Endothelial injury: cause and effect of alloimmune inflammation

Abstract: This review discusses the concept that endothelial cells may facilitate inflammation, but are also targets of the inflammatory response. Endothelial cells express several molecules that promote leukocyte recruitment, and other molecules, such as MHC class I that enable endothelial injury. Circulating alloantibodies produced following transplantation may also target the endothelium for injury. It has been shown that the expression of select protective genes within endothelial cells, including anti‐apoptotic genes, may provide resistance to immune‐mediated injury. Thus, an understanding of the mechanisms by which endothelial cells are injured and by which endothelial cells are protected is important for our understanding of allograft rejection.     

CXCR4在人多发性骨髓瘤细胞的表达及对肿瘤细胞生物学行为的影响

目的　探讨CXCR4在多发性骨髓瘤 (MM)细胞上的表达和CXCR4 SDF 1α相互作用对MM肿瘤细胞生物行为及ICAM 1表达的影响。方法　采用免疫荧光标记和流式细胞仪表型检测分析MM细胞上CXCR4和粘附分子的表达 ;采用体外微孔隔离室实验进行SDF 1诱导的MM细胞迁移实验 ;ELISA方法测定血浆中sICAM 1的水平。结果　①新鲜MM细胞及MM细胞株不同程度地表达功能性CXCR4 [(5 0 .4± 2 7.3) % ],其表达水平与体外对SDF 1α诱导的迁移能力 [(2 3.6± 17.2 ) % ]密切相关 (P <0 .0 1) ;②SDF 1α可上调MM细胞表达粘附分子ICAM 1,ICAM 1的表达和可溶性ICAM 1的产生与CXCR4表达有一定相关性。结论　SDF 1α CXCR4对介导粘附分子的调节效应在MM细胞的生物行为中起重要的作用。     

Porcine IL‐6, IL‐1β, and TNF‐α regulate the expression of pro‐inflammatory‐related genes and tissue factor in human umbilical vein endothelial cells

Whether porcine cytokines are induced after pig‐to‐primate xenotransplantation and activate human cells remains unknown. First, we investigated the regulation of porcine IL‐6, IFN‐γ, IL‐1β, and TNF‐α in xenotransplantation using an in vitro model in which porcine aortic endothelial cells (PAECs) and porcine peripheral blood mononuclear cells (PBMCs) were stimulated with human serum. Downstream cytokines/chemokines were monitored. Pro‐inflammatory cytokines (IL‐6, IFN‐γ, and IL‐1β) and chemokines (IL‐8, MCP‐1, and CXCL2) were upregulated in the both cell types. TNF‐α was induced 10‐fold in PAECs, but not in PBMCs. Then, we assessed the role of porcine IL‐6, IFN‐γ, IL‐1β, and TNF‐α in xenotransplantation using western blotting and real‐time PCR. Human umbilical vein endothelial cells (HUVECs) were selected as the target cells. Signaling pathways and downstream genes, such as those related to adhesion, inflammation, and coagulation, and chemokines were investigated. Porcine IL‐1β and TNF‐α significantly activated NF‐κB and P38, and STAT3 was activated by porcine IL‐6 in HUVECs. The adhesion genes (E‐selectin, VCAM‐1, and ICAM‐1), inflammatory cytokines (IL‐6, IL‐1β, and TNF‐α), chemokines (MCP‐1 and IL‐8), and the pro‐coagulation gene (tissue factor) were upregulated by porcine IL‐1β and TNF‐α. Porcine IL‐6 increased the expression of ICAM‐1, IL‐6, MCP‐1, and tissue factor, but decreased IL‐8 expression slightly. Surprisingly, porcine IFN‐γ could not activate STAT1 or regulate the expression of any of the above genes in HUVECs. In conclusion, these findings suggest that porcine IL‐6, IL‐1β, and TNF‐α activate HUVECs and regulate downstream genes expression, which may promote inflammation and coagulation response after xenotransplantation.     

In breast carcinoma tissue, immature dendritic cells reside within the tumor, whereas mature dendritic cells are located in peritumoral areas

We have analyzed the presence of immature and mature dendritic cells (DCs) within adenocarcinoma of the breast using immunohistochemistry. Immature DCs were defined by expression of CD1a-, Langerin-, and intracellular major histocompatibility complex class II-rich vesicles. Mature DCs were defined by expression of CD83 and DC-Lamp. Breast carcinoma cells were defined by morphology and/or cytokeratin expression. We demonstrate two levels of heterogeneity of DCs infiltrating breast carcinoma tissue: (a) immature CD1a(+) DCs, mostly of the Langerhans cell type (Langerin(+)), were retained within the tumor bed in 32/32 samples and (b) mature DCs, CD83(+)DC-Lamp(+), present in 20/32 samples, are confined to peritumoral areas. The high numbers of immature DCs found in the tumor may be best explained by high levels of macrophage inflammatory protein 3alpha expression by virtually all tumor cells. Confirming the immature/mature DC compartmentalization pattern, in vitro-generated immature DCs adhere to the tumor cells, whereas mature DCs adhere selectively to peritumoral areas. In some cases, T cells are clustering around the mature DCs in peritumoral areas, thus resembling the DC-T cell clusters of secondary lymphoid organs, which are characteristic of ongoing immune reactions.     

CC chemokine receptor (CCR)3/eotaxin is followed by CCR4/monocyte-derived chemokine in mediating pulmonary T helper lymphocyte type 2 recruitment after serial antigen challenge in vivo

Isolated peripheral blood CD4 cells from allergic individuals express CC chemokine receptor (CCR)3 and CCR4 after expansion in vitro. In addition, human T helper type 2 (Th2) cells polarized in vitro selectively express CCR3 and CCR4 at certain stages of activation/differentiation and respond preferentially to the ligands eotaxin and monocyte-derived chemokine (MDC). However, controversy arises when the in vivo significance of this distinct expression is discussed. To address the functional role of CCR3/eotaxin and CCR4/MDC during the in vivo recruitment of Th2 cells, we have transferred effector Th cells into naive mice to induce allergic airway disease. Tracking of these cells after repeated antigen challenge has established that both CCR3/eotaxin and CCR4/MDC axes contribute to the recruitment of Th2 cells to the lung, demonstrating the in vivo relevance of the expression of these receptors on Th2 cells. We have shown that involvement of the CCR3/eotaxin pathway is confined to early stages of the response in vivo, whereas repeated antigen stimulation results in the predominant use of the CCR4/MDC pathway. We propose that effector Th2 cells respond to both CCR3/eotaxin and CCR4/MDC pathways initially, but that a progressive increase in CCR4-positive cells results in the predominance of the CCR4/MDC axis in the long-term recruitment of Th2 cells in vivo.     

Bench-to-bedside review: Acute respiratory distress syndrome – how neutrophils migrate into the lung

Acute lung injury and its more severe form, acute respiratory distress syndrome, are major challenges in critically ill patients. Activation of circulating neutrophils and transmigration into the alveolar airspace are associated with development of acute lung injury, and inhibitors of neutrophil recruitment attenuate lung damage in many experimental models. The molecular mechanisms of neutrophil recruitment in the lung differ fundamentally from those in other tissues. Distinct signals appear to regulate neutrophil passage from the intravascular into the interstitial and alveolar compartments. Entry into the alveolar compartment is under the control of CXC chemokine receptor (CXCR)2 and its ligands (CXC chemokine ligand [CXCL]1–8). The mechanisms that govern neutrophil sequestration into the vascular compartment of the lung involve changes in the actin cytoskeleton and adhesion molecules, including selectins, β₂ integrins and intercellular adhesion molecule-1. The mechanisms of neutrophil entry into the lung interstitial space are currently unknown. This review summarizes mechanisms of neutrophil trafficking in the inflamed lung and their relevance to lung injury.     

血清CXC趋化因子配体16水平与冠心病的相关性研究

目的探讨血清可溶性CXC趋化测子配体16（CXCL16）与冠心病（CHD）的关系,以及其与冠状动脉狭窄严重程度的关系。方法研究对象分为急性冠状动脉综合征（ACS）组（n=163）、稳定型心绞痛（SAP）组（n=36）及对照组（n=34）。双抗体夹心酶标法测定血清CXCL16水平,比较三组患者血清CXCL16水平,根据冠脉造影检查结果,分析血清CXCL16水平与冠状动脉粥样硬化程度的相关性。结果ACS组血清CXCL16水平和超敏C-反应蛋白（highsensitivityC—reactiveprotein,hCRP）水平显著高于SAP组（P〈0．01）。血清CXCL16水平随冠脉病变支数增多而升高。随Gensini积分增加,CXCL16水平和hCRP水平逐渐升高,且CXCL16、hCRP在Gensini积分≤30分、31～60分、≥61分三组间两两比较时亦差异有统计学意义（P〈0．05）。结论ACS患者血清CXCL16水平显著增高。是独立于hCRP及血脂水平的生物标志物。CXCL16水平随病变支数增多和Gensini积分增加而升高,提示血清CXCL16水平与冠状动脉粥样硬化病变程度有关．可以作为冠心病危险分层的指标。