HMGB1 在a2A- 肾上腺素受体介导脓毒血症大鼠急性肺损伤的作用

目的:探讨HMGB1在a2A-肾上腺素受体介导脓毒血症大鼠急性肺损伤(ALI)的作用。方法:64大鼠建立盲肠结扎穿孔法(CLP)脓毒症模型,随机均分为以下两组:CLP组及CLP+马来酸钠组。各组分别于模型建立后2(T1)、6(T2)、12(T3)、24 h(T4)时检测大鼠血清TNF-、高迁移率族蛋白1(HMGB1)及IL-10含量。CLP24 h后检测肺组织干湿重比(W/D)和髓过氧化物酶活性(MPO)及HMGB1表达;并采用HE法进行肺组织学评分。结果:CLP+马来酸钠组T2时的TNF-水平明显低于CLP组(P<0.05);而HMGB1在T2、T3及T4均明显低于CLP组(P<0.05);IL-10在各个时间点比较结果差异无统计学意义(P>0.05)。CLP+马来酸钠组肺组织W/D、MPO活性、肺组织损伤评分均明显低于CLP组(P<0.05)。CLP+马来酸钠组肺组织HMGB1表达明显低于CLP组(P<0.05)。结论:HMGB1参与了ALI的病理过程,a2A-肾上腺素受体阻断可以通过抑制HMGB1从而改善ALI时的肺功能。     

血清降钙素原在脓毒症患儿中的应用价值分析

目的:探讨脓毒症患儿血清降钙素原(PCT)水平变化及临床应用价值。方法:对脓毒症组38例患儿(严重脓毒症组16例、非严重脓毒症组22例)血清PCT、C反应蛋白(CRP)水平和白细胞(WBC)计数等指标进行检测,并与非脓毒症组的40例患儿进行比较分析。结果:脓毒症组患儿血清PCT、CRP水平及WBC计数均显著高于非脓毒症组,差异具有统计学意义(P<0.05);血清PCT、CRP水平对诊断脓毒症的敏感性差异无显著性(P>0.05),均显著高于WBC计数,差异具有统计学意义(P<0.05);血清PCT水平特异性、阳性预测值、阴性预测值及约登指数均显著高于CRP和WBC计数,差异具有统计学意义(P<0.05);严重脓毒症组患儿血清PCT水平显著高于非严重脓毒症组,差异具有统计学意义(P<0.05),而两组间血清CRP水平及WBC计数差异不显著(P>0.05)。结论:PCT可作为敏感性的鉴别诊断患儿脓毒症的血清学指标,其效果优于CRP和WBC计数。     

脓毒症小鼠心肌损伤与中性粒细胞浸润的关系

目的:探讨脓毒症小鼠心肌损伤与中性粒细胞浸润的关系。方法:复制脓毒症动物模型,分对照组、假手术组、造模组,并设不同的时间点(2h、4h、8h、12h)。采用双抗夹心酶联免疫法(ELISA)检测血清肌钙蛋白(IcTnI),并测心肌组织髓过氧化物酶(MPO)活性。结果:正常组与假手术组各时间点血清cTnI、心肌组织MPO活性均无显著性差异。造模组心肌组织MPO活性较正常组和假手术组均有明显升高(P<0.05),且随着时间进展而增加;造模组血清cTnI浓度随着时间进展而增加,2小时与正常组及假手术组无显著性差异(P>0.05),4小时后显著高于正常组和假手术组(P<0.05);血清cTnI浓度与心肌组织MPO活性呈显著正相关(r=0.700,P=0.000)。结论:脓毒症心肌损伤时,心肌组织存在中性粒细胞浸润,中性粒细胞浸润程度与心肌损伤显著正相关。     

Caveolin-1 Protects against Sepsis by Modulating Inflammatory Response,Alleviating Bacterial Burden,and Suppressing Thymocyte Apoptosis

Sepsis is a leading cause of death, which is characterized by uncontrolled inflammatory response. In this study, we report that caveolin-1, a major component of caveolae, is a critical survival factor of sepsis. We induced sepsis using a well established sepsis animal model, cecal ligation and puncture (CLP). CLP induced 67% fatality in caveolin-1 null mice, but only 27% fatality in wild type littermates (p = 0.015). Further studies revealed that mice deficient in caveolin-1 exhibited marked increase in tumor necrosis factor-α and interleukin-6 production 20 h following CLP treatment, indicating uncontrolled inflammatory responses in the absence of caveolin-1. Caveolin-1 null mice also had a significant increase in bacteria number recovered from liver and spleen, indicating elevated bacterial burdens. In addition, caveolin-1 null mice had a 2-fold increase in thymocyte apoptosis compared with wild type littermates, indicating caveolin-1 as a critical modulator of thymocyte apoptosis during sepsis. In conclusion, our findings demonstrate that caveolin-1 is a critical protective modulator of sepsis in mice. Caveolin-1 exerts its protective function likely through its roles in modulating inflammatory response, alleviating bacterial burdens, and suppressing thymocyte apoptosis.     

Granisetron protects polymicrobial sepsis-induced acute lung injury in mice

Sepsis is a serious condition with a high mortality rate worldwide. Granisetron is an anti-nausea drug for patients undergoing chemotherapy. Here we aimed to identify the novel effect of granisetron on sepsis-induced acute lung injury (ALI). Our results showed that mice treated with granisetron displayed less severe lung damage than controls. Granisetron administration reduced pulmonary neutrophil recruitment after CLP. Moreover, the expressions of Cxcl1 and Cxcl2 were diminished in the presence of granisetron in THP-1 macrophages after lipopolysaccharide exposure. Additionally, granisetron could inhibit the activation of p38 MAPK and NLRP3 inflammasome both in vivo and in vitro. Collectively, granisetron protects against sepsis-induced ALI by suppressing macrophage Cxcl1/Cxcl2 expression and neutrophil recruitment in the lung.     

The sepsis model: an emerging hypothesis for the lethality of inhalation anthrax

Inhalation anthrax is often described as a toxin‐mediated disease. However, the toxaemia model does not account for the high mortality of inhalation anthrax relative to other forms of the disease or for the pathology present in inhalation anthrax. Patients with inhalation anthrax consistently show extreme bacteraemia and, in contrast to animals challenged with toxin, signs of sepsis. Rather than toxaemia, we propose that death in inhalation anthrax results from an overwhelming bacteraemia that leads to severe sepsis. According to our model, the central role of anthrax toxin is to permit the vegetative bacteria to escape immune detection. Other forms of B. anthracis infection have lower mortality because their overt symptoms early in the course of disease cause patients to seek medical care at a time when the infection and its sequelae can still be reversed by antibiotics. Thus, the sepsis model explains key features of inhalation anthrax and may offer a more complete understanding of disease pathology for researchers as well as those involved in the care of patients.     

High Density Lipoprotein Protects against Polymicrobe-induced Sepsis in Mice

HDL has been considered to be a protective factor in sepsis; however, most contributing studies were conducted using the endotoxic animal model, and evidence from clinically relevant septic animal models remains limited and controversial. Furthermore, little is known about the roles of HDL in sepsis other than LPS neutralization. In this study, we employed cecal ligation and puncture (CLP), a clinically relevant septic animal model, and utilized apoA-I knock-out (KO) and transgenic mice to elucidate the roles of HDL in sepsis. ApoA-I-KO mice were more susceptible to CLP-induced septic death as shown by the 47.1% survival of apoA-I-KO mice versus the 76.7% survival of C57BL/6J (B6) mice (p = 0.038). ApoA-I-KO mice had exacerbated inflammatory cytokine production during sepsis compared with B6 mice. Further study indicated that serum from apoA-I-KO mice displayed less capacity for LPS neutralization compared with serum from B6 mice. In addition, apoA-I-KO mice had less LPS clearance, reduced corticosterone generation, and impaired leukocyte recruitment in sepsis. In contrast to apoA-I-KO mice, apoA-I transgenic mice were moderately resistant to CLP-induced septic death compared with B6 mice. In conclusion, our findings reveal multiple protective roles of HDL in CLP-induced sepsis. In addition to its well established role in neutralization of LPS, HDL exerts its protection against sepsis through promoting LPS clearance and modulating corticosterone production and leukocyte recruitment. Our study supports efforts to raise HDL levels as a therapeutic approach for sepsis.