糖皮质激素在脓毒症治疗中的研究进展

脓毒症是由致病微生物感染引发的全身炎症反应综合征（SIRS),合并血压降低且经快速液体复苏后血压仍不能恢复正常者 称为脓毒性休克（Septic shock),其中一部分患者发展为多器官功能障碍综合症(MODS)。脓毒症病死率居高不下。每10 万人口中 约50-300 人会发生严重脓毒症,其短期死亡率达20%-25%,当发展为脓毒性休克时其死亡率达50%。整合消灭致病微生物、阻断 炎症介质和处理MODS等措施的" 集束化"治疗并未显著降低脓毒症患者的病死率。糖皮质激素具有强大的抗炎作用,但诸多 的临床研究对糖皮质激素疗效的评价褒贬不一,糖皮质激素是否有利于脓毒症的转归一直饱受争议[3]。本文仅就糖皮质激素在 严重脓毒症及脓毒性休克中的治疗进展综述如下,并希望能进一步探讨发生严重脓毒症及脓毒性休克时,机体对糖皮质激素反 应复杂性的原因,以及在以后的研究中对相对肾上腺皮质功能不全的诊断标准及对糖皮质激素用药和停药时机的选择更加明确。     

脓毒症诊断的生物学标志物的研究进展

脓毒症是由致病微生物感染引发的全身炎症反应综合征(SIRS),合并血压降低且经快速液体复苏后血压仍不能恢复正常者称为脓毒性休克(Septic shock),其中一部分患者发展为多器官功能障碍综合症(MODS)。由于目前临床上仍缺乏早期敏感性诊断手段,脓毒症病死率居高不下。每10万人口中约50-300人会发生严重脓毒症,其短期死亡率达20%-25%,当发展为脓毒性休克时其死亡率达50%。随着分子生物学和现代生物技术的不断发展,人们发现多种生物标志物在脓毒症的早期诊断、病情及预后判断,疗效评估中发挥重要作用。因此深入了解脓毒症病理生理机制中不同生物标志物的意义及价值,对于脓毒症及其并发症的早期识别及干预,降低患者病死率及改善患者生活质量有积极意义。本文综述了近几年来对脓毒症的诊断和预后有一定价值的主要标志物及其应用。     

防御素与脓毒症

脓毒症（sepsis,又名全身性感染）是机体感染后所致的全身炎症反应综合征（systemic inflammatory response syndrome,SIRS）,是创（烧）伤、感染、休克及外科大手术后的常见并发症。重症脓毒症（severe sepsis）、脓毒性休克（septic shock）和多器官功能障碍综合征（multiple organ dysfunction syndrome,     

脓毒性休克的诊疗进展

<正>脓毒症是由于感染引起的全身性炎症反应综合征,为大手术术后、严重创伤或感染后常见并发症。脓毒症的发病机制复杂,病理过程涉及炎症、组织损害、凝血功能、免疫等一系列问题~([1]),且与机体多系统、多器官病理生理性改变相关~([2]),常见致病菌为革兰阴性细菌~([3])。脓毒性休克是重症监护室常见危重症,是脓毒症引起的循环功能障碍表现,具有发病急、进展快,且常累及多个脏器,严重威胁患者生命健康,降低患者的生活质量~([4])。近年来,器官功能支持技术及     

高密度脂蛋白与脓毒症

脓毒症是指由感染引起的全身炎症反应综合征,由于机体应对感染反应失调而导致多器官功能障碍,常危及生命。研究发现,高密度脂蛋白(high-density lipoprotein, HDL)在调节血管内皮细胞功能和机体免疫中发挥着重要作用,提高循环血HDL水平可以有效预防脓毒性休克的发生。本文论述了HDL抗脓毒症的潜在机制以及重组高密度脂蛋白应用于脓毒症治疗的前景和面临的挑战。     

小儿脓毒症心肌损伤的临床诊断与治疗现状

脓毒症是由感染引起的严重威胁儿童生命的危重症之一,临床救治困难。近年,人们对其临床监测与诊断及治疗策略进行了深入探讨。本文从血流动力学监测与心电、心脏生物学标志物监测相结合、集束化与个体化相结合的治疗策略等角度,对脓毒症患儿心肌损伤的临床诊断与治疗进展进行了综述。     

脓毒症早期预警及判断预后生化标志物的研究进展

正脓毒症是指机体对感染的反应失调,从而导致危及生命的器官功能障碍,是感染、烧/创伤、休克等急危重症患者的严重并发症[1]。随着危重病监护救治技术的进步,脓毒症患者的病死率虽然显著下降,但仍有较高的病死率。因此,及早识别诊断脓毒症并实施有效防治措施,是提高患者生存率的关键。本文结合脓毒症的发病机制,对近年来脓毒症早期预警及预后判断生化标志物的研究进展作一综述如下。     

脓毒性脑病的神经化学机制研究进展

脓毒性脑病是一种脓毒症所引起的全身性炎症反应,在多器官功能障碍综合征患者中出现。脓毒性脑病与多种炎症因子及化学物质有关。这些炎症因子可在全身引起炎症反应,破坏血脑屏障并影响脑功能,引起突触传递及可塑性异常等神经系统相关的病症。文中对近年来脓毒性脑病发病过程中所涉及的神经递质失衡、突触传递异常及相关神经调节作用以及检测神经递质的量子点技术进行综述总结,旨在推进未来脓毒性脑病的研究。     

以线粒体通透性转换孔为靶点的脓毒症器官功能保护研究进展

脓毒症是由宿主对感染的反应失调引起的危及生命的器官功能障碍。对于脓毒症的治疗主要是抗感染、抗休克、维持机体组织器官灌注等。但近年来,在对脓毒症诱导的组织器官功能障碍的研究中发现,脓毒症时出现多器官功能障碍的原因不仅在于组织器官的缺血缺氧,而且与线粒体通透性转换孔(mitochondrial permeability transition pore, MPTP)异常开放等机制引起的线粒体功能障碍也有很大关系。本综述主要介绍了MPTP的组成、脓毒症时其异常开放对器官功能的影响,以及作为治疗靶点的应用前景。旨在为脓毒症的器官功能保护研究提供方向。     

The therapeutic value of protein (de)nitrosylation in experimental septic shock

Cardiovascular dysfunction and organ damage are hallmarks of sepsis and septic shock. Protein S-nitrosylation by nitric oxide has been described as an important modifier of protein function. We studied whether protein nitrosylation/denitrosylation would impact positively in hemodynamic parameters of septic rats. Polymicrobial sepsis was induced by cecal ligation and puncture. Female Wistar rats were treated with increasing doses of DTNB [5,5′-dithio-bis-(2-nitrobenzoic acid)] 30 min before or 4 or 12 h after sepsis induction. Twenty-four hours after surgery the following data was obtained: aorta response to phenylephrine, mean arterial pressure, vascular reactivity to phenylephrine, biochemical markers of organ damage, survival and aorta protein nitrosylation profile. Sepsis substantially decreases blood pressure and the response of aorta rings and of blood pressure to phenylephrine, as well as increased plasma levels of organ damage markers, mortality of 60% and S-nitrosylation of aorta proteins increased during sepsis. Treatment with DTNB 12 h after septic shock induction reversed the loss of response of aorta rings and blood pressure to vasoconstrictors, reduced organ damage and protein nitrosylation and increased survival to 80%. Increases in protein S-nitrosylation are related to cardiovascular dysfunction and multiple organ injury during sepsis. Treatment of rats with DTNB reduced the excessive protein S-nitrosylation, including that in calcium-dependent potassium channels (BK_Ca), reversed the cardiovascular dysfunction, improved markers of organ dysfunction and glycemic profile and substantially reduced mortality. Since all these beneficial consequences were attained even if DTNB was administered after septic shock onset, protein (de)nitrosylation may be a suitable target for sepsis treatment.     

Glucan phosphate attenuates cardiac dysfunction and inhibits cardiac MIF expression and apoptosis in septic mice

Myocardial dysfunction is a major consequence of septic shock and contributes to the high mortality of sepsis. We have previously reported that glucan phosphate (GP) significantly increased survival in a murine model of cecal ligation and puncture (CLP)-induced sepsis. In the present study, we examined the effect of GP on cardiac dysfunction in CLP-induced septic mice. GP was administered to ICR/HSD mice 1 h before induction of CLP. Sham surgically operated mice served as control. Cardiac function was significantly decreased 6 h after CLP-induced sepsis compared with sham control. In contrast, GP administration prevented CLP-induced cardiac dysfunction. Macrophage migration inhibitory factor (MIF) has been implicated as a major factor in cardiomyocyte apoptosis and cardiac dysfunction during septic shock. CLP increased myocardial MIF expression by 88.3% (P < 0.05) and cardiomyocyte apoptosis by 7.8-fold (P < 0.05) compared with sham control. GP administration, however, prevented CLP-increased MIF expression and decreased cardiomyocyte apoptosis by 51.2% (P < 0.05) compared with untreated CLP mice. GP also prevented sepsis-caused decreases in phospho-Akt, phospho-GSK-3beta, and Bcl-2 levels in the myocardium of septic mice. These data suggest that GP treatment attenuates cardiovascular dysfunction in fulminating sepsis. GP administration also activates the phosphoinositide 3-kinase/Akt pathway, decreases myocardial MIF expression, and reduces cardiomyocyte apoptosis.     

CD204-positive monocytes and macrophages ameliorate septic shock by suppressing proinflammatory cytokine production in mice

Sepsis is defined as a life-threatening multiorgan dysfunction caused by dysregulated inflammatory response to infection. It remains the primary cause of death from infection if not diagnosed and treated promptly. Therefore, a better understanding of the mechanism for resolving inflammation is needed. Monocytes and macrophages play a pivotal role not only in the induction but also in the suppression of inflammation. However, a tissue-resident macrophage subset that regulates a hyperinflammatory state during sepsis has not been explored. Here we show that CD204⁺ monocytes and/or macrophages rescued mice from endotoxin-induced septic shock. Serum and tissue proinflammatory cytokine levels were significantly upregulated in the absence of these cells. This study provided evidence that CD204⁺ monocytes and/or macrophages ameliorate septic shock by suppressing proinflammatory cytokine production.     

Disruption of Calcium Homeostasis in Cardiomyocytes Underlies Cardiac Structural and Functional Changes in Severe Sepsis

Sepsis, a major cause of morbidity/mortality in intensive care units worldwide, is commonly associated with cardiac dysfunction, which worsens the prognosis dramatically for patients. Although in recent years the concept of septic cardiomyopathy has evolved, the importance of myocardial structural alterations in sepsis has not been fully explored. This study offers novel and mechanistic data to clarify subcellular events that occur in the pathogenesis of septic cardiomyopathy and myocardial dysfunction in severe sepsis. Cultured neonatal mice cardiomyocytes subjected to serum obtained from mice with severe sepsis presented striking increment of [Ca²⁺]_i and calpain-1 levels associated with decreased expression of dystrophin and disruption and derangement of F-actin filaments and cytoplasmic bleb formation. Severe sepsis induced in mice led to an increased expression of calpain-1 in cardiomyocytes. Moreover, decreased myocardial amounts of dystrophin, sarcomeric actin, and myosin heavy chain were observed in septic hearts associated with depressed cardiac contractile dysfunction and a very low survival rate. Actin and myosin from the sarcomere are first disassembled by calpain and then ubiquitinated and degraded by proteasome or sequestered inside specialized vacuoles called autophagosomes, delivered to the lysosome for degradation forming autophagolysosomes. Verapamil and dantrolene prevented the increase of calpain-1 levels and preserved dystrophin, actin, and myosin loss/reduction as well cardiac contractile dysfunction associated with strikingly improved survival rate. These abnormal parameters emerge as therapeutic targets, which modulation may provide beneficial effects on future vascular outcomes and mortality in sepsis. Further studies are needed to shed light on this mechanism, mainly regarding specific calpain inhibitors.     

Inflection points in sepsis biology: from local defense to systemic organ injury

Sepsis and septic shock lead to considerable morbidity and mortality in developed and developing countries. Despite advances in understanding the innate immune events that lead to septic shock, molecular therapies based on these advances have failed to improve sepsis mortality. The clinical failure of laboratory-derived therapies may be, in part, due to the pleiotropic consequences of the acute inflammatory response, which is the focus of this review. A brisk response to infecting organism is essential for pathogen containment and eradication. However, systemic spread of inflammation beyond a single focus leads to organ injury and higher mortality. The primary goal of this article is to discuss recent animal- and human-based scientific advances in understanding the host response to infection and to highlight how these defense mechanisms can be locally beneficial but systemically detrimental. There are other factors that determine the severity of sepsis that are beyond the scope of this review, including the virulence of the pathogen and regulation by Toll-like receptors. Specifically, this review focuses on how the effector mechanisms of platelets, mast cells, neutrophil extracellular traps (NETs), and the endothelium participate in combating local infections yet can induce organ injury during systemic infection.     

Inhibition of c-Jun-N-terminal kinase increases cardiac peroxisome proliferator-activated receptor alpha expression and fatty acid oxidation and prevents lipopolysaccharide-induced heart dysfunction

Septic shock results from bacterial infection and is associated with multi-organ failure, high mortality, and cardiac dysfunction. Sepsis causes both myocardial inflammation and energy depletion. We hypothesized that reduced cardiac energy production is a primary cause of ventricular dysfunction in sepsis. The JNK pathway is activated in sepsis and has also been implicated in impaired fatty acid oxidation in several tissues. Therefore, we tested whether JNK activation inhibits cardiac fatty acid oxidation and whether blocking JNK would restore fatty acid oxidation during LPS treatment. LPS treatment of C57BL/6 mice and adenovirus-mediated activation of the JNK pathway in cardiomyocytes inhibited peroxisome proliferator-activated receptor α expression and fatty acid oxidation. Surprisingly, none of the adaptive responses that have been described in other types of heart failure, such as increased glucose utilization, reduced αMHC:βMHC ratio or induction of certain microRNAs, occurred in LPS-treated mice. Treatment of C57BL/6 mice with a general JNK inhibitor (SP600125) increased fatty acid oxidation in mice and a cardiomyocyte-derived cell line. JNK inhibition also prevented LPS-mediated reduction in fatty acid oxidation and cardiac dysfunction. Inflammation was not alleviated in LPS-treated mice that received the JNK inhibitor. We conclude that activation of JNK signaling reduces fatty acid oxidation and prevents the peroxisome proliferator-activated receptor α down-regulation that occurs with LPS.     

GSK‐3β inhibition protects the rat heart from the lipopolysaccharide‐induced inflammation injury via suppressing FOXO3A activity

Sepsis‐induced cardiac dysfunction represents a main cause of death in intensive care units. Previous studies have indicated that GSK‐3β is involved in the modulation of sepsis. However, the signalling details of GSK‐3β regulation in endotoxin lipopolysaccharide (LPS)‐induced septic myocardial dysfunction are still unclear. Here, based on the rat septic myocardial injury model, we found that LPS could induce GSK‐3β phosphorylation at its active site (Y216) and up‐regulate FOXO3A level in primary cardiomyocytes. The FOXO3A expression was significantly reduced by GSK‐3β inhibitors and further reversed through β‐catenin knock‐down. This pharmacological inhibition of GSK‐3β attenuated the LPS‐induced cell injury via mediating β‐catenin signalling, which could be abolished by FOXO3A activation. In vivo, GSK‐3β suppression consistently improved cardiac function and relieved heart injury induced by LPS. In addition, the increase in inflammatory cytokines in LPS‐induced model was also blocked by inhibition of GSK‐3β, which curbed both ERK and NF‐κB pathways, and suppressed cardiomyocyte apoptosis via activating the AMP‐activated protein kinase (AMPK). Our results demonstrate that GSK‐3β inhibition attenuates myocardial injury induced by endotoxin that mediates the activation of FOXO3A, which suggests a potential target for the therapy of septic cardiac dysfunction.     

The Septic Brain

Sepsis is a major disease entity with important clinical implications. Sepsis-induced multiple organ failure is associated with a high mortality rate in humans and is clinically characterized by pulmonary, cardiovascular, renal and gastrointestinal dysfunction. Recently, several studies have demonstrated that sepsis survivors present long-term cognitive impairment, including alterations in memory, attention, concentration and/or global loss of cognitive function. However, the pathogenesis and natural history of septic encephalopathy and cognitive impairment are still poorly known and further understanding of these processes is necessary for the development of effective preventive and therapeutic interventions. This review discusses the clinical presentation and underlying pathophysiology of the encephalopathy and cognitive impairment associated with sepsis.