杀菌/通透性增加蛋白对休克大鼠肺组织细胞因子mRNA表达的影响

作者在大鼠失血性休克（４ｋＰａ，１８０分钟）模型上，观察了重组杀菌／通透性增加蛋白（ＢＰＩ）对肺组织肿瘤坏死因子（ＴＮＦ）、白介素－６（ＩＬ－６）ｍＲＮＡ表达及急性肺损伤的影响，并对肠源性内毒素血症与炎症细胞因子诱发的关系进行了探讨。结果显示：失血性休克可导致血浆内毒素含量显著升高，肺组织ＴＮＦ、ＩＬ－６ｍＲＮＡ表达分别在复苏后２、８小时明显增多（Ｐ＜０．０５～０．０１）；给予ＢＰＩ治疗则完全中和休克所致内毒素血症，并不同程度地抑制肺组织ＴＮＦ、ＩＬ－６ｍＲＮＡ的表达（Ｐ＜０．０５～０．０１）；肺毛细血管通透性与髓过氧化物酶活性均明显降低。作者认为，ＢＰＩ可有效防止失血性休克诱发的急性肺损伤，其作用机制可能与抑制肠源性内毒素血症所介导的局部组织炎症细胞因子基因表达有关。     

地塞米松对创伤性急性肺损伤家兔肿瘤坏死因子-α的干预作用

目的 探讨地塞米松（Ｄｅｘ）对创伤性急性肺损伤（ＡＬＩ）治疗作用的可能机制。方法 采用逆转录聚合酶链反应（ＲＴ－ＰＣＲ）、酶联免疫吸附法（ＥＬＩＳＡ）检测２４只大耳白兔肺组织肿瘤坏死因子－α基因（ＴＮＦ－αｍＲＮＡ）表达及肺泡巨噬细胞（ＡＭ）培养上清液中肿瘤坏死因子－α（ＴＮＦ－α）、白细胞介素（ＩＬ）－６水平。结果 创伤性ＡＬＩ兔肺组织ＴＮＦ－αｍＲＮＡ表达及ＡＭ培养上清液中ＴＮＦ－α,ＩＬ－６含量较正常对照组比较明显升高（Ｐ〈０．０１）。Ｄｅｘ治疗后能显著下调ＴＮＦ－αｍＲＮＡ的表达（６８％,Ｐ〈０．０１）,降低ＡＭ分泌ＴＮＦ－α（Ｐ〈０．０５）及ＩＬ－６水平（Ｐ〈０．０１）。结论 Ｄｅｘ能缓解创伤性ＡＬＩ的发生、发展。其机制与其对ＴＮＦ－α、ＩＬ－６等炎性介质的调节作用密切相关。     

家兔创伤休克后血浆内毒素,TNF和IL—6的动态变化

目的：探讨创伤休克对内毒素移位的影响及其与ＴＮＦ、ＩＬ－６产生的关系。方法：选用家兔１６只，随机分为创伤合并失血性休克（Ⅰ组）和单纯失血性休克组（Ⅱ组），采用鲎试验基质显色法，ＥＬＩＳＡ和细胞生物测定法分别测定血浆内毒素、ＴＮＦ和ＩＬ－６水平。结果：休克１．５小时，Ⅰ组血浆内毒素水平即明显高于伤前，至复苏后０．５小时达峰值，复苏后１小时仍明显高于伤前。休克后Ⅰ组血浆内毒素水平明显高于Ⅱ组；休克及复苏后，血浆ＴＮＦ、ＩＬ－６水平也先后显著升高，其中ＴＮＦ升高较早，Ⅰ组血浆细胞因子水平明显高于Ⅱ组；相关分析表明，创伤休克后血浆ＴＮＦ、ＩＬ－６均值分别与血浆内毒素均值呈显著正相关。结论：创伤休克可导致明显的内毒素血症及ＴＮＦ、ＩＬ－６等细胞因子过量产生，且较单纯休克时明显，创伤后细胞因子产生与内毒素移位有一定的内在联系。     

己酮可可碱对内毒素肺损伤肺组织TNFmRNA表达的影响

目的：观察己酮可可碱对内毒素血症引起的肺组织ＴＮＦｍＲＮＡ表达及血浆ＴＮＦ的影响。方法：选用ＳＤ大鼠６３只，分三组：①生理盐水组（Ｃ组）；②内毒素组（Ｅ组），大肠杆菌Ｏ５５Ｂ５内毒素１５ｍｇ／ｋｇ静注；③内毒素＋己酮可可碱组（Ｅ＋Ｐ组），１５ｍｇ／ｋｇ内毒素加２０ｍｇ／ｋｇ己酮可可碱静注，６ｍｇ／ｋｇ己酮可可碱维持。每组分１、３、６小时三个时间点，用差别聚合酶链反应测定肺组织ＴＮＦｍＲＮＡ的变化，双抗体夹心法测定血浆ＴＮＦ的变化。结果：内毒素组血浆ＴＮＦ在１小时达高峰，３小时仍升高，６小时接近生理盐水组水平，己酮可可碱组１小时和３小时血浆ＴＮＦ与相应内毒素组比明显下降（Ｐ分别＜０．０１，０．０５）；ＴＮＦｍＲＮＡ表达在内毒素组１小时和３小时明显升高，己酮可可碱治疗后ＴＮＦｍＲＮＡ表达和内毒素组比明显下降（Ｐ＜０．０１），己酮可可碱组病理损害明显减轻。结论：ＴＮＦ是一个早期的重要炎症介质，己酮可可碱能抑制ＴＮＦ的产生，通过抑制其转录而产生作用，己酮可可碱对内毒素肺损伤具有保护作用。     

山莨菪碱对创伤性肺损伤细胞因子及其mRNA表达的影响

目的 研究山莨菪碱（６５４－２）对创伤性急性肺损伤（ＡＬＩ）家兔血浆中肿瘤坏死因子－α（ＴＮＦ－α）、白细胞介素－６（ＩＬ－６）的含量及其在内脏组织中ｍＲＮＡ表达的影响。方法 用ＥＬＩＳＡ和ＲＴＰＣＲ方法测定２４只大耳白兔血ＴＮＦ－α、ＩＬ－６的含量及其在内脏组织中ｍＲＮＡ的表达。结果 创伤性ＡＬＩ家兔与正常组比较,血浆中ＴＮＦ－α、ＩＬ－６的含量升高,内脏组织中ＴＮＦ－α、ＩＬ－６ｍＲＮＡ的表达     

腹腔感染后低白蛋白血症的分子机理和防治实验研究

腹腔感染常伴有低白蛋白血症，为探讨其发生机理和防治方法，作者应用ＲＴ－ＰＣＲ方法，在大鼠体内体外进行了实验研究。结果显示：（１）腹腔感染后白蛋白ｍＲＮＡ显著下降，是发生低白蛋白血症的重要原因，而内毒素是重要的介导因素。（２）内毒素在体内显著抑制白蛋白ｍＲＮＡ表达，其机理系通过剌激非实质细胞产生ＴＮＦ、ＩＬ－１、ＩＬ－６而起作用。（３）ＴＮＦ、ＩＬ－１、ＩＬ－６显著抑制肝细胞白蛋白ｍＲ－ＮＡ表达，但以局部作用为主。（４）代谢激素对白蛋白合成有重要的调节，但在感染时它们的变化并非导致低白蛋白血症的原因。（５）生长激素和黄芪多糖在体外可明显减轻内毒素对白蛋白合成的抑制，并显著提高腹腔感染大鼠血浆白蛋白水平。作者认为，本研究结果表明，低白蛋白血症的发生机理是：腹腔感染引起内毒素吸收，内毒素刺激ｋｕｐｆｅｒ细胞等非实质细胞，产生ＴＮＦ、ＩＬ－１、ＩＬ－６等介质，它们作用于肝细胞抑制白蛋白ｍＲＮＡ表达，最终导致低白蛋白血症。减少内毒素吸收是重要防治环节，重组生长激素和黄芪多糖有明显的防治效果。     

思密达在重度失血性休克中的应用

目的 研究口服思密达对重度失血性休克预后的影响。方法 经股动脉放血制作兔失血性休克模型，分为休克组、思密达组（休克前经胃管注入思密达），观察休克前后血浆内毒素、肿瘤坏死因子α（ＴＮＦα）、白介素６（ＩＬ－６）、一氧化氮（ＮＯ）水平的动态变化及２４、４８小时的存活率。结果 休克组休克后血浆ＴＮＦα、ＩＬ－６、ＮＯ水平明显高于休克前（Ｐ〈０．０１）；与休克组比较，思密达组动态休克后血浆上述物质水平时显     

烧伤并发内毒素血症早期肝损害与TNF-α mRNA表达的实验研究

目的观察ＴＮＦαｍＲＮＡ及其蛋白的组织分布和细胞定位,探讨烧伤并发内毒素血症早期肝损害的发生机理。方法选用２０％Ⅲ度ＴＢＳＡ烧伤大鼠合并腹腔内毒素（ＬＰＳ）注射造成烧伤复合内毒素血症肝损害模型,采用光镜,电镜及免疫组化原位杂交染色观察大鼠肝脏的形态功能变化、血清ＴＮＦα含量变化、肝组织ＴＮＦα和ＴＮＦαｍＲＮＡ的细胞定位及其分布。结果烧伤复合内毒素血症组,光镜下主要表现肝窦反应,枯否细胞（ＫＣｓ）激活与增生以及肝细胞（ＨＣｓ）变性坏死等;电镜下主要表现肝窦内血小板聚集、纤维素沉积与中性粒细胞（ＰＭＮｓ）扣押以及ＫＣｓ、肝细胞退变溶解等。血清丙氨酸氨基转氨酶（ＡＬＴ）显著升高（Ｐ＜０．０１）和白蛋白（ＡＬＢ）轻度下降。组织ＴＮＦα主要定位于肝窦内皮细胞（ＳＥＣｓ）、ＫＣｓ。ＴＮＦαｍＲＮＡ主要定位于ＫＣｓ、ＰＭＮｓ、巨噬细胞（ＭＰｓ）。而在单因素组主要特点为病变程度轻,肝功能损害不明显,血清ＴＮＦα峰值滞后以及组织ＴＮＦα和ＴＮＦαｍＲＮＡ表达相对较弱等。结论ＴＮＦα是参与烧伤复合内毒素血症早期肝脏损害的重要细胞因子。     

大面积烧伤休克期切痂对全身炎症反应综合征的防治

目的 探讨休克期切痂对全身炎症反应综合征（ＳＩＲＳ）的作用。方法 临床观察８１例烧伤患者，根据切痂植皮的时间不同成分休克期切痂组（Ａ组）及非休克期切痂组（Ｂ组）。结果 Ｂ组术前及术后ＳＩＲＳ发生率均高于Ａ组（Ｐ〈０．０１），且切痂前、后血浆内毒素（ＬＰＳ）、肿瘤坏死因子（ＴＮＦ－α）、白介素－６（ＩＬ－６）及白介素－８（ＩＬ－８）含量居高不下，显著高于Ａ组（Ｐ〈０．０５￣０．０１），Ａ组ＳＩＲＳ并     

磷脂酶A2抑制剂溴苯乙酮对大鼠急性失血性休克复苏后早期肺损伤的保护作用

目的观察磷脂酶Ａ_２抑制剂４－二溴苯乙酮（４－ＢＰＢ）对大鼠急性失血性休克复苏后早期肺损伤的保护作用。方法纯种ＳＤ大鼠３６只,随机分为假手术组（对照组）、乳酸林格氏液复苏组（ＬＲ组）、乳酸林格氏液＋４－ＢＰＢ复苏组（保护组）。两复苏组动物放血并维持低血压（ＭＡＰ ４～５．３ｋＰａ） ６０分钟,其后１０分钟内分别输入全部自体抗凝血或同时静注４－ＢＰＢ（２５μｍｏｌ）;２０分钟内输入２倍放血量的乳酸林格氏液,观察６０分钟。实验结束时收集血清、肺组织标本或作支气管肺泡灌洗。双缩脲法测定支气管肺泡灌洗液（ＢＡＬＦ）及血清中蛋白的浓度;放免法检测血清中ＴＮＦａ、ＩＬ－１β、ＩＬ－６及ＩＬ－８水平。光镜下比较观察各组大鼠肺组织形态学改变。结果保护组血清ＴＮＦα水平明显低于 ＬＲ组（Ｐ＜０． ０１）,而与对照组无明显差异。三组血清ＩＬ－１β,ＩＬ－６及ＩＬ－８水平除ＬＲ组ＩＬ－６与对照组比较有明显差别外,其余则均无明显差异。保护组肺通透指数与对照组比较无显著性差异,而ＬＲ组明显高于其它两组（Ｐ＜０．０１）。支气管肺泡灌洗液中蛋白含量ＬＲ组明显高于其它两组,保护组明显高于对照组（Ｐ＜０．０１）。各组支气管肺泡灌洗液中细胞数及ＰＭ     

Effect of TLR-4 and HO-1 on acute lung injury induced by hemorrhagic shock in mice

Objective： To examine whether TLR-4 has an ettect on hemorrhage induced changes in lung, and to investigate the change of heme oxygenase-1 （HO-1） on acute lung injury （ALl） induced by hemorrhagic shock in mice.
Methods： Forty-eight male mice, including C3H/HeN mice and C3H/HeJ mice, were randomly divided into sham group （n=12）, hemorrhagic shock group with twelve mice in each phase. Blood pressure （BP） was monitored continuously by attaching carotid artery catheter to a strain gauge pressure transducer/ polygraph. Arterial blood samples were taken for blood gas analysis. A mouse model of non-lethal hemorrhagic shock and resuscitation was used to observe pulmonary myeloperoxidase （MPO） activity and wet/dry weight ratio （W/D）. The expression of HO- 1 was observed by means of RT-PCR and immunohistochemistry. IL-6 and IL-10 in lung tissue homogenate were assayed by enzyme-linked immunosorbent assay （ELISA）. The pulmo- nary pathologic changes were observed under electron microscope and light microscope.
Results： Compared with sham group, the expression of HO- 1 in lung tissue was significantly higher in Hem 24 h and Hem 48 h of C3H/HeN mice （P〈0.01）. The expression of HO-1 mRNA and the levels of IL-6, IL-10 and MPO in lung tissue were markedly increased in Hem 24 h （P〈0.01 or P〈0.05）; Compared with C3H/HeN mice, the expression of HO- 1 rnRNA and the levels of IL-6 and IL-10 in C3H/HeJ mice significantly decreased in Hem 24 h and Hem 48 h （P〈0.01 or P〈O.05）, and the W/D, MPO in C3H/HeJ mice were obvi- ously lower in Hem 24 h （P〈0.05）. The injuries of lung tissues after hemorrhagic shock have been demonstrated by histological examination with electron microscope and light microscope.
Conclusions： TLR-4 and HO-1 might modulate the bal- ance of pro- and anti-inflammatory processes in inflamma- tory reaction of hemorrhagic shock-induced ALl, and the activation of Toll-like receptor might induce the transcrip- tion activity of HO- 1, which may play a k     

维生素C减轻失血性休克引起的大鼠肺树突细胞聚集及肺损伤

目的 探讨失血性休克对大鼠肺组织树突细胞聚集及肺损伤的影响,以及维生素C的保护作用.方法 SD大鼠(6～7周龄)42只,按数字随机法随机分为对照组、失血性休克2h、6h、24 h组及失血性休克+维生素C2h、6h、24 h组等7组,每组各6只.以股动脉放血法建立大鼠失血性休克模型.免疫组化和逆转录聚合酶链反应(RT-PCR)法检测肺组织树突细胞特异性细胞间粘附分子非整合素蛋白-3(DC-SIGN)表达情况.同时检测肺TNF-α、IL-6含量,髓过氧化物酶(MPO)活性,并进行肺损伤评分.结果 对照组肺中DC-SIGN蛋白表达很少,失血性休克组表达显著升高(P＜0.05),失血性休克后2h肺DC-SIGNmRNA含量就开始增高,休克后24 h仍呈升高趋势.失血性休克组大鼠肺TNF-α、IL-6 mRNA水平升高(P＜0.05),MPO活性增加(P＜0.05),病理损伤显著加重(P＜0.05).失血性休克大鼠在复苏前给予维生素C干预后,上述现象均减轻(P＜0.05).结论 失血性休克可能通过促进肺组织树突细胞聚集引起急性肺损伤.维生素C对这一过程有抑制作用.     

Toll样受体4对失血性休克小鼠肺组织血红素加氧酶和诱导型一氧化氮合酶的影响

目的 观察Toll样受体4(TLR4)对失血性休克小鼠所致急性肺损伤(ALI)中肺组织血红素加氧酶-1(HO-1)和诱导型一氧化氮合酶(iNOS)的影响.方法 TLR4基因突变型小鼠C3H/HeJ和野生型小鼠C3H/HeN(48只),随机分为假手术组和失血性休克(6、24、48 h)组.采用小鼠失血性休克致急性肺损伤模型,观察血气分析,HO-1和iNOS蛋白表达,白细胞介素-6(IL-6)水平,肺组织肺湿/干重比和病理形态学改变.结果 与假手术组比较,C3H/HeN和C3H/HeJ小鼠失血休克后24 h肺组织HO-1蛋白强阳性表达,IL-6含量明显增加为365.38±48.26和300.89±39.34;6 h肺组织iNOS蛋白强阳性表达(P＜0.01).与C3H/HeN小鼠比较,C3H/HeJ小鼠失血休克后24 h肺组织HO-1、IL-6含量和W/D明显降低(P＜0.05);6 h肺组织iNOS蛋白显著减少为0.049±0.013.病理学检查显示失血休克后各时点肺组织损伤程度较假手术组明显加重.结论 TLR4在失血性休克后ALI过程中被激活,通过影响HO-1和iNOS的表达参与了失血性休克致急性肺损伤的过程.     

Exogenous nitric oxide donor and related compounds protect against lung inflammatory response after hemorrhagic shock and resuscitation

BACKGROUND: Resuscitation from hemorrhagic shock triggers an inflammatory response characterized by upregulation of cytokine and adhesion molecule expression, increased leukocyte activity, and accumulation of polymorphonuclear neutrophils in a variety of tissues. This study investigated the capability of an exogenous nitric oxide (NO) donor, sodium nitroprusside (NP); a NO substrate, L-arginine; and an inducible NO synthase inhibitor, L-N6-(1-iminoethyl)lysine (L-NIL) to reduce lung injury in an animal model of mixed controlled and uncontrolled hemorrhagic shock. METHODS: For this study, 72 Sprague-Dawley rats weighing 250 to 300 g were subjected to a model of uncontrolled hemorrhagic shock for 150 minutes. Six groups of animals were included in this study (12 per group): sham-saline, sham-NP, shock-saline, shock-NP, shock-L-arginine, and shock-L-N6-(1-iminoethyl)lysine. After the period of hemorrhagic shock, resuscitation of the groups was accomplished using normal saline (groups 1 and 3), NP (0.5 mg/kg) (groups 2 and 4), L-arginine (300 mg/kg) (group 5), or L-NIL (50 mg/kg) (group 6). The following indices were evaluated: fluid requirements for resuscitation, mean arterial pressure (MAP), arterial po2, pco2, and pH, lung wet-to-dry weight ratio, lung histology and cytokine (interleukin [IL]-1 alpha, IL-beta 1, tumor necrosis factor-beta [TNF beta], IL-3, IL-4, IL-5, IL-6, IL-10, TNF alpha, IL-2, interferon-gamma [IFN gamma]), and mRNA expression in the lung by a ribonuclease protection assay (RPA). RESULTS: Sodium nitroprusside significantly increased MAP and reduced fluid requirements during resuscitation after hemorrhage. There also was a significant improvement in lung function, as expressed by improvements in po2, pco2, and pH, and reduction of the wet-to-dry weight ratio. In addition, a significant reduction in acute lung injury was observed in the histologic studies. Furthermore, the expression of cytokines was reduced by NP treatment. The use of L-arginine and L-NIL offered similar protective results for the injured lung. CONCLUSIONS: These data suggest that limiting inducible NO synthase-generated NO availability with the exogenous NO donor, sodium nitroprusside, may reduce lung injury after severe hemorrhage, possibly, among other effects, by downregulating the expression of inflammatory cytokines. L-arginine and L-NIL also had a beneficial effect on lung function and structure.     

Bactericidal/permeability-increasing protein attenuates systemic inflammation and acute lung injury in porcine lower limb ischemia-reperfusion injury

OBJECTIVE: To investigate the role of recombinant bactericidal/permeability-increasing protein (rBPI21) in the attenuation of the sepsis syndrome and acute lung injury associated with lower limb ischemia-reperfusion (I/R) injury. SUMMARY BACKGROUND DATA: Gut-derived endotoxin has been implicated in the conversion of the sterile inflammatory response to a lethal sepsis syndrome after lower torso I/R injury. rBPI21 is a novel antiendotoxin therapy with proven benefit in sepsis. METHODS: Anesthetized ventilated swine underwent midline laparotomy and bilateral external iliac artery occlusion for 2 hours followed by 2.5 hours of reperfusion. Two groups (n = 6 per group) were randomized to receive, by intravenous infusion over 30 minutes, at the start of reperfusion, either thaumatin, a control-protein preparation, at 2 mg/kg body weight, or rBPI21 at 2 mg/kg body weight. A control group (n = 6) underwent laparotomy without further treatment and was administered thaumatin at 2 mg/kg body weight after 2 hours of anesthesia. Blood from a carotid artery cannula was taken every half-hour for arterial blood gas analysis. Plasma was separated and stored at -70 degrees C for later determination of plasma tumor necrosis factor (TNF)-alpha, interleukin (IL)-6 by bioassay, and IL-8 by enzyme-linked immunosorbent assay (ELISA), as a markers of systemic inflammation. Plasma endotoxin concentration was measured using ELISA. Lung tissue wet-to-dry weight ratio and myeloperoxidase concentration were used as markers of edema and neutrophil sequestration, respectively. Bronchoalveolar lavage protein concentration was measured by the bicinclinoic acid method as a measure of capillary-alveolar protein leak. The alveolar-arterial gradient was measured; a large gradient indicated impaired oxygen transport and hence lung injury. RESULTS: Bilateral hind limb I/R injury increased significantly intestinal mucosal acidosis, intestinal permeability, portal endotoxemia, plasma IL-6 concentrations, circulating phagocytic cell priming and pulmonary leukosequestration, edema, capillary-alveolar protein leak, and impaired gas exchange. Conversely, pigs treated with rBPI21 2 mg/kg at the onset of reperfusion had significantly reduced intestinal mucosal acidosis, portal endotoxin concentrations, and circulating phagocytic cell priming and had significantly less pulmonary edema, leukosequestration, and respiratory failure. CONCLUSIONS: Endotoxin transmigration across a hyperpermeable gut barrier, phagocytic cell priming, and cytokinemia are key events of I/R injury, sepsis, and pulmonary dysfunction. This study shows that rBPI21 ameliorates these adverse effects and may provide a novel therapeutic approach for prevention of I/R-associated sepsis syndrome.     

Pathogenesis of hemorrhage-induced bacteria/endotoxin translocation in rats. Effects of recombinant bactericidal/permeability-increasing protein.

OBJECTIVES: This study was conducted to determine the role of gut-derived bacteria/endotoxin in the pathogenesis of the multiple-organ damage and mortality, the possible beneficial effect of recombinant bactericidal/permeability-increasing protein (rBPl21), and whether neutralizing endotoxemia by rBPl21 treatment influences tumor necrosis factor (TNF) formation in rats after hemorrhagic shock and resuscitation. SUMMARY BACKGROUND DATA: Hypovolemic shock might be associated with bacterial or endotoxin translocation as well as systemic sepsis. Similar to bactericidal/permeability-increasing (BPl) protein, rBPl21 has been found to bind endotoxin and inhibit TNF production. METHODS: A rat model of prolonged hemorrhagic shock (30 to 35 mm Hg for 180 min) followed by adequate resuscitation was employed. Recombinant bactericidal/permeability-increasing protein was administered at 5 mg/kg intravenously. The control group was treated similarly to the BPl group, but received thaumatin as a protein-control preparation in the same dose as rBPl21. RESULTS: Immediately after resuscitation (230 min), plasma endotoxin levels in the control group (61.0 +/- 16.3 pg/mL) were almost neutralized by rBPl21 treatment (13.8 +/- 4.8 pg/mL, p < 0.05). Plasma TNF levels were not significantly influenced by rBPl21 treatment. The 48-hour survival rate was 68.8% in the treatment group versus 37.5% in the control group (p = 0.08). Microscopic histopathologic examination revealed relatively minor damage to various organs in the treatment group. CONCLUSIONS: These data suggest that hemorrhagic shock may lead to bacterial/endotoxin translocation with concomitant TNF formation, endogenous endotoxemia may play an important role in the pathogenesis of multiple-organ failure after shock and trauma, TNF formation at an early stage might be related mainly to mechanisms other than Kupffer's cells activation via lipopolysaccharide, and rBPl21 might be a useful therapeutic agent against endogenous bacteria/endotoxin related disorders in severe hemorrhagic shock.     

Hypertonic resuscitation of hemorrhagic shock upregulates the anti-inflammatory response by alveolar macrophages

BACKGROUND: Resuscitated hemorrhagic shock predisposes patients to the development of acute respiratory distress syndrome (ARDS). Hypertonic saline (HTS) has been shown to inhibit immune cell activation in response to lipopolysaccharide (LPS) in vitro and to reduce lung damage when used for resuscitation of hemorrhagic shock in vivo. We hypothesize that HTS resuscitation of hemorrhagic shock may exert this anti-inflammatory effect by modulating alveolar macrophage function leading to an altered balance between the proinflammatory and the counter-inflammatory response. METHODS: A 2-hit rat model of shock resuscitation was used. Alveolar macrophages were harvested by bronchoalveolar lavage (BAL), and tumor necrosis factor (TNF)-alpha and interleukin (IL)-10 were quantified in the cell culture supernatants by enzyme-linked immunosorbent assay (ELISA). Alternatively, 1 hour after resuscitation, animals received endotracheal LPS followed by endotracheal anti-IL-10 neutralizing antibody. Lung injury was determined by measuring BAL neutrophil counts 4 hours after LPS in vivo administration. RESULTS: Systemic administration of HTS significantly modulates the responsiveness of alveolar macrophages. Specifically, HTS resuscitation inhibited LPS-induced TNF-alpha production while enhancing IL-10 release in response to LPS administered ex vivo and in vivo. Anti-IL-10 antibody in vivo partially reversed the lung protective effect of HTS resuscitation. CONCLUSIONS: HTS resuscitation exerts an immunomodulatory effect on alveolar macrophages by shifting the balance of pro- and counter-inflammatory cytokine production in favor of an anti-inflammatory response. The in vivo data suggest a causal role for HTS-induced augmented IL-10 as protective. These findings suggest a novel mechanism for the in vivo salutary effect of HTS resuscitation on lung injury after resuscitated hemorrhagic shock.     

盐酸戊乙奎醚预先给药对失血性休克大鼠急性肺损伤时TLR4 mRNA表达的影响

目的 探讨盐酸戊乙奎醚预先给药对失血性休克大鼠急性肺损伤时Toll样受体4(TLR4)mRNA表达的影响.方法 健康SD大鼠40只,体重200～250 g,随机分为5组(n=8):假手术组(S组)、失血性休克致急性肺损伤组(ALI组)和低、中、高剂量盐酸戊乙奎醚预先给药组(P1～3组).S组仅行动静脉穿刺,不放血,ALI组股动脉放血至35～45 mm Hg制备急性肺损伤模型,P1～3组分别于放血前30 min股静脉注射盐酸戊乙奎醚0.3、1.0、3.0 mg/kg,随后制备急性肺损伤模型.各组复苏后4 h时处死大鼠取肺,称重后计算肺湿干重比,检测TLR4 mRNA和NF-κB p65蛋白的表达水平,观察病理学结果.结果 与S组比较,ALI组和P1组TLR4 mRNA、NF-κB p65蛋白表达水平及肺湿干重比升高(P＜0.05或0.01),P2.3组差异无统计学意义(P＞0.05);与ALI组比较,P2,3组TLR4 mRNA、NF-κB p65蛋白表达水平及肺湿干重比降低(P＜0.05或0.01);P2组和P3组上述指标比较差异无统计学意义(P＞0.05).P2,3组肺组织病理学损伤程度较ALI组明显减轻.结论 盐酸戊乙奎醚预先给药可通过抑制肺组织TLR4 mRNA表达上调,进而降低NF-κB活性,从而减轻失血性休克诱发大鼠的急性肺损伤.     

Hemodynamic and pulmonary effects of fluid resuscitation from hemorrhagic shock in the presense of mild pulmonary edema

The hemodynamic and pulmonary effects of fluid resuscitation with crystalloid and colloid solutions in the presence of mild pulmonary edema were investigated. Anesthetized dogs received oleic acid to increase pulmonary capillary permeability, and one hour later bled to produce hemorrhagic shock. One hour after the shock, resuscitation was performed with Ringer's lactate, 6% hydroxyethyl starch (HES) solution, or dog's plasma. Resuscitation from hemorrhagic shock restored hemodynamics to pre-hemorrhagic levels with all of the above solutions. Ringer's lactate resuscitation resulted in increases in extravascular lung water volume (EVLWV) and oxygen consumption, and decreases in colloid osmotic pressure and oxygen delivery. Resuscitation with HES solution and plasma did not result in increases in EVLWV, but with HES solution resulted in decreases in colloid osmotic pressure to pre-hemorrhagic levels in two hours. This suggests that the resuscitation with HES solution can not maintain colloid osmotic pressure for more than two hours. The author concludes that the hemodynamic and pulmonary effects of HES solution and plasma are similar in mild lung injury cases.