青蒿素对脓毒症大鼠肝脏脂质过氧化损伤的影响

目的：观察青蒿素对脓毒症大鼠肝脏脂质过氧化损伤的影响.方法：采用盲肠结扎穿孔术（cecal ligation and puncture,CLP）制作大鼠脓毒症模型,观察青蒿素治疗对CLP大鼠术后2、6、12、24、48、72 h 大鼠血清内毒素（lipopolysaccharide, LPS）含量以及肝组织中超氧化物歧化酶 （superoxide dismutase, SOD）、丙二醛 （malondialdehyde, MDA）、肿瘤坏死因子α（tumor necrosis factor α,TNF-α）和白细胞介素-6（IL-6）水平的影响.结果：青蒿素治疗降低大鼠CLP术后血清LPS以及肝组织中MDA、TNF-α和IL-6的峰值,维持SOD接近正常水平.结论：青蒿素可减轻CLP大鼠肝脏的脂质过氧化损伤,减少脓毒症大鼠肝脏的炎症反应损害.     

乌司他丁调控脓毒症大鼠TNF-α与IL-6及IL-10水平的研究

目的:探讨乌司他丁对脓毒症大鼠血清TNF-α、L-6、IL-10水平的调控作用。方法:将雄性SD大鼠随机分为正常对照组、假手术组、模型组和乌司他丁组。采用盲肠结扎穿孔术(CLP)制备脓毒症模型,于造模后2.0,8.0,12.0,24.0h处死大鼠,双抗体夹心酶联免疫吸附法(ELISA)测定血清TNF-α、L-6、IL-10水平;留取完整左肺组织行病理切片,评估肺脏损伤情况。结果:模型组各时间点TNF-α、L-6、IL-10水平均高于假手术组(P<0.05);乌司他丁组与模型组相比,除24.0h外TNF-α水平明显降低(P<0.01),IL-6水平各时间点均明显下降(P<0.01),IL-10水平各时间点均明显升高(P<0.01),病理切片显示乌司他丁组肺损伤轻于模型组。结论:乌司他丁能下调脓毒症大鼠TNF-α、L-6水平,对IL-10有上调作用,并能减轻脓毒症肺损伤。     

盐酸氨溴索对败血症大鼠保护作用的实验研究

目的:探讨盐酸氨溴索对腹腔感染败血症大鼠的保护作用机制。方法:60只大鼠随机分对照组、CLP组和实验组,每组20只。CLP组和实验组采用盲肠结扎穿孔(CLP)法复制腹腔感染败血症动物模型。实验组于术毕腹腔注射盐酸氨溴索6mg/kg。取术后6h肺组织进行光镜检查,测定超氧化物歧化酶(SOD)活性、丙二醛(MDA)含量、诱导型一氧化氮合酶(iNOS)mRNA的表达,以及血浆中肿瘤坏死因子-α(TNF-α)水平的变化。观察24h内3组大鼠的总体生存状况。结果:与CLP组相比,实验组大鼠24h总体生存只数明显增加,分别为4/10和7/10(P=0.025)。实验组肺组织病理改变较CLP组明显减轻。实验组肺组织MDA含量较CLP组降低(P<0.05);SOD活性较CLP组升高(P<0.05)。实验组肺组织iNOS mRNA阳性表达数低于CLP组,分别为3只和9只(P<0.05)。实验组血浆TNF-α浓度低于CLP组(P<0.05)。结论:盐酸氨溴索可能通过抑制肺组织iNOSmRNA的表达,拮抗自由基产生,增加自由基清除,降低血浆中促炎性细胞因子的水平,发挥其对肺组织的保护作用。     

姜黄素对脓毒症小鼠肝脏炎性反应的抑制作用

目的:观察姜黄素对脓毒症小鼠肝脏炎性反应的抑制作用及其可能机制.方法:BALB/c小鼠行盲肠结扎穿孔术(cecal ligation and puncture,CLP)建立脓毒症动物模型.将40只雄性BALB/c小鼠随机分成对照组、CLP组、CLP+二甲亚砜(DMSO姜黄素溶剂)组和CLP+姜黄素干预组.CLP+姜黄素组及CLP+DMSO组除伤后分别使用姜黄素、DMSO外,其余处理同CLP组.于伤后24h取肝脏做病理学检查;检测小鼠血清丙氨酸转氨酶(ALT)及天冬氨酸转氨酶(AST)的水平;测血浆肿瘤坏死因子-α(TNF-α)、白介素-1B(IL-1β)水平.结果:与对照组比较,CLP组血浆ALT、AST、TNF-α、IL-1β水平明显高于正常对照组[(398±27) U/L vs (64± 10) U/L,P＜0.01、(122±22)U/Lvs (42±8)U/L,P＜0.01,(24.45±6.80)pg/mL vs (5.33±1.48)pg/mL,P＜0.01、(4.95± 1.55) pg/mL vs (0.89±0.07)pg/mL,P＜0.01)],用姜黄素干预后,ALT、AST、TNF-α、IL-1β血浆水平显著降低[(202±28)U/L vs (398±27)U/L,P＜0.05、(66±11)U/Lvs(122±22)U/L,P＜0.05、(14.38±2.79)pg/mL vs(24.45±6.80)pg/mL,P＜0.05、(2.06±0.39)pg/mL vs (4.95±1.55)pg/mL,P＜0.05].结论:姜黄素能明显降低脓毒症小鼠血清中的TNF-α、IL-1β表达水平,减轻肝脏组织中白细胞滞留,改善肝功能,可有效减轻肝脏炎性反应.     

低氧诱导因子-1α对脓毒症肠黏膜屏障的保护作用

目的:探讨低氧诱导因子-1α(HIF-1α)对脓毒症肠黏膜屏障的影响及机制。方法:SD大鼠随机分4组:假手术组、脓毒症组、脓毒症+HIF-1α刺激剂组(脓毒症+DMOG组)、脓毒症+HIF-1α抑制剂组(脓毒症+Bay87-2243组),每组6只。采用盲肠结扎穿孔(cecal ligation and perforation,CLP)建立脓毒症模型。ELISA检测大鼠血浆炎性标记物IL-1β、IL-6、TNF-α,氧化应激标记物丙二醛(MDA)以及抗氧化因子超氧化物歧化酶(SOD)、过氧化氢酶(CAT)的水平。Western blot检测大鼠肠黏膜HIF-1α表达。HE染色检测肠黏膜病理学损伤。结果:与假手术组相比,脓毒症大鼠炎症因子、氧化应激因子以及HIF-1α显著上调(P<0.05);给予腹腔注射DMOG明显降低脓毒症大鼠血浆IL-1β、IL-6、TNF-α、MDA水平(P<0.05);增加血浆SOD、CAT水平(P<0.05);HIF-1α表达上调(P<0.05),肠黏膜病理损伤减轻,Chiu's评分显著降低(P<0.05)。口服灌胃Bay87-2243则得到相反的结果。结论:HIF-1α对脓毒症肠黏膜损伤具有保护作用,其机制可能与缓解脓毒症炎性反应和抑制氧化应激水平有关。     

氯化钆对脓毒症大鼠急性肺损伤的肺保护作用

目的探讨氯化钆(GdCl3)在脓毒症大鼠急性肺损伤中的肺保护作用及可能机制。方法采用盲肠结扎穿孔术(CLP)建立脓毒症模型。将36只成年Wistar大鼠随即均分为假手术组(Sham组)、脓毒症组(CLP组)和氯化钆治疗组(GdCl3组),GdCl3组术后经尾静脉注射氯化钆溶液。检测血浆TNF-α、丙二醛(MDA)水平,用HE染色法观察肺组织形态,测定肺湿/干重比,统计方法采用SPSS19.0。结果 GdCl3组血浆TNF-α及MDA水平、肺湿/干重比均显著低于CLP组(P<0.05),光镜下可见GdCl3组肺组织病理学改变明显减轻。结论 GdCl3可明显减轻脓毒症所致的急性肺损伤的炎性反应。     

辛伐他汀对脓毒症小鼠肺损伤的保护作用

目的观察辛伐他丁对脓毒症小鼠急性肺损伤的保护作用,并探讨其可能机制。方法采用盲肠结扎穿孔术制备脓毒症小鼠模型,将72只雄性C57BL/6小鼠随机分成3组:假手术组、脓毒症急性肺损伤组(脓毒症组)、脓毒症+辛伐他汀治疗组(治疗组)。治疗组给予辛伐他汀0.2μg/g,q12h腹腔注射1周;假手术组、脓毒症组给予等量安慰剂腹腔注射1周。分别于造模后6、12、24 h留取肺脏标本。HE染色观察肺组织病理学变化,免疫组化检测肺组织toll样受体4(Toll-like receptor 4,TLR4)蛋白的表达,ELISA测定肺组织匀浆中IL-1β及TNF-α的表达水平。结果与假手术组比较,造模后6、12、24 h,脓毒症组肺组织病理学评分、肺组织TLR4蛋白的表达,以及TNF-α、IL-1β水平明显升高(P<0.05);与脓毒症组相比,治疗组上述指标明显降低(P<0.05)。结论辛伐他汀通过抑制TLR4信号转导通路,减少其下游炎症介质TNF-α、IL-1β的释放,对脓毒症导致的急性肺损伤具有一定保护作用。     

当归精油对脓毒症小鼠的治疗作用

目的:观察当归精油对脓毒症小鼠的治疗作用。方法:i.v.给予细菌脂多糖复制小鼠脓毒症模型,i.v.给予不同剂量的当归精油,记录小鼠7 d生存率,ELISA法测定血清中细胞因子TNF-α和IL-6含量。结果:在100 mg/kg剂量下,当归精油可提高内毒素(25 mg/kg)攻击小鼠的生存率(P<0.01);在内毒素(25 mg/kg)攻击前、后2 h内给药能提高小鼠生存率,提前1 h预防性给药生存率最高(P<0.01);25～100 mg/kg当归精油能对抗0.125 mg/kg内毒素引起的TNF-α、IL-6水平增高,降低小鼠血清TNF-α、IL-6水平(P<0.05或P<0.01)。结论:当归精油能拮抗内毒素引起的炎症反应,对脓毒症有一定的治疗作用。     

己酮可可碱对大鼠脓毒症急性肺损伤p38MAPK活性的影响

目的　探讨己酮可可碱(pentoxifylline,PTX)对腹腔感染致脓毒症急性肺损伤发挥肺保护作用与p38MAPK活化的关系。方法　采用盲肠结扎穿孔致脓毒症模型,将大鼠随机分为Ⅰ组(Sham组)、Ⅱ组(脓毒症CLP组)、Ⅲ组(脓毒症加西黄著胶CLP+V组)、Ⅳ组(脓毒症加生理盐水CLP+N组)、Ⅴ组(脓毒症加SB203580 CLP+SB组)、Ⅵ组(脓毒症加己酮可可碱CLP+PTX组),其中Ⅲ组、Ⅳ组为溶媒对照组。用Western Blot检测假手术组,脓毒症1,3,6,12,24 h后p38MAPK的磷酸化,然后选择1,6,24 h分别检测应用SB203580或PTX后p38MAPK的表达,同时检测血浆TNF-α、IL-6的含量并观察24 h内肺组织病理改变。结果　与假手术组比较,脓毒症组在各个时间点p38MAPK均有较强的表达,SB203580或PTX预处理后各组的p38MAPK的磷酸化明显受到抑制,且与血浆TNF-α、IL-6的含量以及肺的病理切片变化一致。结论　己酮可可碱可能是通过抑制p38MAPK的磷酸化抑制促炎因子的过度表达,发挥对脓毒症急性肺损伤的保护作用。     

甘氨酸对烧伤大鼠失控炎症反应的调控作用及机制研究探讨

目的 探讨对于烧伤大鼠采用甘氨酸调控过度炎症反应的作用及其相关机制.方法 本次研究主要是通过对大鼠腹腔巨噬细胞内游离钙离子浓度影响的分析来确定甘氨酸对烧伤大鼠失控炎症反应的调控作用.结果 3、6、12、24 h,烧伤合并脓毒症组血浆LPS水平与其他3组比较,差异具有统计学意义(均P＜ 0.05).3h,烧伤合并脓毒症组血浆TNF-α水平与单纯烧伤组比较,差异具有统计学意义(P＜0.05);6、12h,烧伤合并脓毒症组TNF-α水平与其他3组比较,差异具有统计学意义(均P＜ 0.05);24h,烧伤合并脓毒症、谷氨酰胺治疗组TNF-α水平与其他3组比较,差异具有统计学意义(均P＜ 0.05).:3h,4组大鼠血浆IL-10水平整体比较,差异无统计学意义(均P＞0.05);6h,烧伤合并脓毒症、甘氨酸治疗组血浆IL-10水平与其他3组比较,差异具有统计学意义(均P＜0.05);12、24 h,烧伤合并脓毒症、甘氨酸治疗组血浆IL-10水平与烧伤合并脓毒症、谷氨酰胺治疗组比较,差异具有统计学意义(均P＜ 0.05).结论 Gln及Gly在临床上具有抗炎及抗脓毒症作用,能够在一定程度上降低烧伤后脓毒症大鼠血浆LPS水平以及抑制炎性细胞因子TNF-α分泌,并促进抗炎因子IL-10分泌.     

The beneficial effect of trolox on sepsis-induced hepatic drug metabolizing dysfunction

Trolox is a hydrophilic analogue of vitamin E. The aim of this study was to investigate its effects on hepatic injury, especially alteration in cytochrome P450 (CYP)-dependent drug metabolism during polymicrobial sepsis. Rats were subjected to polymicrobial sepsis by cecal ligation and puncture (CLP). The rats were treated intravenously with Trolox (2.5 mg/kg) or vehicle, immediately after CLP. Serum aminotransferases and lipid peroxidation levels were markedly increased 24 h after CLP. This increase was attenuated by Trolox. Total CYP content and NADPH-P450 reductase activity decreased significantly 24 h after CLP. This decrease in CYP content was attenuated by Trolox. At 24 h after CLP, there was a significant decrease in the activity of these CYP isozymes: CYP1A1, 1A2, 2B1, and 2E1. However, Trolox differentially inhibited the decrease in CYP isozyme activity. Trolox had little effect on the decrease in CYP1A1 activity but Trolox significantly attenuated decreases in CYP1A2 and 2E1 activities. In fact, Trolox restored CYP2B1 activity to the level of activity found in control rats. Our findings suggest that Trolox reduces hepatocellular damage as indicated by abnormalities in hepatic drug-metabolizing function during sepsis. Our data also indicates that this protection is, in part, caused by decreased lipid peroxidation.     

Sepsis induces variation of intestinal barrier function in different phase through nuclear factor kappa B signaling

The intestinal barrier function disrupted in sepsis, while little is known about the variation in different phases of sepsis. In this study, mouse models of sepsis were established by caecal ligation and puncture (CLP). The H&E staining of sections and serum diamine oxidase concentration were evaluated at different timepoint after CLP. TUNEL assay and EdU staining were performed to evaluate the apoptosis and proliferation of intestinal epithelium. Relative protein expression was assessed by Western blotting and serum concentrations of pro-inflammatory cytokines was measured by ELISA. The disruption of intestinal barrier worsened in the first 24 h after the onset of sepsis and gradually recovered over the next 24 h. The percentage of apoptotic cell increased in the first 24 h and dropped at 48 h, accompanied with the proliferative rate of intestinal epithelium inhibited in the first 6 h and regained in the later period. Furthermore, the activity of nuclear factor kappa B (NF-κB) presented similar trend with the intestinal barrier function, shared positive correction with apoptosis of intestinal epithelium. These findings reveal the conversion process of intestinal barrier function in sepsis and this process is closely correlated with the activity of NF-κB signaling.     

卡巴胆碱对脓毒症大鼠肠组织缺血和氧自由基损伤的保护作用

目的研究卡巴胆碱(CAR)对脓毒症大鼠肠组织缺血引起的脂质过氧化损伤的保护作用。方法雄性SD大鼠32只,采用盲肠结扎穿孔术(CLP)制备大鼠脓毒症模型。随机分为CLP组和卡巴胆碱干预组(CAR组),每组16只。CLP后立即静脉注射CAR 10μg/kg(CAR组)或等量生理盐水(CLP组)。用激光多普勒血流仪测定于CLP后6 h和12 h空肠黏膜血流量(IMBF);然后处死动物,取空肠组织,测定丙二醛(MDA)含量、黄嘌呤氧化酶(XOD)和二胺氧化酶(DAO)活性及组织含水率。结果CLP后6 h和12 h CAR组IMBF分别为(66±10)BFU和(56±9)BFU,显著高于CLP组[(46±10)BFU和(38±8)BFU](P<0.05)。CAR组空肠组织XOD活性和MDA含量显著低于CLP组,但DAO活性高于CLP组(P均<0.05)。CAR组空肠组织含水率也低于CLP组,6 h[(66.3±4.5)%vs(71.6±3.2)%]和12 h[(66.8±3.4)%vs(72.1±2.8)%]差异均有统计学意义(P均<0.05)。结论卡巴胆碱能改善脓毒症大鼠小肠缺血、抑制氧自由基生成,减轻肠组织水肿和功能损害。     

Liu-Shen-Wan, a traditional Chinese medicine, improves survival in sepsis induced by cecal ligation and puncture via reducing TNF-alpha levels, MDA content and enhancing macrophage phagocytosis

Sepsis in humans is a difficult condition to treat and is often associated with a high mortality rate. Here, we investigated putative protective effects of Liu-Shen-Wan (LSW), a well-known Chinese formula used in treating infectious diseases, against polymicrobial sepsis induced by cecal ligation and puncture (CLP). The oral administration of LSW, at the first dose of 60 mg/kg and then 30 mg/kg every 12 h, significantly improved the survival of CLP mice during a 4-day observation period. The effects of LSW on the inflammatory response (circulating tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1) levels and malondialdehyde (MDA) content-an index of lipid peroxidation), infectious degree (peritoneal bacteria counts), and innate immunity function (leukocyte counts, macrophage phagocytosis and neutrophil respiratory burst) were further examined in rats. We demonstrated that treatment of LSW significantly decreased elevated levels of circulating TNF-alpha at 4 h and further reduced plasma MDA levels at 24 h after CLP, at first doses of 15 and 30 mg/kg and then 7.5 and 15 mg/kg every 12 h. Moreover, LSW markedly enhanced clearance of intraperitoneal bacteria associated with the increasing count of peritoneal leukocytes and enhancing phagocytic activity of macrophages partly impaired at 24 h after CLP. In contrast, LSW lightly reduced IL-1 levels at 4 h and failed to improve deactivated respiratory burst activity of neutrophils at 24 h after CLP. Thus, LSW exerts protective effects against sepsis induced by CLP, mainly by reducing plasma TNF-alpha and MDA levels and enhancing peritoneal macrophage phagocytosis, suggesting that it is a potential agent in the prevention and treatment of sepsis.     

The protective effect of atractylenolide I on systemic inflammation in the mouse model of sepsis created by cecal ligation and puncture

Context: Atractylenolide I (AT-I), an active compound isolated from Atractylodes macrocephala Koidz (Compositae), shows several pharmacological activities.

Objective: Our present study is designed to investigate the protective effect of AT-I on systemic inflammation in the mouse model of sepsis created by cecal ligation and puncture (CLP), and explore the possible mechanism.

Materials and methods: Sepsis mouse model was established by CLP, and the tested dosages of AT-I were 10, 20, and 40?mg/kg (ip). Pro-inflammatory cytokines in serum (TNF-α, IL-1β and IL-6) were determined by the ELISA method; serum lipopolysaccharide (LPS) level was measured by the Limulus Amebocyte Lysate (LAL) test; white blood cells (WBC) were counted by Blood cell analyzer; contents of alanine transaminase (ALT), aspartate transarninase (AST), creatinine (Cre), and blood urea nitrogen (BUN) in serum were determined by automatic biochemistry analyzer. For survival rate tests, CLP mice were observed within 7 days, and body temperature was measured at 0, 4, 8, 12, 24, 48 and 72?h after surgery.

Results: Our results indicated that AT-I significantly increased the survival rate of mice with sepsis (p?<?0.05), whereas the WBCs and levels of LPS, pro-inflammatory cytokines (TNF-α, IL-1β and IL-6), ALT, AST, Cre, and BUN decreased significantly after treatment with AT-I (p?<?0.05).

Conclusion: In conclusion, the AT-I ameliorates sepsis syndrome by reduction of pro-inflammatory cytokines and LPS, and provides an improvement in liver and kidney functions.     

小檗碱在大鼠腹腔感染早期对肠屏障的保护作用

目的观察小檗碱(Ber)对大鼠腹腔感染早期肠屏障的保护作用及机制。方法将SD大鼠随机分为盲肠结扎穿孔(CLP)组和Ber组,随后再按术后取材时间分为0,2,6,12 h和24 h组。Ber组在造模前给大鼠灌胃Ber,CLP组则灌胃与Ber组等量生理盐水。实验检测炎症因子水平,紧密连接蛋白表达及肠上皮细胞死亡情况,以及肠道通透性水平。结果 Ber组炎症因子水平要显著低于CLP组,而紧密连接蛋白和细胞死亡情况以及肠通透性要明显好于CLP组,其差异有显著统计学意义。结论①在腹腔感染早期,Ber可以通过降低促炎因子的表达量,来降低炎症反应的强度,②Ber可能是通过减缓紧密连接蛋白的消失和肠上皮细胞的死亡,进而起到肠屏障保护功能。     

The effect of progesterone on systemic inflammation and oxidative stress in the rat model of sepsis

Objectives:

To explore the protective effect of progesterone on inflammation and oxidative stress in a rat model of sepsis created by cecal ligation and puncture (CLP).

Materials and Methods:

Rats were randomly divided into 4 groups: Overiectomy group (OVX), sham operated (control), sepsis (CLP) group and progesterone-treated CLP group (CLP+ progesterone). The rats in CLP+ progesterone group received intraperitoneal progesterone (2 mg/kg). Cardiac blood samples were obtained for the measurement levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Tissue samples, including liver, kidney and uterus of rats were prepared to determine activities of myeloperoxidase (MPO), glutathione peroxidase (GPx) and levels of malondialdehyde (MDA).

Results:

Increased serum IL-6 and TNF-α levels were found in the CLP group in comparison with the control group (P = 0.01, P = 0.02; respectively). In CLP+ progesterone group, mean MDA concentration of kidney tissue was significantly lower than in CLP group (P = 0.003). Liver MDA concentration of the CLP+ progesterone group was not significantly different from that of the control group. While there were no significant differences among groups regarding liver MPO; in the CLP group, MPO activity in kidney (P = 0.02) and uterine tissues (P = 0.03) were found to be significantly higher compared to the control group. In CLP+ progesterone group, mean MPO activities of all tissues were not different than those of control group. The uterine tissue GPx activity in the CLP+ progesterone group was not statistically significantly different from control group.

Conclusions:

We suggest that progesterone ameliorates sepsis syndrome by reduction of the inflammatory cytokines IL-6 and TNF-α, and by restoration of antioxidant enzyme activities in some tissues.KEY WORDS: Inflammation, oxidative stress, progesterone, sepsis     

Effects of ketamine on pulmonary inflammatory responses and survival in rats exposed to polymicrobial sepsis.

PURPOSE: Ketamine is reported to suppress production of proinflammatory cytokines and activity of nuclear factor-kappa B (NF-kappaB) after lipopolysaccharide (LPS) stimulation. Our study was designed to investigate the effects of ketamine on pulmonary inflammatory responses and survival in a clinically relevant model of polymicrobial sepsis, induced by cecal ligation and puncture (CLP). METHODS: After the induction of sepsis or sham-operation, animals were treated with ketamine (0.5, 5 or 10 mg/kg) or saline (10 ml/kg) at 3h after operation. At 6 h post-operation, the levels of tumor necrosis factor alpha (TNF-alpha) and interleukin (IL)-6, activity of NF-kappaB, expression of Toll-like receptor 2 (TLR2) and Toll-like receptor 4 (TLR4) of the lungs were measured. And the mortality was recorded for 7 days. RESULTS: TNF-alpha and IL-6 production, NF-kappaB activity, TLR2 and TLR4 expression in rat lungs were increased after CLP. Ketamine at the doses of 5 mg/kg and 10 mg/kg suppressed CLP-induced elevation of TNF-alpha and IL-6 production, NF-kappaB activity and TLR2 expression. Ketamine 0.5, 5 and 10 mg/kg inhibited TLR4 expression in sepsis. Ketamine 5mg/kg and 10 mg/kg after CLP improved the survival of rats. CONCLUSIONS: Ketamine at sub-anesthetic doses could suppress the production of inflammatory cytokines such as TNF-alpha and IL-6, attenuate NF-kappaB activity, and inhibit TLR2 and TLR4 expression in polymicrobial sepsis. These anti-inflammatory effects of ketamine may correlate with improved survival in sepsis.     

Curcumin suppresses inflammatory cytokines and heat shock protein 70 release and improves metabolic parameters during experimental sepsis

Context: Curcumin has been reported to have anti-inflammatory, antioxidant and hypoglycaemic properties, besides reducing mortality in sepsis.

Objective: This study evaluates the biological activities of a curcumin dispersion formulated by spray-drying in experimental sepsis.

Materials and methods: Male Wistar rats were subjected to sepsis by caecal ligation and puncture (CLP), controls were sham operated. The animals were treated with curcumin dispersion (100?mg/kg, p.o.) or water for 7 days prior to CLP and at 2?h after surgery. One group was used to analyze curcumin absorption through HPLC; another had the survival rate assessed during 48?h; and from a third group, blood was collected by decapitation to analyze metabolic and inflammatory parameters.

Results: The plasma curcumin levels reached 2.5?ng/mL at 4?h, dropped significantly (p?p?p?p?p?p?Discussion and conclusion: Our results show that the curcumin dispersion dose employed was not detrimental to the septic rats. In fact, it temporarily increased their survival rate, improved important metabolic parameters, reduced proinflammatory cytokines and HSP70 production.     

Rho-kinase regulates adhesive and mechanical mechanisms of pulmonary recruitment of neutrophils in abdominal sepsis

We hypothesized that Rho-kinase signaling plays a role in mechanical and adhesive mechanisms of neutrophil accumulation in lung. Male C57BL/6 mice were treated with the Rho-kinase inhibitor Y-27632 prior to cecal ligation and puncture (CLP). Lung levels of myeloperoxidase (MPO) and histological tissue damage were determined 6h and 24h after CLP. Expression of Mac-1 and F-actin formation in neutrophils were quantified by using flow cytometry 6h after CLP. Mac-1 expression and F-actin formation were also determined in isolated neutrophils up to 3h after stimulation with CXCL2. Labeled and activated neutrophils co-incubated with Y-27632, an anti-Mac-1 antibody and cytochalasin B were adoptively transferred to CLP mice. Y-27632 reduced the CLP-induced pulmonary injury and MPO activity as well as Mac-1 on neutrophils. Neutrophil F-actin formation peaked at 6h and returned to baseline levels 24h after CLP induction. Rho-kinase inhibition decreased CLP-provoked F-actin formation in neutrophils. CXCL2 rapidly increased Mac-1 expression and F-actin formation in neutrophils. Co-incubation with Y-27632 abolished CXCL2-induced Mac-1 up-regulation and formation of F-actin in neutrophils. Notably, co-incubation with cytochalasin B inhibited formation of F-actin but did not reduce Mac-1 expression on activated neutrophils. Adoptive transfer experiments revealed that co-incubation of neutrophils with the anti-Mac-1 antibody or cytochalasin B significantly decreased pulmonary accumulation of neutrophils in septic mice. Our data show that targeting Rho-kinase effectively reduces neutrophil recruitment and tissue damage in abdominal sepsis. Moreover, these findings demonstrate that Rho-kinase-dependent neutrophil accumulation in septic lung injury is regulated by both adhesive and mechanical mechanisms.