白细胞介素37在感染性疾病中的作用

白细胞介素37(IL-37)是IL-1家族的细胞因子,可在多种细胞中表达。IL-37可通过负反馈免疫调节机制调节先天性和适应性免疫系统,具有抑制炎症反应的作用。在抗感染免疫应答中,IL-37可通过抑制单核细胞、树突状细胞的功能抑制细菌、病毒和真菌等病原生物感染引起的炎症反应,减轻病原体或免疫应答对机体的损伤,从而在感染性休克的防治中发挥作用,另一方面,IL-37也可通过抑制单核巨噬细胞和中性粒细胞等免疫细胞的功能,影响机体抗感染免疫应答,导致病原微生物不能被及时清除,引起持续感染或严重感染,本文就IL-37在感染性疾病中的作用进行综述。     

女性生殖道感染中IL-1的检测及其相关性分析

白细胞介素(IL)由活化的单核/巨噬细胞及淋巴细胞等所产生的一类细胞因子,均为小分子多肤或糖蛋白类物质.作为一个家族,在机体炎症反应中,作用于淋巴细胞、巨噬细胞或其他细胞,参与炎症反应的部分过程或全过程.在免疫激活免疫趋化,免疫应答,炎症放大或炎症抑制方面起重要作用.已知,大多数白介素在免疫反应中都发挥免疫增强作用,只有少数几种白介素具有免疫抑制作用,其中,IL-4,IL-10,IL-13最为典型.多项研究显示,该组因子水平在一些感染性炎症(感染性休克)及自身免疫类炎症时均有不同变化[1-2].IL-4、IL-10、IL-13作为抗炎因子,主要由Th2细胞产生,参与炎症反应的整个过程中,影响炎症的发展及结局.我们采用双抗体夹心ELISA方法,检测女性生殖道感染后IL-1的水平.     

脓毒症中免疫负调控途径的研究进展

传统观念认为脓毒症(sepsis)是一种失控的、持久性全身炎症反应.目前,人们渐渐认识到,在脓毒症的发病过程中机体并非处于一成不变的免疫激活状态,负向调控机制在脓毒症的发生与发展中也发挥着重要作用.在脓毒症的初始阶段,以大量的促炎介质释放为主要特征,但随着病程的进展,机体可能经历了一个免疫负调控阶段,表现为淋巴细胞增殖能力下降,并呈现以辅助性T细胞(helper T-cell,Th)2为主的免疫反应和大量淋巴细胞凋亡等,从而使机体对病原体的易感性增加.     

益气养阴活血法对脓毒血症模型大鼠血清TNF-α、IL-6与IL-10的影响

脓毒症(Sepsis)是机体在受感染后或在休克、创伤等应激状态下自身免疫系统被过度激活致使大量炎性介质失控性释放,继而引起的全身炎症反应综合征(Systemic inflammatory response syndrome,SIRS)[1],因其常并发脓毒症休克及多器官功能衰竭,成为各地医院重症监护病房患者死亡的主要原因之一。目前对预测脓毒症的发展方向和预后评估上临床仍缺乏有效的手段,因此积极探索脓毒症炎     

脓毒症炎症反应与内皮细胞损伤研究进展

脓毒症被定义为机体对感染的异常反应最终引起危及生命的器官功障碍综合征.血管内皮细胞在多种炎症细胞和因子的作用下经历活化一损伤过程是脓毒症发展恶化的中心环节.了解炎症反应与血管内皮损伤关系对理解脓毒症发生发展及其治疗具有重要意义.     

脓毒血症中固有免疫细胞的调节机制研究进展

<正>1文献检索Treg也是固有免疫细胞一部分脓毒血症是由潜在或已知感染因素引起的全身炎症反应综合征,其进展后可出现休克及多器官功能不全,是ICU病房病人死亡的主要原因。尽管基于靶向治疗的分子学发病机制的研究大量开展,但严重脓毒症和脓毒性休克的生存率近年来未得到明显改善。宿主细胞介导免疫对深刻理解脓毒血症及其多脏器损伤并发症的病理过程至关重要。研究表明固有免疫细胞如中性粒细胞、巨噬细胞、树突细     

巨噬细胞LPS相关模式识别受体的研究进展

脓毒症(sepsis)是由各种致病微生物或其毒素引起的全身炎症反应综合征(systemic inflammatory response syndrome, SIRS),是严重感染、重度创伤、大手术后和休克常见的并发症,进一步发展可导致脓毒性休克、急性呼吸窘迫综合征(acute respiratory distress syndrome, ARDS)和多器官功能障碍综合征(multi-organ dysfunction syndrome,MODS)等致命性并发症.     

全身性感染与细胞因子基因多态性的相关性

机体在遭受细菌或毒素损害时,炎症细胞被激活,细胞因子过量释放,产生持续的全身性炎症反应,介导广泛的组织损伤,导致感染性休克和多器官功能衰竭.细胞因子的基因多态性与机体受到刺激后细胞因子的分泌水平相关,与全身性感染的易感性、严重程度及预后相关.探明细胞因子基因多态性与全身性感染的关系,将为全身性感染的个体化免疫基因调控治疗奠定基础.     

Toll 样受体信号转导通路与急性肺损伤的研究进展

急性肺损伤(ALI)是由感染性和非感染性的炎症刺激因子启动的细胞内“瀑布式”反应所产生的,是一种具有高发病率和死亡率的急性炎症性疾病,其进一步发展将演变为急性呼吸窘迫综合征(ARDS)。ALI作为一种复杂的临床综合征,发病率和病死率很高,目前发病机制仍不完全明确,大量研究表明细胞因子的过度表达及其相互作用是发生ALI的根本原因。Toll样受体(TLRs)是一类在先天免疫系统中起重要作用并参与炎症过程的跨膜蛋白,可识别外源性病原体或细胞损伤。近年来研究发现,TLRs在调节ALI后的炎症和修复机制方面扮演着重要的角色,是一个潜在的治疗靶点。本文将就TLRs在急性肺损伤中的研究进展作一综述。     

拮抗内毒素的研究进展

由创伤及感染引起的脓毒症是导致临床病人死亡的主要原因.脓毒症的本质是机体对侵入机体的病原微生物所产生的过度炎症性反应,通常而言,内毒素与免疫炎症细胞,特别是巨噬细胞上相应的受体结合,是启动机体产生防御反应及由此而形成脓毒性反应或脓毒症的关键.研究内毒素介导脓毒症的分子病理学机制及近年有关拮抗内毒素措施的研究进展很重要.     

Peroxisome proliferator-activated receptor gamma contributes to T lymphocyte apoptosis during sepsis

In the last two decades, extensive research failed to significantly improve the outcome of patients with sepsis. In part, this drawback is based on a gap in our knowledge about molecular mechanisms understanding the pathogenesis of sepsis. During sepsis, T cells are usually depleted. Recent studies in mice and human cells suggested a role of the peroxisome proliferator-activated receptor gamma (PPARgamma) in provoking apoptosis in activated T lymphocytes. Therefore, we studied whether expression/activation of PPARgamma might contribute to T cell death during sepsis. We observed PPARgamma up-regulation in T cells of septic patients. In contrast to controls, PPARgamma expressing cells from septic patients responded with apoptosis when exposed to PPARgamma agonists. Cell demise was attenuated by SR-202, a synthetic PPARgamma antagonist, and specificity was further verified by excluding a proapoptotic response to a PPARalpha agonist. We propose that up-regulation of PPARgamma sensitizes T cells of septic patients to undergo apoptosis. PPARgamma activation in T cells requires an exogenous PPARgamma agonist, which we identified in sera of septic patients. Septic sera were used to study reporter gene expression containing a PPAR-responsive element. We conclude that PPARgamma plays a significant role in T cell apoptosis, contributing to lymphocyte loss in sepsis. Thus, inhibition of PPARgamma may turn out to be beneficial for patients suffering from lymphopenia during sepsis.     

Intra-abdominal sepsis: an immunocytochemical study of the small intestine mucosa.

AIM: To investigate immunocytochemical changes in intestinal tissues from patients with intra-abdominal sepsis, and to relate the changes to the possibility of enhanced bacterial adhesion and translocation. METHODS: Tissues from 17 patients suffering from intra-abdominal sepsis and from controls were sectioned and stained immunocytochemically for IgA, IgM, secretory component, J chain, and HLA-DR. Differences in the distribution and characteristics of positively staining cells between the patient groups were assessed. RESULTS: Patients with intra-abdominal sepsis had noticeable reductions in numbers of IgA and IgM plasma cells, reduced J chain staining, and had little immunoglobulin on the surfaces of enterocytes. In contrast, HLA-DR positive cells were increased in the sepsis compared with the control group. The plasma cells present showed cytological changes suggestive of apoptosis. CONCLUSIONS: Stress associated with sepsis and its immediate causes might result in increased plasma glucocorticoid levels that bring about apoptosis of mucosal plasma cells (or their precursors). The consequent reduction in expression of IgA and IgM may favour bacterial adhesion to the enterocytes and facilitate bacterial translocation into the tissues.     

Local thymic caspase-9 inhibition improves survival during polymicrobial sepsis in mice

Caspase-9 is believed to play an essential role in sepsis-induced lymphocyte apoptosis. The aim of this study was therefore to evaluate its contribution within the caspase-dependent apoptosis pathway in a murine model of polymicrobial sepsis. Local injections of Z-LEHD-fmk, a specific caspase-9 inhibitor, into thymi of septic mice led to the complete inhibition of caspase-9, decreased apoptosis of resident tissue cells, and, in addition, reduced further downstream caspase-3 activity. In contrast to its systemic administration, only local injections improved the overall survival of septic mice. However, local injections of a pancaspase inhibitor (Z-VAD-fmk) did not improve survival, although caspase-3 activity was reduced to a similar degree as by the administration of Z-LEHD-fmk. These results indicate that local apoptosis of lymphatic tissue in polymicrobial sepsis is processed dependent of caspase-9 and suggests alternative caspase-dependent beneficial effects, which may determine a positive outcome.     

Reduced Expression of SARM in Mouse Spleen during Polymicrobial Sepsis

Objective Immune dysfunction, including prominent apoptosis of immune cells and decreased functioning of the remaining immune cells, plays a central role in the pathogenesis of sepsis. Sterile α and HEAT/armadillo motif-containing protein (SARM) is implicated in the regulation of immune cell apoptosis. This study aimed to elucidate SARM contributes to sepsis-induced immune cell death and immunosuppression. Methods A mouse model of polymicrobial sepsis was generated by cecum ligation and puncture (CLP). SARM gene and protein expression, caspase 3 cleavage and intracellular ATP production were measured in the mouse spleens. Results CLP-induced polymicrobial sepsis specifically attenuated both the gene and protein expression of SARM in the spleens. Moreover, the attenuation of SARM expression synchronized with splenocyte apoptosis, as evidenced by increased caspase 3 cleavage and ATP depletion. Conclusions These findings suggest that SARM is a potential regulator of sepsis-induced splenocyte apoptosis.     

脓毒症大鼠心肌细胞凋亡和p53蛋白表达相关性的研究

目的研究脓毒症大鼠心肌细胞凋亡的变化及其与p53蛋白表达的关系。方法以盲肠结扎穿刺法复制脓毒症大鼠模型,以电镜和凋亡原位末端标记法（TUNEL法）检测其心肌细胞凋亡变化,用免疫组化方法检测p53蛋白的表达。结果一定时间内脓毒症大鼠心肌细胞凋亡率均明显高于正常对照组和假手术对照组（P均〈0.05）,p53蛋白表达阳性数均较正常对照或假手术组明显升高（P均〈0.05）,其变化与TUNEL法检测凋亡的结果一致（P〈0.05）。结论细胞凋亡可能是脓毒症时心肌损害的机制之一,其调控基因p53的改变或许可以作为脓毒症病情改变的标志,可利用它对脓毒症进行干预,以改善脓毒症的预后。     

Human anti-microbial cathelicidin peptide LL-37 suppresses the LPS-induced apoptosis of endothelial cells

Sepsis is a systemic disease resulting from harmful host response to bacterial infections. During the exacerbation of severe sepsis or septic shock, apoptosis of endothelial cells is induced in susceptible organs such as the lung and liver and triggers microcirculatory disorder and organ dysfunction. LPS, an outer membrane component of Gram-negative bacteria, is one of the major virulence factors for the pathogenesis. We previously reported that LL-37, a human anti-microbial cathelicidin peptide, potently neutralizes the biological activity of LPS and protects mice from lethal endotoxin shock. However, the effect of LL-37 on the LPS-induced endothelial cell apoptosis remains to be clarified. In this study, to further elucidate the action of LL-37 on severe sepsis/endotoxin shock, we investigated the effects of LL-37 on the LPS-induced endothelial cell apoptosis in vitro and in vivo using lung-derived normal human microvascular blood vessel endothelial cells (HMVEC-LBls) and D-galactosamine hydrochloride (D-GalN)-sensitized murine endotoxin shock model. LL-37 suppressed the LPS-induced apoptosis of HMVEC-LBls. In addition, LL-37 inhibited the binding of LPS possibly to the LPS receptors (CD14 and toll-like receptor 4) expressed on the cells. Thus, LL-37 can suppress the LPS-induced apoptosis of HMVEC-LBls via the inhibition of LPS binding to the cells. Furthermore, LL-37 drastically suppressed the apoptosis of hepatic endothelial cells as well as hepatocytes in the liver of murine endotoxin shock model. Together, these observations suggest that LL-37 could suppress the LPS-induced apoptosis of endothelial cells, thereby attenuating lethal sepsis/endotoxin shock.     

T helper type 2-polarized invariant natural killer T cells reduce disease severity in acute intra-abdominal sepsis

Sepsis is characterized by a severe systemic inflammatory response to infection that is associated with high morbidity and mortality despite optimal care. Invariant natural killer T (iNK T) cells are potent regulatory lymphocytes that can produce pro- and/or anti-inflammatory cytokines, thus shaping the course and nature of immune responses; however, little is known about their role in sepsis. We demonstrate here that patients with sepsis/severe sepsis have significantly elevated proportions of iNK T cells in their peripheral blood (as a percentage of their circulating T cells) compared to non-septic patients. We therefore investigated the role of iNK T cells in a mouse model of intra-abdominal sepsis (IAS). Our data show that iNK T cells are pathogenic in IAS, and that T helper type 2 (Th2) polarization of iNK T cells using the synthetic glycolipid OCH significantly reduces mortality from IAS. This reduction in mortality is associated with the systemic elevation of the anti-inflammatory cytokine interleukin (IL)-13 and reduction of several proinflammatory cytokines within the spleen, notably interleukin (IL)-17. Finally, we show that treatment of sepsis with OCH in mice is accompanied by significantly reduced apoptosis of splenic T and B lymphocytes and macrophages, but not natural killer cells. We propose that modulation of iNK T cell responses towards a Th2 phenotype may be an effective therapeutic strategy in early sepsis.     

脓毒症大鼠心肌细胞凋亡与Bcl-2蛋白表达关系的研究

目的研究脓毒症大鼠心肌细胞凋亡的变化及其与Bcl-2蛋白表达的关系,探讨Bcl-2在心肌细胞凋亡中的作用。方法以盲肠结扎穿刺法复制脓毒症大鼠模型,以电镜和TUNEL法检测其心肌细胞凋亡变化,用免疫组化方法检测Bcl-2和蛋白的表达。用SPSS10.0软件完成统计分析。结果一定时间内脓毒症大鼠心肌细胞凋亡率均明显高于正常对照组和假手术对照组（P均〈0.05）,Bcl-2蛋白表达阳性数均较正常对照组和假手术组明显降低（P均〈0.05）,其变化与TUNEL法检测凋亡的结果趋势相反。结论细胞凋亡可能是脓毒症中心肌损害的机制之一,Bcl-2基因的改变或许可以作为脓毒症病情改变的标志,可利用它们对脓毒症进行干预,以改善脓毒症的预后。     

Effects of simvastatin on the function of splenic CD4<Superscript>+</Superscript> and CD8<Superscript>+</Superscript> T cells in sepsis mice

Simvastatin may be beneficial for treating sepsis due to its immune-regulating properties, although the mechanisms remain elusive. Herein, we hypothesized simvastatin may attenuate T cell dysfunction induced by sepsis. To test this hypothesis, we used a model based on cecal ligation and puncture (CLP) to induce sepsis in mice. Male C57BL/6 mice were pre-treated with simvastatin (0.2 μg/g of body weight) before CLP. The expression of B and T lymphocyte attenuator (BTLA) on splenic CD4⁺ T cells and T cell apoptosis, CD4⁺ and CD8⁺ T cells were quantified by flow cytometry. Immunohistochemical staining was performed to evaluate the loss of immune effector cells. Formation of TNF-α and interleukin 10 (IL-10) in the spleen and plasma levels of presepsin, IL-1β, and IL-6 were determined using enzyme-linked immunosorbent assay. Simvastatin markedly inhibited the reduction in cytokine secretion from lipopolysaccharide (LPS)-stimulated splenocytes. Simvastatin-treated mice had significantly decreased the percentages of negative costimulatory receptor BTLA on CD4 T cell expression. Simvastatin markedly reduced T cell apoptosis through downregulating the Fas/FasL expression and decrease the percentage of caspase-3 activity in spleen tissue. There was significantly less depletion of splenic CD4⁺ and CD8⁺ T cells in simvastatin-treated mice. Simvastatin reduced plasma levels of presepsin, IL-1β, and IL-6. Simvastatin can be a powerful regulator of immune function under sepsis conditions by improving T cell function in sepsis.     

Inhibition of Fas/Fas ligand signaling improves septic survival: differential effects on macrophage apoptotic and functional capacity

Signaling through the Fas/Fas ligand (FasL) pathway plays a central role in immune-cell response and function; however, under certain pathological conditions such as sepsis, it may contribute to the animal's or patient's morbidity and mortality. To determine the contribution of FasL to mortality, we conducted survival studies by blocking Fas/FasL with Fas receptor fusion protein (FasFP) in vivo. C3H/HeN mice received FasFP or the saline vehicle (veh) immediately (0 h) or delayed (12 h), after sepsis induced by cecal ligation and puncture (CLP). Subsequently, we examined the effect of FasFP treatment (12 h post-CLP) on macrophage apoptosis and functional capacities. Peritoneal and splenic macrophages and Kupffer cells from sham-veh-, CLP-veh-, sham-FasFP-, or CLP-FasFP-treated mice were harvested 24 h after CLP and stimulated with lipopolysaccharide (LPS) for 24 h. The results indicate that only delayed (12 h) but not 0 h administration of FasFP demonstrated a significant increase in survival. The ability of all macrophage populations to release interleukin (IL)-6 was significantly depressed, and IL-10 release was augmented after CLP. FasFP treatment attenuated the increased IL-10 release in Kupffer cells. However, althogh enhanced susceptibility to LPS-induced apoptosis could be suppressed in CLP mouse Kupffer cells by FasFP, FasFP did not change the peritoneal or splenic macrophage response. Furthermore, FasFP attenuated the elevated plasma levels of liver enzymes after sepsis. These data indicate that in vivo inhibition of Fas/FasL signaling has tissue-specific effects on the induction of macrophage apoptosis, functional changes, and liver damage, which may contribute to the host's ability to ward off a septic challenge.