Inflammation in atherosclerosis

Abundant data link hypercholesterolaemia to atherogenesis. However, only recently have we appreciated that inflammatory mechanisms couple dyslipidaemia to atheroma formation. Leukocyte recruitment and expression of pro-inflammatory cytokines characterize early atherogenesis, and malfunction of inflammatory mediators mutes atheroma formation in mice. Moreover, inflammatory pathways promote thrombosis, a late and dreaded complication of atherosclerosis responsible for myocardial infarctions and most strokes. The new appreciation of the role of inflammation in atherosclerosis provides a mechanistic framework for understanding the clinical benefits of lipid-lowering therapies. Identifying the triggers for inflammation and unravelling the details of inflammatory pathways may eventually furnish new therapeutic targets.     

Targeting C-reactive protein for the treatment of cardiovascular disease

Complement-mediated inflammation exacerbates the tissue injury of ischaemic necrosis in heart attacks and strokes, the most common causes of death in developed countries. Large infarct size increases immediate morbidity and mortality and, in survivors of the acute event, larger non-functional scars adversely affect long-term prognosis. There is thus an important unmet medical need for new cardioprotective and neuroprotective treatments. We have previously shown that human C-reactive protein (CRP), the classical acute-phase protein that binds to ligands exposed in damaged tissue and then activates complement, increases myocardial and cerebral infarct size in rats subjected to coronary or cerebral artery ligation, respectively. Rat CRP does not activate rat complement, whereas human CRP activates both rat and human complement. Administration of human CRP to rats is thus an excellent model for the actions of endogenous human CRP. Here we report the design, synthesis and efficacy of 1,6-bis(phosphocholine)-hexane as a specific small-molecule inhibitor of CRP. Five molecules of this palindromic compound are bound by two pentameric CRP molecules, crosslinking and occluding the ligand-binding B-face of CRP and blocking its functions. Administration of 1,6-bis(phosphocholine)-hexane to rats undergoing acute myocardial infarction abrogated the increase in infarct size and cardiac dysfunction produced by injection of human CRP. Therapeutic inhibition of CRP is thus a promising new approach to cardioprotection in acute myocardial infarction, and may also provide neuroprotection in stroke. Potential wider applications include other inflammatory, infective and tissue-damaging conditions characterized by increased CRP production, in which binding of CRP to exposed ligands in damaged cells may lead to complement-mediated exacerbation of tissue injury.     

Interaction of C-reactive protein with artificial phosphatidylcholine bilayers.

C-Reactive protein (CRP), the most characteristic of the 'acute phase proteins' (ref. 1) is thought to participate in the mediation and/or modulation of acute inflammatory processes, but its exact function is unknown. CRP has a Ca2+-dependent binding specificity for phosphorylcholine, the polar head group of two widely distributed lipids, lecithin (phosphatidylcholine, PC) and sphingomyelin (SM). A number of observations suggest that at least some of the biological activities of CRP depend on its interaction with phospholipids of cell membranes. In addition, interaction of CRP with PC- and SM-containing lipid dispersions and with PC-containing liposomes can activate the complement system. We report here that binding of CRP to model membranes of PC requires the incorporation into the bilayer of lysophosphatidylcholine (LPC). Thus, a disturbance of the molecular organisation of the bilayer appears to be necessary for binding of CRP. These findings provide a possible biochemical explanation for binding of CRP to damaged but not intact cell membranes and might be relevant to its biological function.     

A mechanosensory complex that mediates the endothelial cell response to fluid shear stress

Shear stress is a fundamental determinant of vascular homeostasis, regulating vascular remodelling, cardiac development and atherogenesis, but the mechanisms of transduction are poorly understood. Previous work showed that the conversion of integrins to a high-affinity state mediates a subset of shear responses, including cell alignment and gene expression. Here we investigate the pathway upstream of integrin activation. PECAM-1 (which directly transmits mechanical force), vascular endothelial cell cadherin (which functions as an adaptor) and VEGFR2 (which activates phosphatidylinositol-3-OH kinase) comprise a mechanosensory complex. Together, these receptors are sufficient to confer responsiveness to flow in heterologous cells. In support of the relevance of this pathway in vivo, PECAM-1-knockout mice do not activate NF-kappaB and downstream inflammatory genes in regions of disturbed flow. Therefore, this mechanosensing pathway is required for the earliest-known events in atherogenesis.     

血清C反应蛋白水平与急性脑梗死病情及预后的关系

目的探讨急性脑梗死患者血清C反应蛋白（CRP）水平的变化与病情严重程度及其预后的关系。方法分别测定大动脉粥样硬化性脑梗死患者（LAA组）78例、腔隙性脑梗死患者（LCI组）36例和健康体检者（对照组）40例血清CRP含量,并进行比较。按脑卒中患者临床神经功能缺损程度评分（NDS）标准对患者进行评分。结果LAA组CRP含量高于LCI组,LCI组高于对照组（P〈0．05）;IAA组中,CRP异常率高于LCI组（P〈0．05）,CRP异常的患者NDS评分的改善低于CRP正常组,且CRP异常者预后中无变化者高于正常对照组（P〈0．01）。结论CRP水平增高与脑梗死的发生和严重程度预后有密切关系。     

Upstream CRP-binding site is not essential for CRP-cAMP-mediated inhibition on the nifU promoter

When the NifA-mediated activation of Klebsiella pneumoniae nifU promoter is recreated in Escherichia coli, it has been observed that CRP-cAMP has an inhibitory effect on the nifU promoter. Sequence analysis indicates that there is a strong CRP-binding site located upstream of the nifU promoter, overlapping completely with a previously identified NifA-binding site. In vitro gel retardation analysis indicates that this putative CRP-binding site has similar affinity for CRP, when compared with that at the lac promoter, suggesting that CRP could effectively compete with NifA for such a binding site under physiological conditions. When this putative CRP-binding site on nifU was mutated, in vitro gel retardation analysis indicates that CRP can no longer bind to the mutant promoter. However, when constitutively expressed NifA is used as the activator, CRP-cAMP-mediated inhibitory effect on this mutant nifU promoter has no significant difference when compared with that obtained from its wild-type promoter. These results suggest that direct interaction between CRP and Eσ54, other than the DNA binding site(s) competition between CRP and NifA, plays the principal role in the CRP-cAMP-mediated inhibitory effect on nifU.     

Subendothelial retention of atherogenic lipoproteins in early atherosclerosis

Complications of atherosclerosis are the most common cause of death in Western societies. Among the many risk factors identified by epidemiological studies, only elevated levels of lipoproteins containing apolipoprotein (apo) B can drive the development of atherosclerosis in humans and experimental animals even in the absence of other risk factors. However, the mechanisms that lead to atherosclerosis are still poorly understood. We tested the hypothesis that the subendothelial retention of atherogenic apoB-containing lipoproteins is the initiating event in atherogenesis. The extracellular matrix of the subendothelium, particularly proteoglycans, is thought to play a major role in the retention of atherogenic lipoproteins. The interaction between atherogenic lipoproteins and proteoglycans involves an ionic interaction between basic amino acids in apoB100 and negatively charged sulphate groups on the proteoglycans. Here we present direct experimental evidence that the atherogenicity of apoB-containing low-density lipoproteins (LDL) is linked to their affinity for artery wall proteoglycans. Mice expressing proteoglycan-binding-defective LDL developed significantly less atherosclerosis than mice expressing wild-type control LDL. We conclude that subendothelial retention of apoB100-containing lipoprotein is an early step in atherogenesis.     

CRP检测的临床意义

人类C-反应蛋白(CRP)是急性时相蛋白之一，实验室把CRP作为系统炎症疾病的指示指标，同时对于一些疾病的诊断、鉴别及预后推断都有重大意义．     

C反应蛋白与急性冠脉综合症的相关性及PCI术后的变化

探讨C反应蛋白(CRP)水平与急性冠脉综合征的相关性及行经皮冠状动脉介入治疗(PCI)术后的变化。采用酶联免疫吸附试验(ELISA)法测定经冠状动脉造影确诊的57例冠心病患者及28例冠状动脉造影正常者的血清CRP水平,并比较16例行PCI术的患者术前、术后的血清CRP水平变化。血清CRP在急性心肌梗死组(15.74±1.62)mg/L明显高于不稳定型心绞痛组(11.35±2.52)mg/L,且两者明显高于稳定型心绞痛组(4.68±2.61)mg/L和正常对照组(2.68±1.16)mg/L,(P<0.01)。同时冠心病患者PCI术后血清CRP水平明显高于术前。CRP水平与ACS的临床类型密切相关,可以作为判断ACS预后的指标;PCI能导致冠心病患者的内皮损伤,加重炎症反应,可能是引起管腔内再狭窄的因素。     

C-反应蛋白对弥漫大B淋巴瘤的表达意义

目的探讨弥漫性大B淋巴瘤(DLBCL)患者的血清中C-反应蛋白(CRP)的表达以及其与病程和预后之间的关系.方法选取健康体检者47例,并收集同时期经病理确诊的DLBCL患者51例,采用酶联免疫法检测所有受试人群的CRP浓度.结果 DLBCL患者的CRP浓度为(23.85±7.22)mg/L,相对于健康人群的(6.64±3.17)mg/L明显升高.随着临床分期的进展,CRP水平逐渐上升,与对照组及不同分期之间比较差异均具有统计学意义(P0.05).高表达CRP患者化疗有效率为44.83%,低表达CRP组为77.27%,组间比较差异具有统计学意义(P0.05,χ2=31.728).GCB组患者的血清CRP水平明显低于NGCB组,且均显著高于对照组,组间比较差异均具有统计学意义(P0.05).结论 DLBCL患者进行CRP检测能够反映其疾病变化,并且能够应用于评估不同类型、分期和严重度.     

炎症因子在兔动脉粥样硬化易损斑块模型中表达

目的探讨在兔动脉粥样硬化易损斑块模型中的炎症因子C反应蛋白（CRP）及白介素-6（IL-6）的表达特点。方法雄性纯种新西兰大白兔分为对照模型组（n=8）、兔动脉粥样硬化模型组（n=8）和兔易损斑块模型组,采用ELISI法检测血清CRP、IL-6浓度。结果兔动脉粥样硬化斑块模型及易损斑块模型血清浓度CRP（8．68±1．30、13．97±2．85）mg／L均明显高于兔对照组模型（0．80±0．15）mg／L;兔动脉粥样硬化斑块模型及易损斑块模型血清浓度IL-6（180．67±14．93、237．99±41．10）pg/ml均明显高于兔对照组模型（85．65±13．55）pg／ml;兔易损斑块模型组的血清CRP、IL-6浓度（13．97±2．85mg／L、237．99±41．10pg／ml）明显高于兔动脉粥样硬化斑块模型组（8．68±1．30mg／L、180．67±14．93pg／ml）。结论兔动脉粥样硬化模型组及易损斑块模型组血清CRP、IL-6浓度明显高于兔对照组模型组血清CRP、IL-6浓度;兔易损斑块模型组血清CRP、IL-6浓度明显高于兔动脉粥样硬化组。     

多糖类生物活性的研究在医药领域的应用

多糖是生物体内除蛋白质和核酸外又一类重要的生物大分子,在医药领域有着广阔的应用前景.本文就多糖类具有抗感染、免疫促进、肿瘤防治和抗氧化等多方面功能和生物活性的特征进行了综述,引用近年来国内外相关文献21篇.     

外胚层发育不全症的免疫水平研究

目的：探讨外胚层发育不全症（anhydrite ectodermic dysplasia，EDA）的免疫学特征．方法：采用免疫透射比浊方法以及流式细胞技术进行免疫功能检测．结果：患者的免疫球蛋白、补体、类风湿等指标以及T细胞亚群与其正常同胞、对照组之间差异不明显．患者ASO明显低于正常同胞和对照组差异显著（P〈0．05），CRP指标患者以及正常的同胞均高于对照组，差异显著（P〈0．05），结论：外胚层发育不全症患者的免疫功能与正常个体间差异不明显，但相关指标有明显差异，其机理有待进一步研究．     

Interaction of Rabbit C-reactive Protein with Phospholipid Monolayers at Air/Water Interface

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Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance

Obesity and insulin resistance, the cardinal features of metabolic syndrome, are closely associated with a state of low-grade inflammation. In adipose tissue chronic overnutrition leads to macrophage infiltration, resulting in local inflammation that potentiates insulin resistance. For instance, transgenic expression of Mcp1 (also known as chemokine ligand 2, Ccl2) in adipose tissue increases macrophage infiltration, inflammation and insulin resistance. Conversely, disruption of Mcp1 or its receptor Ccr2 impairs migration of macrophages into adipose tissue, thereby lowering adipose tissue inflammation and improving insulin sensitivity. These findings together suggest a correlation between macrophage content in adipose tissue and insulin resistance. However, resident macrophages in tissues display tremendous heterogeneity in their activities and functions, primarily reflecting their local metabolic and immune microenvironment. While Mcp1 directs recruitment of pro-inflammatory classically activated macrophages to sites of tissue damage, resident macrophages, such as those present in the adipose tissue of lean mice, display the alternatively activated phenotype. Despite their higher capacity to repair tissue, the precise role of alternatively activated macrophages in obesity-induced insulin resistance remains unknown. Using mice with macrophage-specific deletion of the peroxisome proliferator activated receptor-gamma (PPARgamma), we show here that PPARgamma is required for maturation of alternatively activated macrophages. Disruption of PPARgamma in myeloid cells impairs alternative macrophage activation, and predisposes these animals to development of diet-induced obesity, insulin resistance, and glucose intolerance. Furthermore, gene expression profiling revealed that downregulation of oxidative phosphorylation gene expression in skeletal muscle and liver leads to decreased insulin sensitivity in these tissues. Together, our findings suggest that resident alternatively activated macrophages have a beneficial role in regulating nutrient homeostasis and suggest that macrophage polarization towards the alternative state might be a useful strategy for treating type 2 diabetes.     

急性胰腺炎患者CRP和IL-6水平检测及临床意义

目的:C-反应蛋白和IL-6测定在诊断轻、重型胰腺炎患者中的临床应用价值。方法:血清CRP测定采用快速比浊法,IL-6测定采用双抗体夹心ELISA法。结果:重型胰腺炎患者CRP和IL-6水平显著高于轻型胰腺炎患者;显著高于正常健康对照组(P<0.01)。结论:CRP和IL-6水平测定可为早期诊断和区别轻、重型胰腺炎提供可靠的实验依据。     

白细胞介素-1的结构、来源、分布、功能及其与疾病的关系

白细胞介素-1(IL-1)不仅作为一种重要的细胞因子,是体内调节免疫和炎症反应的中心介质,而且它也作为神经递质或生长因子参与了机体多个系统的病理生理活动,其生物学作用非常广泛.近年来,随着对神经系统、免疫系统和内分泌系统之间相互作用研究的日益深入,IL-1在各系统中的作用与机制也得到了相应的证实,并为一些临床疾病的诊治提供了有力依据.文章针对IL-1作为脑源性白介素在中枢神经系统的病理生理功能进行了研究.     

Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage.

Inappropriate or prolonged inflammation is the main cause of many diseases; for this reason it is important to understand the physiological mechanisms that terminate inflammation in vivo. Agonists for several Gs-protein-coupled receptors, including cell-surface adenosine purinergic receptors, can increase levels of immunosuppressive cyclic AMP in immune cells; however, it was unknown whether any of these receptors regulates inflammation in vivo. Here we show that A2a adenosine receptors have a non-redundant role in the attenuation of inflammation and tissue damage in vivo. Sub-threshold doses of an inflammatory stimulus that caused minimal tissue damage in wild-type mice were sufficient to induce extensive tissue damage, more prolonged and higher levels of pro-inflammatory cytokines, and death of male animals deficient in the A2a adenosine receptor. Similar observations were made in studies of three different models of inflammation and liver damage as well as during bacterial endotoxin-induced septic shock. We suggest that A2a adenosine receptors are a critical part of the physiological negative feedback mechanism for limitation and termination of both tissue-specific and systemic inflammatory responses.