外膜滋养血管在动脉粥样硬化易损斑块中的研究现状

随着对动脉粥样硬化(As)的深入研究,促进易损斑块的稳定性成为As新的治疗理念。在As"由内而外"学说中血管内膜的病理改变成为始动因素,然而近年研究表明外膜新生滋养血管(VV)在As"由外向内"发病机制中起到关键作用,总之,对于As的治疗已从保护血管内膜转变为调节外膜VV。     

外膜是血管病变的积极参与者

长期以来对动脉外膜与血管病灶形成关系的研究较少。一般认为动脉外膜炎性细胞聚集是晚期动脉粥样硬化病灶的病理学特征之一,外膜炎症的严重程度与病灶的严重程度呈正相关。近年来有报告发现动脉外膜炎症是诱发动脉内膜粥样硬化病灶形成的早期事件。研究发现血管成形术后动脉还原型辅酶Ⅱ氧化酶活性增强,氧自由基生成增多,刺激外膜成纤维细胞增殖、肌化并向内膜迁移,参与新内膜增生,促使血管再狭窄。由此抑制外膜成纤维细胞还原型辅酶Ⅱ氧化酶活性成为有关基因治疗的新途径。     

血管外膜与动脉粥样硬化

动脉粥样硬化(AS)是一种由脂质沉积引起的血管系统多病灶慢性免疫炎性疾病,主要累及大、中动脉,其发病机制十分复杂.长期以来,对AS机制的研究主要集中在内膜和中膜.最近越来越多的研究表明,血管外膜与动脉硬化形成密切相关.现就血管外膜及其相关血管活性肽在AS发生中所起的作用作一综述.     

消化系统疾病

的.141,66原位杂交检测人动脉粥样硬化斑块组织中人巨细胞病毒DNA/陈瑞珍…刀中华医学杂志一1995,75(10)一592~593 用生物素标记的HCMVDNA(人巨细胞病毒DNA)探针作原位杂交检测32例动脉粥样梗化患者的动脉血管组织及32例其他疾病患者的正常血管组织(其中22例脑外伤死亡取动脉,10例动脉硬化于搭桥术时取大隐静脉组织)中HCMVDNA序列。结果其阳性分别为13/32及3/ 22,示HCMV感染与动脉粥样硬化的发生密切相关。在HCMV DNA阳性标本中,HCMV DMA主要见于血管内皮,内膜下平滑肌及中膜平滑肌,并多集聚于细胞核中,外膜组织及细胞外…     

血管外膜在调节血管张力中的作用

动脉壁有三层结构：内膜、中膜、外膜,每一层均具有独特的组织学、生物学及功能特征,并且每层以独特的方式来维持血管稳定及调节血管对各种刺激及损伤的反应。近20年,有关血管内膜对血管功能的影响得到深入广泛的研究,血管内膜在调节血管平滑肌功能中的作用已得到普遍的认同。血管外膜是非常复杂的一层,由较厚的致密结构组成,含有大量的胶原纤维和弹性纤维,细胞成分主要是成纤维细胞及少量平滑肌细胞。支配血管舒缩的交感及副交感神经纤维从外膜进入血管;滋养血管也从外膜进入,     

血管外膜成纤维细胞在动脉粥样硬化及PCI后再狭窄中的作用

血管外膜是动脉粥样硬化(AS)和经皮冠状动脉介入治疗(PCI)后再狭窄等血管重构疾病的"积极参与者"。血管外膜不仅发挥简单的支持血管、提供营养物质的作用,越来越多的研究表明,外膜还主动参与了AS和PCI后再狭窄的病理过程。作为血管外膜最重要的组成部分,外膜成纤维细胞(AF)通过活化、增殖、迁移,分泌细胞因子和细胞外基质导致血管外膜和内膜的增厚和管腔狭窄。另外,AF活化后还通过参与一氧化氮的调节、氧化应激和炎症反应等促进AS和PCI后再狭窄的形成。     

去除外膜对血管内膜增殖及反应性的影响

目的:观察去血管外膜后兔颈动脉血管内膜增殖及血管反应性改变的情况。方法:在体去除兔颈动脉外膜,于术后0周及1周时取出动脉作组织学检查,血管张力测试,免疫组织化学染色,用RT-PCR法测定返原型辅酶Ⅱ氧化酶P22亚单位(NADPH Oxidase P22Phox)信使核糖核酸(mRNA)。结果:(1)外膜去除方法对血管内皮及中层平滑肌无明显损伤;(2)外膜去除后血管内膜增生,增生成分为血管平滑肌细胞;(3)与完整外膜血管比较,去外膜血管对去甲肾上腺素(NE)的收缩反应在术后即刻及1周均减弱(P<0.05),对乙酰胆碱(Ach)的舒张反应在术后即刻增强(P<0.05);(4)与完整外膜血管比较,去外膜血管NADPH Oxidase P22Phox在1周时表达增高(P<0.05)。结论:外膜去除可致兔颈动脉内膜增生,同时引起血管舒缩反应性发生改变。     

肾上腺髓质素是一种血管保护因子

肾上腺髓质素(adrenomedullin,AM)是一种扩血管多肽,具有多种生物学功能,如降低氧化应激和抑制内皮细胞凋亡。AM基因在三层血管壁中均有表达,培养的血管内皮细胞、平滑肌细胞和血管外膜成纤维细胞也能分泌AM。动脉粥样硬化性血管疾病患者血浆AM水平可能与疾病的严重程度相关。在急性动物实验中,用AM处理的血管发生内皮依赖性或非内皮机制的扩张。体外实验发现,AM能对培养的血管细胞产生多种保护或抑制效应:如对抗血管损伤、延缓动脉硬化进程。延长AM灌注时间或过表达AM可抑制血管重构或动脉粥样硬化动物模型中的内膜增厚、脂纹形成和…     

卵巢肿瘤组织血管内皮生长因子的表达及意义

实体肿瘤的发展依赖于血管形成[1] ,无血管期的肿瘤细胞团只能长至直径 1～ 2 mm,新生血管是肿瘤快速生长不可缺少的条件 ,并为肿瘤细胞进入血液和淋巴循环提供了最直接的途径。血管内皮生长因子 ( VEGF)是一个特殊的促内皮细胞有丝分裂原 ,并可增加血管通透性 ,促进肿瘤新生血管及基质形成 ,导致肿瘤细胞迅速增殖 ,并具有转移潜能[2 ] 。本研究采用免疫组化方法检测了 5 3例卵巢肿瘤患者肿瘤组织及 1 0例正常卵巢者卵巢组织中 VEGF的表达 ,旨在探讨其与卵巢肿瘤临床、病理指标之间的关系。现报告如下。1　资料与方法1 .1　临床资料　收…     

高血压与动脉硬化

高血压是一种损害体循环大、小动脉的疾病,同时相应动脉的病变又参与高血压的发生与发展.高血压时的血管病变主要为动脉硬化,其病理改变涉及动脉壁全层(内皮、内膜、中层和外膜),病理生理结局为动脉壁的弹性或顺应性下降以及僵硬度增加.在此基础和其他因素的作用下,可合并发生动脉粥样硬化.     

动脉粥样硬化的炎症应答特征及运用

动脉粥样硬化是多种心血管疾病的共同病理基础。越来越多证据表明,炎症在动脉粥样硬化的病理生理过程中发挥重要作用。动脉粥样硬化的发展受先天性免疫与适应性免疫细胞成分调控,且与全身炎症水平相关,多种炎症因子可作为动脉粥样硬化相关心血管疾病的预测指标。同时,一些抗炎治疗的临床试验表明,降低系统性炎症因子水平能够减少心血管事件风险。文章重点阐述了炎症在动脉粥样硬化中的作用、动脉粥样硬化发展中免疫应答的特征,以及目前针对动脉粥样硬化抗炎治疗的临床研究进展,以期为动脉粥样硬化治疗提供新的策略及靶点。     

Alternative pathways for the development of lymphoid structures in humans

Lymphoid tissue inducer (LTi) cells are critical for inducing the differentiation of most secondary lymphoid organs (SLOs) in mice. In humans, JAK3 and γc deficiencies result in severe combined immunodeficiency (SCIDs) characterized by an absence of T cells, natural killer cells, innate lymphoid cells (ILCs), and presumably LTi cells. Some of these patients have undergone allogeneic stem cell transplantation (HSCT) in the absence of myeloablation, which leads to donor T cell engraftment, while other leukocyte subsets are of host origin. By using MRI to look for SLOs in nine of these patients 16 to 44 y after HSCT, we discovered that SLOs were exclusively found in the three areas of the abdomen that drain the intestinal tract. A postmortem examination of a child with γc-SCID who had died 3.5 mo after HSCT showed corticomedullary differentiation in the thymus, T cell zones in the spleen, and the appendix, but in neither lymph nodes nor Peyer patches. Tertiary lymphoid organs were observed in the lung. No RAR-related orphan receptor-positive LTi cells could be detected in the existing lymphoid structures. These results suggest that while LTi cells are required for the genesis of most SLOs in humans, SLO in the appendix and in gut-draining areas, as well as tertiary lymphoid organs, can be generated likely by LTi cell-independent mechanisms.

Lymphoid organogenesis in mammals is organized into three chronologically and mechanistically distinct steps: 1) the genesis of primary lymphoid organs, such as the thymus and the bone marrow; 2) the development of secondary lymphoid organs (SLOs), including lymph nodes, Peyer patches, and the spleen; and 3) the formation of tertiary lymphoid organs (TLOs) within tissues after the initiation of an immune response (1–3). In mice, lymphoid tissue-inducer (LTi) cells, a cell subset of hematopoietic origin that is related to the natural killer (NK)-innate lymphoid cell (ILC) lineage, orchestrate the generation of most SLOs with the exception of the splenic white pulp (4–8). The differentiation of LTi cells is dependent on an interleukin (IL)-7 signal, since IL-7 receptor knockout mice are devoid of LTi cells and most of the SLOs (4–7, 9–12).Little is known about lymphoid organogenesis in humans. LTi-like cells (i.e., cells expressing molecules, such as the RAR-related orphan receptor C [RORC], lymphotoxin, and RANK ligand) have been detected in several sets of lymphoid structures (13–16). In humans, a hereditary lack of molecules required for LTi cell development (e.g., γc, JAK3, and IL-7Rα) causes severe combined immunodeficiency (SCID) and thus the absence of T cells, NK lymphocytes, and ILCs to which LTi cells are related (17–22). One can reasonably presume that these patients also lack LTi cells. Indeed, the patients with SCID caused by γc or JAK3 deficiency do not have detectable peripheral lymph nodes, in contrast to SCID caused by RAG-1 deficiency, in which only T and B cell development is impaired (23).In order to provide these patients with an adaptive immune system, allogeneic hematopoietic stem cell transplantation (HSCT) can be performed after limited myeloablative chemotherapy or even in the absence of conditioning (18, 24–26). In many cases, the HSCT results in split chimerism that can persist for decades: that is, the T cells are of donor origin but all other blood lineages (including B cells and myeloid cells) are of host origin (18, 27). We have reported previously that these SCID patients also lack NK cells and ILCs long after HSCT (19). Taken as a whole, these data indicate that long-lived donor T cells and, perhaps, residual thymopoiesis persist in the absence of long-term donor stem cell engraftment (18). We took advantage of this unique setting to investigate the development of lymphoid structures. Hence, we used MRI to visualize SLOs in nine patients (P1 to P9) with SCID due to γc, JAK3, or IL-7Rα deficiency 16 to 44 y after HSCT. We also analyzed tissue samples from two other patients (P10, P11) having undergone HSCT, one who had died and another who had additionally received a lung transplant.     

IL-22 regulates lymphoid chemokine production and assembly of tertiary lymphoid organs

The series of events leading to tertiary lymphoid organ (TLO) formation in mucosal organs following tissue damage remain unclear. Using a virus-induced model of autoantibody formation in the salivary glands of adult mice, we demonstrate that IL-22 provides a mechanistic link between mucosal infection, B-cell recruitment, and humoral autoimmunity. IL-22 receptor engagement is necessary and sufficient to promote differential expression of chemokine (C-X-C motif) ligand 12 and chemokine (C-X-C motif) ligand 13 in epithelial and fibroblastic stromal cells that, in turn, is pivotal for B-cell recruitment and organization of the TLOs. Accordingly, genetic and therapeutic blockade of IL-22 impairs and reverses TLO formation and autoantibody production. Our work highlights a critical role for IL-22 in TLO-induced pathology and provides a rationale for the use of IL-22–blocking agents in B-cell–mediated autoimmune conditions.Tertiary lymphoid organs (TLOs) are organized clusters of immune cells that preferentially form in autoimmune diseases such as Sjogren’s syndrome and Hashimoto thyroiditis (1). TLOs’ cellular compartments, spatial organization, vasculature, and function are similar to those of secondary lymphoid organs (SLOs), providing a local hub for autoreactive B-cell proliferation and affinity maturation. TLOs appear to contribute to disease progression and to the emergence of malignant B clones responsible for lymphoma development (2). Within TLOs, the ectopic expression of lymphoid chemokines has been shown to correlate with the size or degree of organization of lymphoid aggregates and with the production of autoantibodies (3, 4). In the case of malignant transformation, lymphoid chemokine expression increases during disease progression (5). The pathways regulating chemokine expression in SLOs during embryonic life have been largely described and mainly involve the engagement of lymphotoxin β receptor on a family of gp38⁺ lymphoid tissue-organizer stromal cells (6). At sites of TLO formation, lymphotoxin and lymphotoxin-producing cells appear to be dispensable for the early production of lymphoid chemokines required during SLO formation, raising the possibility that signals other than lymphotoxin can regulate the formation of TLOs, stimulating the production of lymphoid chemokines during inflammation (7, 8). Some of these signals have been identified in the family of the IL-23/IL-17 cytokines (9), but other cytokines have been advocated in TLO formation; thus different molecules may play differential roles depending on site and nature of the etiological agent (10).IL-22, a member of the IL-10 cytokine superfamily, regulates mucosal responses to danger and wound healing (11). IL-22 promotes tissue repair, inducing epithelial cell proliferation and survival, in both physiological and pathological conditions (12–15). Recently, an association between IL-22 expression and autoimmune B-cell activation has been proposed (16). In Sjogren’s syndrome, serum levels of IL-22 correlate with clinical manifestations including autoantibody production (17). Furthermore, B-cell–depleting treatment modulates salivary gland expression of IL-22, thus suggesting a potential functional relationship between IL-22 expression, B-cell infiltration, and local pathology (18). Previously we have demonstrated that direct cannulation of murine salivary glands with a replication-deficient adenovirus induces the formation of organized T-cell and B-cell aggregates, local expression of lymphoid chemokines, and the enzyme aicda [activation-induced cytidine deaminase (AID)] required for affinity maturation and isotype switching in B cells (19). Exploiting this model, we tested the hypothesis that IL-22 is involved in the generation of a humoral response within the TLOs (19). Here we demonstrate that early expression of IL-22 is instrumental for lymphoid chemokine production by stromal cells that, in turn, regulates B-cell aggregation. This work highlights a novel role for IL-22 in lymphoid chemokine expression and provides a mechanistic link between deranged mucosal responses and autoantibody production.     

Relative and absolute numbers of E- and EAC rosette-forming cells in lymphoid organs

Summary The percentage of lymphocytes of the blood and lymphoid organs of young pigs were determined by forming rosettes with pretreated sheep red blood cells (AET-rosettes) or with sheep red blood cells coated with antibody and complement (EAC-rosettes). The mean figures for AET-rosettes were 70% for the blood, 93% for the thymus, 78% for lymph-nodes and 68% for the spleen. For EAC-rosettes the numbers were 16%, 0%, 16% and 19% respectively.The absolute numbers of rosette-forming lymphocytes were estimated on the basis of previously determined numbers of lymphoid cells in young pigs. Even by excluding the data for the thymus, there would be about three times more AET-rosette forming lymphocytes than EAC-rosette forming cells in the whole animal. About 11% of all lymphocytes did not show any of these markers.Data on the numbers of B and T lymphocytes in human lymphoid organs from the literature were summarized and compared to those found in pigs and thus, the absolute numbers for a young adult man estimated.

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Zusammenfassung Es wurden die prozentualen Anteile von Lymphozyten im Blut und den lymphatischen Organen des jungen Schweins bestimmt, die mit vorbehandelten Schaferythrozyten (AET-Rosetten) oder mit Antikörper- und Complement-beladenen Schaferythrozyten (EAC-Rosetten) Rosetten bildeten. Die Mittelwerte für die Spontanrosetten (AET) waren 70% für Blutlymphozyten und für Lymphozyten aus dem Thymus 93%, aus Lymphknoten 78% und aus der Milz 68%. Die entsprechenden Werte für EAC-Rosetten betrugen 16% (Blut), 0% (Thymus), 16% (Lymphknoten) und 19% (Milz).Mit Hilfe der früher bestimmten Gesamtzahl von Lymphozyten konnten die Absolutzahlen von E- und EAC-Rosetten-bildenden Lymphozyten ermittelt werden. Auch wenn die Thymuslymphozyten nicht berücksichtigt wurden, so wurden für den Gesamtorganismus eine etwa 3mal höhere Anzahl an AET- als an EAC-Rosettenbildenden Zellen errechnet. Etwa 11% aller Lymphozyten hatten keinen dieser beiden Marker. Angaben aus der Literatur über T- und B-Lymphozyten in den lymphatischen Organen des Menschen wurden zusammengefaßt, mit den Daten für Schweine verglichen und die Absolutzahlen von Rosetten bildenden Lymphozyten in lymphatischen Organen eines jungen Erwachsenen geschätzt.

     

Circulation and migration of small blood lymphocytes in the rat: II. Study of the lymphocyte selective migration by light and electron microscopic autoradiography

Fourteen male Wistar rats were the recipients of labeled small lymphocytes (1.5 x 10(7) each) collected from the peripheral blood of syngeneic donors. The migrating labeled lymphocytes were traced in the various organs from one to 60 minutes following their transfusion. Sections from the lymph nodes, bone marrow, spleen, thymus, ileum, liver, lung, and kidney were analyzed morphologically by autoradiographic studies. The results showed that some of the labeled small blood lymphocytes migrate to the lymph node and bone marrow as early as one minute following transfusion; their exodus from these two organs occurs within three minutes. In the case of the spleen, the lymphocytes did not migrate selectively to the marginal zone of the lymphoid follicles until ten minutes following transfusion. The electron microscopic study of the spleen and lymph node showed that the labeled lymphocytes selectively migrate to certain areas which consist of reticulum cells, macrophages, unlabeled lymphocytes, and plasma cells. The term "immunocompetent zones" is proposed for these areas because of the biological significance of this selective migration with reference to immunity.     

Displacement of T Lymphocytes with the ‘Helper/Inducer’ Phenotype from Peripheral Blood to Lymphoid Organs in Untreated Patients with Hodgkin's Disease

A panel of previously characterized monoclonal antibodies: B67.6, OKT3, OKT4, B53.4, Leu3a, OKT8, Leu2a, OKM1, M12 and B52.1 were used as a probe to assess mononuclear cells in peripheral blood (PB), lymph nodes (LN) and spleens of untreated patients with Hodgkin's disease (HD). The mean % and absolute number of T lymphocytes were significantly decreased in PB of HD patients when compared with control values. Reduction of circulating T lymphocytes reflected the selective loss of cells showing the ‘helper/inducer’ (‘H/I’) phenotype. In fact, a lower number of these cells was demonstrated in HD patients with advanced disease and, even though to a lesser extent, in those with localized disease. In contrast, decreased values of T cells with the ‘cytotoxic/syppressor’ (‘C/S’) phenotype were only found in patients with advanced disease, showing pan-lymphocytopenia. Unlike PB, LN and spleens involved by HD usually showed increased %s of T lymphocytes, especially of those possessing the ‘H/I’ phenotype. The displacement of T lymphocytes with ‘H/I’ phenotype from PB to lymphoid organs further supports the possibility of a chronic immune response against abnormal cells or unknown antigens in the affected organs of patients with HD.     

Outcome of primary cutaneous anaplastic large cell lymphoma: a 20‐year British Columbia Cancer Agency experience

Primary cutaneous anaplastic large cell lymphoma (PCALCL ) is a rare CD 30⁺ lymphoproliferative disorder with excellent outcomes reported despite frequent cutaneous relapses. Limited information exists on the development of systemic lymphoma. The British Columbia Cancer Agency (BCCA ) Lymphoid Cancer Database was searched to identify all adults diagnosed with PCALCL from 1993 to 2013. From 2005, the BCCA endorsed radiotherapy (RT ) alone for limited stage with data failing to support chemotherapy. Forty‐seven patients were identified with a male predominance (n  = 31, 66%), median age of 64 years and predominantly limited stage (n  = 40, 85%). Median follow‐up was 8·4 years. The 5‐year time to progression (TTP ) was 58% (64% limited versus 29% advanced stage). The 5‐year disease‐specific survival (DSS ) and overall survival was 86% and 75%, respectively. In an as‐treated analysis, the 5‐year DSS for limited stage patients was similar comparing RT to combined modality treatment or chemotherapy alone but the 5‐year TTP favoured RT (82% vs. 33%, P  =  0·004). The 5‐year cumulative risk of developing systemic lymphoma was 14%. Our results confirm the favourable prognosis of PCALCL despite a high relapse rate. Limited stage patients treated with RT alone have excellent outcomes. There is a small risk of systemic lymphoma in PCALCL .     

General features of steroid resistance in lymphoid cell lines

Some general features of dexamethasone resistance in five murine lymphoid cell lines were investigated. To obtain large numbers of dexamethasone-resistant (Dex^r) variants, a technique was developed by which mouse lymphoid cell lines can be grown with high efficiency on the surface of agar plates without a feeder layer. A total of 271 Dex^r variants were investigated, and 90% of them turned out to lack detectable steroid receptor whereas 10% have receptor with, in most cases, a normal affinity for the steroid hormone. Most of this latter class of variants, however, have reduced amounts of receptor and the receptor of all of them displayed altered nuclear binding characteristics. None of the five investigated lymphoid cell lines yielded a Dex^r variant with a normal receptor. These results confirm the idea that the high incidence of receptor variant may be due, at least in part, to the haploid state of a gene coding for the receptors. In cell fusion experiments it could be shown that Dex^s is dominant over Dex^r, but that a Dex^r allele in a tetraploid cell can lead to an increased frequency of steroid resistance.