. Therapeutic targeting of lymphangiogenesis can have paradoxical effects depending on the pathology including lymphedema, cancer, organ transplant, and inflammation. In this review, we describe and compare lymphangiogenic outcomes and metrics between in vitro and in vivo studies, specifically reviewing only those publications in which both testing formats are used. We find that in vitro studies correlate well with in vivo in wound healing and development, but not in the reproductive tract or the complex tumor microenvironment. Considerations for improving in vitro models are to increase complexity with perfusable microfluidic devices, co-cultures with tissue-specific support cells, the inclusion of fluid flow, and pairing in vitro models of differing complexities. We believe that these changes would strengthen the correlation between in vitro and in vivo outcomes, giving more insight into lymphangiogenesis in healthy and pathological states.     

心淋巴管研究现状

心淋巴系统是心脏的重要组成部分,对维持心肌正常代谢,心肌细胞内环境稳定起重要的作用.心淋巴循环与心脏病理有一定的联系,但目前对心淋巴管的研究相对缺乏,现就心淋巴管的分布、淋巴管标记物和形态学研究方法进行综述以便进一步对心淋巴管进行深入研究.     

Abnormal lymphangiogenesis in idiopathic pulmonary fibrosis with insights into cellular and molecular mechanisms

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, debilitating respiratory disease whose pathogenesis is poorly understood. In IPF, the lung parenchyma undergoes extensive remodeling. We hypothesized that lymphangiogenesis is part of lung remodeling and sought to characterize pathways leading to lymphangiogenesis in IPF. We found that the diameter of lymphatic vessels in alveolar spaces in IPF lung tissue correlated with disease severity, suggesting that the alveolar microenvironment plays a role in the lymphangiogenic process. In bronchoalveolar lavage fluid (BALF) from subjects with IPF, we found short-fragment hyaluronic acid, which induced migration and proliferation of lymphatic endothelial cells (LECs), processes required for lymphatic vessel formation. To determine the origin of LECs in IPF, we isolated macrophages from the alveolar spaces; CD11b⁺ macrophages from subjects with IPF, but not those from healthy volunteers, formed lymphatic-like vessels in vitro. Our findings demonstrate that in the alveolar microenvironment of IPF, soluble factors such as short-fragment hyaluronic acid and cells such as CD11b⁺ macrophages contribute to lymphangiogenesis. These results improve our understanding of lymphangiogenesis and tissue remodeling in IPF and perhaps other fibrotic diseases as well.