D2/D1 ratio in the medial preoptic area affects copulation of male rats

The D1/D2 dopamine agonist apomorphine, microinjected into the medial preoptic area (MPOA), facilitates male rat sexual behavior and the D1/D2 antagonist cis-flupenthixol in the MPOA impairs it. The present study investigated the roles of D1 and D2 receptors in the regulation of copulation by microinjecting drugs selective for these receptors into the MPOA. The D2 agonist LY-163502 delayed the onset and slowed the rate of copulation and also reduced the number of vaginal intromissions required to trigger ejaculation (reduced ejaculatory threshold). The D1 agonist SKF-82526 had no effect, either alone or together with LY-163502. The D1 antagonist SCH-23390 delayed the onset of copulation and decreased ejaculatory threshold, as had the D2 agonist. A low dose of the D2 agonist alone and together with the D1 antagonist delayed the onset of copulation and reduced ejaculatory threshold; the combination of drugs was more effective than LY-163502 alone. Only the combination of drugs slowed the rate of copulation and delayed the resumption of copulation after an ejaculation. Thus, increasing the D2/D1 ratio in the MPOA, by selective stimulation of D2 and/or antagonism of D1 receptors, delays the onset of copulation and reduces ejaculatory threshold, possibly by altering autonomic control of penile reflexes.     

Atrial natriuretic peptide regulation of noradrenaline release in the anterior hypothalamic area of spontaneously hypertensive rats.

In spontaneously hypertensive rats (SHR), high NaCl diets increase arterial pressure and sympathetic nervous system activity by decreasing noradrenaline release in the anterior hypothalamic area (AHA), thereby reducing the activation of sympathoinhibitory neurons in AHA. Atrial natriuretic peptide (ANP) can inhibit the release of noradrenaline, and ANP concentration is elevated in the AHA of SHR. The present study tests the hypothesis that in SHR, local ANP inhibits noradrenaline release from nerve terminals in AHA. Male SHR fed a basal or high NaCl diet for 2 wk and normotensive Wistar Kyoto rats (WKY) fed a basal NaCl diet were studied. In SHR on the basal diet, microperfusion of exogenous ANP into the AHA elicited a dose-related decrease in the concentration of the major noradrenaline metabolite 3-methoxy-4-hydroxy-phenylglycol (MOPEG) in the AHA; this effect was attenuated in the other two groups. In a subsequent study, the ANP-C (clearance) receptor agonist c-ANP was microperfused into the AHA to increase extracellular concentration of endogenous ANP in AHA. c-ANP reduced AHA MOPEG concentration in SHR on the basal NaCl diet but not in the other two groups. These data support the hypothesis that local ANP inhibits noradrenaline release in the AHA and thereby contributes to NaCl-sensitive hypertension in SHR.     

The posterior ventral tegmental area mediates alcohol-seeking behavior in alcohol-preferring rats

The mesolimbic dopamine (DA) system is involved in the rewarding process of drugs of abuse and is activated during the anticipation of drug availability. However, the neurocircuitry that regulates ethanol (EtOH)-seeking has not been adequately investigated. The objectives of the present study were to determine 1) whether the posterior ventral tegmental area (p-VTA) mediates EtOH-seeking, 2) whether microinjections of EtOH into the p-VTA could stimulate EtOH-seeking, and (3) the involvement of p-VTA DA neurons in EtOH-seeking. Alcohol-preferring rats were trained to self-administer 15% EtOH and water. After 10 weeks, rats underwent extinction training, followed by 2 weeks in their home cages. During the home-cage period, rats were then bilaterally implanted with guide cannulae aimed at the p-VTA or anterior ventral tegmental area (a-VTA). EtOH-seeking was assessed by the Pavlovian spontaneous recovery model. Separate experiments examined the effects of: 1) microinjection of quinpirole into the p-VTA, 2) EtOH microinjected into the p-VTA, 3) coadministration of EtOH and quinpirole into the p-VTA, 4) microinjection of quinpirole into the a-VTA, and 5) microinjection of EtOH into the a-VTA. Quinpirole microinjected into the p-VTA reduced EtOH-seeking. Microinjections of EtOH into the p-VTA increased EtOH-seeking. Pretreatment with both quinpirole and EtOH into the p-VTA reduced EtOH-seeking. Microinjections of quinpirole or EtOH into the a-VTA did not alter EtOH-seeking. Overall, the results suggest that the p-VTA is a neuroanatomical substrate mediating alcohol-seeking behavior and that activation of local DA neurons is involved.     

LPS诱导急性肺损伤大鼠肺组织甲状腺转录因子-1表达变化

目的探讨内毒素（LPS）诱导的急性肺损伤（ALI）大鼠肺组织甲状腺转录因子-1（TTF-1）、肺表面活性物质相关蛋白-A（SP—A）表达的变化。方法采用免疫组化和RT—PCR检测各组肺组织TTF-1、SP—A表达。结果ALI后12、24h，肺组织中TIF-1、SP—A表达水平明显降低，且TTF-1蛋白变化与SP—A mRNA变化呈显著正相关。结论ALI大鼠肺组织TIF-1表达明显降低可能与ALI发生、发展有关。     

Activation of hypothalamic S6 kinase mediates diet-induced hepatic insulin resistance in rats

Prolonged activation of p70 S6 kinase (S6K) by insulin and nutrients leads to inhibition of insulin signaling via negative feedback input to the signaling factor IRS-1. Systemic deletion of S6K protects against diet-induced obesity and enhances insulin sensitivity in mice. Herein, we present evidence suggesting that hypothalamic S6K activation is involved in the pathogenesis of diet-induced hepatic insulin resistance. Extending previous findings that insulin suppresses hepatic glucose production (HGP) partly via its effect in the hypothalamus, we report that this effect was blunted by short-term high-fat diet (HFD) feeding, with concomitant suppression of insulin signaling and activation of S6K in the mediobasal hypothalamus (MBH). Constitutive activation of S6K in the MBH mimicked the effect of the HFD in normal chow-fed animals, while suppression of S6K by overexpression of dominant-negative S6K or dominant-negative raptor in the MBH restored the ability of MBH insulin to suppress HGP after HFD feeding. These results suggest that activation of hypothalamic S6K contributes to hepatic insulin resistance in response to short-term nutrient excess.     

Essential role of P-selectin in the initiation of the inflammatory response induced by hemorrhage and reinfusion

Resuscitation from hemorrhage induces profound pathophysiologic alterations and activates inflammatory cascades able to initiate neutrophil accumulation in a variety of tissues. This process is accompanied by acute organ damage (e.g., lungs and liver). We have previously demonstrated that significant leukocyte-endothelium interactions occur very early in other forms of ischemia/reperfusion (i.e., splanchnic ischemia/reperfusion and traumatic shock) which are largely mediated by increased expression of the adhesion molecule, P-selectin, on the vascular endothelium. Here we postulated that increased endothelial expression of P-selectin in the microvasculature would play an essential role in initiating the inflammatory signaling of hemorrhagic shock. Using intravital microscopy, we found that hemorrhagic shock significantly increased the number of rolling and adherent leukocytes in the mouse splanchnic microcirculation. In contrast, mice genetically deficient in P-selectin, or wild-type mice given either an anti-P-selectin monoclonal antibody or a recombinant soluble P-selectin glycoprotein ligand (PSGL)-1 immunoglobulin, exhibited markedly attenuated leukocyte-endothelium interaction after hemorrhagic shock. Thus, activation of P-selectin protein on the microvascular endothelium is essential for the initial upregulation of the inflammatory response occurring in hemorrhagic shock. Moreover, endogenous levels of PSGL-1 mRNA were significantly increased in the lung, liver, and small intestine of wild-type mice subjected to hemorrhagic shock. Since PSGL-1 promotes adhesive interactions largely through P-selectin expressed on the vascular endothelium, this result further supports the crucial role played by P-selectin in the recruitment of leukocytes during hemorrhagic shock.     

Cardiovascular and respiratory effects of mu-, delta- and kappa-opiate agonists microinjected into the anterior hypothalamic brain area of awake rats

Relatively selective mu-, delta- and kappa-opiate agonists were microinjected into anterior hypothalamic and septal brain regions of the unanesthetized rat in order to investigate the potential role of specific opiate receptors in central cardiovascular regulation. Low doses (0.2-3 nmol) of both [D-Ala2,MePhe4,Gly-(ol)5] enkephalin (DAGO, mu-agonist) and [D-Ala2,D-Leu5]enkephalin (DADL, delta-agonist) caused dose-dependent increases in blood pressure and heart rate which were naloxone reversible. Higher doses (7.5-30 nmol) of DAGO and DADL produced pressor responses but had little effect on heart rate. The kappa-agonist MR 2034 had no effect on cardiovascular parameters at these doses. DAGO but not MR 2034 also depressed respiration at the higher doses resulting in hypoxia, hypercapnia and acidosis while DADL only slightly depressed respiration. DAGO was approximately 10-fold more potent than DADL in eliciting cardiovascular and respiratory responses. These findings implicate mu-receptors in mediating the cardiovascular and respiratory effects of opiates at anterior hypothalamic sites.     

全身炎症反应综合征-急性肺损伤大鼠肺组织IL-4 mRNA表达及AP-1活性变化的研究

目的 复制脂多糖（LPS）致伤的全身炎症反应综合征（SIRS）-急性肺损伤（ALI）的大鼠模型。观察肺组织白介素-4（IL-4）mRNA表达量和激活蛋白-1（AP-1）活性的变化，探讨SIRS-ALI中抗炎机制及其调控的意义。方法 经Wistar大鼠尾静脉注射递增剂量LPS，复制SIRS-ALI大鼠模型；逆转录PCR法（RT-PCR）检测肺组织IL-4mRNA表达量；凝胶迁移率分析法（EMSAs)检测肺组织AP-1活性。结果 （1）LPS可以介导大鼠发生SIRS-ALI；（2）LPS≥6mg/kg可致SIRS-ALI失控，形成ARDS；（3）LPS可诱导肺组织IL-4mRNA表达量和AP-1活性升高；（4）LPS≥6mg/kg时，肺组织IL-4mRNA表达量和AP-1活性的升高幅度最大。结论 （1）LPS≥6mg/kg是大鼠SIRS-ALI发生失控的临界剂量；（2）SIRS-ALI失控伴有IL-4基因转录水平明显上调，可能与上游调控因子AP-1活性异常增强有关；（3）抗炎机制增强在SIRS-ALI发生，发展过程中发挥了重要作用。     

The behavioral and neuronal effects induced by repetitive nociceptive stimulation are affected by gonadal hormones in male rats

The role of gonadal hormones in inducing long-term modifications in response to transient nociceptive stimuli was investigated in adult male rats. Three weeks after gonadectomy or sham surgery, animals were randomly divided into groups to be exposed to sham (only a prick in the dorsal hind paw) or formalin treatment (50 microl, 5% s.c. in the dorsal hind paw) once a week for the following 3 weeks. In gonadectomized animals the formalin-induced responses (licking, flexing and jerking of the injected paw) did not differ from those of intact animals after the first formalin injection. However, their levels were higher after the second or third injections. Indeed, in intact animals the formalin-induced responses progressively decreased, being significantly lower after the third injection than after the first; in gonadectomized animals, the formalin-induced responses did not change with repetition of the formalin treatment. In intact rats, c-Fos expression in the paraventricular nucleus of the thalamus and arcuate nucleus of the hypothalamus remained at control levels or decreased in animals injected two or three times with formalin; in gonadectomized rats, c-Fos expression increased with repetition of the noxious stimulation, reaching the highest levels in animals injected three times with formalin. These results show that male gonadal hormones have an inhibitory, adaptive effect on the behavioral and neuronal responses to repeated nociceptive stimulation.     

KLF4在LPS诱导的心肌细胞损伤中的作用研究

背景:KLF4作为一种转录因子在保持血管内皮功能中发挥重要作用,然而其是否能够保护心肌细胞免受脂多糖诱导的损伤尚不清楚。目的探讨KLF4在脂多糖诱导的心肌细胞损伤中的作用。方法:分离培养原代大鼠乳鼠心肌细胞,将其随机（随机数字法）分为5组：空白组,阴性对照组（NC组）,NC+脂多糖刺激组（NC+LPS组）,KLF4过表达组,KLF4过表达+LPS组。采用MTT法检测细胞活性,采用试剂盒检测细胞活性氧（ROS）,超氧化物歧化酶（SOD2）,谷胱甘肽过氧化物酶（Gpx）和丙二醛（MDA）的水平;采用酶联免疫吸附法（Elisa）检测细胞中肿瘤坏死因子（TNFa）,白细胞介素-1β（IL-1β）和IL-6的水平。采用Tunel染色检测细胞凋亡。采用免疫印迹检测TLR4和核因子E2相关因子2（NRF2）的蛋白水平。结果:心肌细胞转染KLF4过表达腺病毒后,细胞中KLF4的表达明显高于NC组（ P<0.05）。NC+LPS组细胞活性明显低于NC组（ P<0.05）,KLF4过表达+LPS组细胞活性高于NC+LPS组（ P<0.05）。与对照组相比,NC+LPS组中的心肌细胞TNFα、IL-1β、IL-6蛋白表达水平明显升高（ P<0.0001）,KLF4过表达+LPS组心肌细胞TNFα、IL-1β、IL-6蛋白表达水平则显著降低（ P<0.0001）。NC+LPS组心肌细胞ROS和MDA水平明显高于NC组,而SOD2和Gpx的活性低于NC组（ P<0.0001）;KLF4过表达+LPS组心肌细胞ROS和MDA水平的水平明显降低,而SOD2和Gpx的活性明显升高（ P<0.0001）。LPS组心肌细胞凋亡数量明显高于NC组,KLF4过表达+LPS组心肌细胞凋亡数量明显降低（ P<0.001）。LPS组心肌细胞TLR4总蛋白水平高于NC组,NRF2的核蛋白水平低于NC组;KLF4过表达+LPS组心肌细胞TLR4的总蛋白水平降低,NRF2的核蛋白水平显著增高（ P<0.001）。 结论：:KLF4可抑制LPS诱导的心肌细胞损伤,其作用机制可能是通过抑制LPS诱导的心肌细胞中TLR4的表达,促进NRF2向细胞核转移来抑制炎症因子释放,减轻氧化应激损伤及抑制细胞凋亡。     

胰岛素对内毒素所致的急性肺损伤保护作用的研究

目的 观察胰岛素(Insulin)对脂多糖(LPS)引起的兔急性肺损伤(ALI)的预防与治疗作用,并初步探讨其作用机制.方法 将新西兰兔随机分为生理盐水(NS)对照组,LPS组,Insulin + LPS组及LPS + Insulin组,气管内滴注LPS建立兔急性肺损伤模型.采用微量注射泵经兔耳缘静脉注射液体,NS组和LPS组注射生理盐水,持续4 h;Insulin+LPS组注射胰岛素混合液,0.5 h后再于气管内滴注LPS、胰岛素混合液持续4 h;LPS+Insulin组先经气管内滴注LPS, 0.5 h后再注射胰岛素混合液,持续4 h.4.5 h后处死实验动物,取肺组织观察形态学改变、测定肺湿/干质量比值(W/D),肺泡灌洗液(BALF)中蛋白含量,肺组织匀浆中TNF-α、IL-6、LDH和MPO的含量.结果 形态学观察表明LPS组肺组织水肿,点、片状出血,大量炎性细胞浸润,肺泡间隔显著增厚,肺泡腔变窄,结构消失.Insulin+LPS组及LPS+Insulin组肺损伤明显减轻,肺组织结构均趋于正常;肺泡腔及支气管腔炎性细胞及渗出物明显减少.LPS组肺W/D与NS组相比明显增加(P＜0.05),BALF中蛋白含量显著增加(P＜0.05),肺组织匀浆中TNF-α、IL-6、LDH和MPO的含量显著增加(P＜0.05);而给予胰岛素预防及治疗后,肺W/D、BALF中蛋白含量、肺组织匀浆中TNF-α、IL-6、LDH和MPO的含量与LPS组相比均明显减少(P＜0.05).结论 Insulin能够防治LPS导致的兔急性肺损伤,这种保护作用可能与其抑制肺组织中炎症介质的作用有关.     

KLF4在LPS诱导的心肌细胞损伤中的作用研究

背景:KLF4作为一种转录因子在保持血管内皮功能中发挥重要作用,然而其是否能够保护心肌细胞免受脂多糖诱导的损伤尚不清楚。目的探讨KLF4在脂多糖诱导的心肌细胞损伤中的作用。方法:分离培养原代大鼠乳鼠心肌细胞,将其随机（随机数字法）分为5组：空白组,阴性对照组（NC组）,NC+脂多糖刺激组（NC+LPS组）,KLF4过表达组,KLF4过表达+LPS组。采用MTT法检测细胞活性,采用试剂盒检测细胞活性氧（ROS）,超氧化物歧化酶（SOD2）,谷胱甘肽过氧化物酶（Gpx）和丙二醛（MDA）的水平;采用酶联免疫吸附法（Elisa）检测细胞中肿瘤坏死因子（TNFa）,白细胞介素-1β（IL-1β）和IL-6的水平。采用Tunel染色检测细胞凋亡。采用免疫印迹检测TLR4和核因子E2相关因子2（NRF2）的蛋白水平。结果:心肌细胞转染KLF4过表达腺病毒后,细胞中KLF4的表达明显高于NC组（ P<0.05）。NC+LPS组细胞活性明显低于NC组（ P<0.05）,KLF4过表达+LPS组细胞活性高于NC+LPS组（ P<0.05）。与对照组相比,NC+LPS组中的心肌细胞TNFα、IL-1β、IL-6蛋白表达水平明显升高（ P<0.0001）,KLF4过表达+LPS组心肌细胞TNFα、IL-1β、IL-6蛋白表达水平则显著降低（ P<0.0001）。NC+LPS组心肌细胞ROS和MDA水平明显高于NC组,而SOD2和Gpx的活性低于NC组（ P<0.0001）;KLF4过表达+LPS组心肌细胞ROS和MDA水平的水平明显降低,而SOD2和Gpx的活性明显升高（ P<0.0001）。LPS组心肌细胞凋亡数量明显高于NC组,KLF4过表达+LPS组心肌细胞凋亡数量明显降低（ P<0.001）。LPS组心肌细胞TLR4总蛋白水平高于NC组,NRF2的核蛋白水平低于NC组;KLF4过表达+LPS组心肌细胞TLR4的总蛋白水平降低,NRF2的核蛋白水平显著增高（ P<0.001）。 结论：:KLF4可抑制LPS诱导的心肌细胞损伤,其作用机制可能是通过抑制LPS诱导的心肌细胞中TLR4的表达,促进NRF2向细胞核转移来抑制炎症因子释放,减轻氧化应激损伤及抑制细胞凋亡。     

恐惧应激对雄性大鼠生殖相关参数的影响

目的 观察比较恐惧应激状态下不同应激时间段大鼠体重、睾丸和附睾重量、精子数目、3β-羟类固醇脱氢酶（3β-HSD）蛋白表达的变化。方法 建立SD大鼠的恐惧应激模型,分别取急性应激和慢性应激状态下SD大鼠睾丸、附睾称重,并对附睾尾精子计数,HE染色观察睾丸结构,免疫组织化学和western blotting分析3β-HSD表达,比较各实验组和对照组间上述指标的变化。结果 急性应激组与对照组相比,大鼠体重、睾丸重量、附睾重量、精子数量没有明显变化（P〉0．05）,HE染色显示睾丸结构无明显变化,免疫组化显示3β-HSD表达降低,western blotting分析3β-HSD降低了7％;慢性应激组与对照组相比,大鼠体重、睾丸重量、附睾重量、精子数量都有显著差异,P〈0．05。HE染色显示睾丸内生精小管细小,管腔内生精细胞稀少,免疫组化显示3β-HSD表达降低,western blotting分析3β-HSD降低了19．8％。结论 急性应激没有破坏雄性大鼠机体内稳态的调节能力,对生殖的影响仅见于睾丸功能的改变,睾丸组织结构未发生变化;而长期处于应激状态下的雄性大鼠,超出机体内稳态的调节能力,对生殖的影响不仅表现在3β-HSD的表达下降,而且睾丸组织结构发生变化。提示应激是影响大鼠生殖功能的一个因素。     

急性肺损伤大鼠肺组织血管紧张素转换酶表达的变化及其意义

目的探讨脂多糖性急性肺损伤大鼠肺组织血管紧张素转换酶的表达变化和可能的作用机制。方法 32只健康雄性Wistar大鼠随机分为正常0.9%氯化钠注射溶液对照组(NS组)、急性肺损伤后6、12、24 h三组(LPS时间组),每组8只,LPS时间组通过股静脉注射LPS(5 mg/kg)建立急性肺损伤模型。NS组给予等量NS。在相应时间点检测血气分析、肺组织湿/干重比(W/D)、HE染色、Real-timePCR方法检测肺组织ACE和ACE2 mRNA表达,免疫组织化学检测ACE和ACE2蛋白表达。结果 LPS组大鼠表现出急性肺损伤症状,随时间点延长,PaO2逐渐降低,肺W/D比值升高(P<0.05),HE染色显示肺组织损伤明显。LPS组大鼠肺组织ACE mRNA和蛋白表达随时间组延长明显增强(P<0.05),而ACE2mRNA和蛋白表达却明显减弱(P<0.05)。结论肺组织ACE、ACE2表达的改变在急性肺损伤大鼠的发病机制中可能起到重要作用。     

丹参酮对脂多糖性急性肺损伤大鼠肺组织ACE2表达的影响

目的:探讨血管紧张素转换酶2(ACE2)在脂多糖性急性肺损伤大鼠中的表达变化和作用机制及丹参酮IIA磺酸钠(STS)干预的影响.方法:45只健康雄性Wistar大鼠随机分为正常生理盐水对照组(NS组)、急性肺损伤组(LPS组)、丹参酮IIA磺酸钠干预组(STS组),LPS组和STS组通过股静脉注射LPS(5 mg/kg)建立急性肺损伤模型.STS组在注射LPS前30 min静脉给药10 mg/kg,NS组和LPS组给予等量NS.3组又分为6 h、12 h、24 h 3个时间点亚组,每组5只,检测血气分析、肺组织湿/干重比(W/D)、苏木精-伊红染色、ACE2免疫组织化学表达.结果:与LPS组相比,STS组急性肺损伤的程度明显减轻,PaO2显著改善(P<0.05),肺W/D比值降低(P<0.05),苏木精-伊红染色显示肺组织损伤减轻.免疫组织化学检测ACE2表达明显上升(P<0.05).结论:肺组织中ACE2表达的下降在急性肺损伤的发病机制中起到重要作用,而丹参酮可以改善急性肺损伤大鼠的肺损伤程度,其机制可能与增加ACE2的表达有关.     

下丘脑瘦素对大鼠胃运动的作用

目的:观察下丘脑外侧区(LH)及腹内侧区(VMH)微量注射瘦素对大鼠胃运动的作用。方法:应用慢性植入应力传感器记录清醒大鼠胃体和胃窦运动,颈外静脉插管取血样品,血清瘦素用放射免疫分析法(RIA)测定。采用不锈钢管插入LH及VMH,供注射瘦素用。结果:大鼠胃运动类型:空腹胃体与胃窦出现典型的消化间期移行性复合运动(MMC),分Ⅰ、Ⅱ、Ⅲ、Ⅳ时相,其Ⅲ相高振幅收缩波可从胃体传至胃窦;下丘脑注射瘦素对胃运动的作用:下丘脑LH和VMH注射0.3、0.6、1.2μg/2μl瘦素均明显抑制大鼠胃体和胃窦MMCⅢ相收缩运动(均P<0.01),呈剂量反应效应。VMH与LH瘦素两者对胃运动抑制作用比较,VMH瘦素对MMCⅢ相收缩活动的抑制作用强于LH(P<0.05);下丘脑注射瘦素对外周瘦素影响:当给LH和VMH注射瘦素时外周血中瘦素浓度上升,与胃运动抑制同步。LH与VMH注射瘦素分别使血清瘦素较对照组增加(38.21±9.42)%(P<0.05)和(54.25±11.37)%(P<0.01);迷走神经和拮抗剂作用:切断膈下迷走神经,阿托品及胆囊收缩素A(CCK-A)受体拮抗剂loxiglumide均可阻断下丘脑瘦素对胃运动的抑制效应及外周释放瘦素的作用。结论:下丘脑瘦素对胃运动有持续性抑制作用,其作用可能通过迷走-胆碱能神经及CCK-A受体介导。     

ASK1-p38 cascaded signal mediates pulmonary microvascular endothelial barrier injury induced by the return of PHSML in rats

The return of post-hemorrhagic shock mesenteric lymph (PHSML) induces pulmonary vascular endothelial barrier dysfunction, which results in acute lung injury. Activation of the apoptosis signal-regulated kinase 1 (ASK1) and p38 mitogen-activated protein kinase (p38 MAPK) pathway has been shown to trigger inflammatory responses. However, whether the ASK1-p38 MAPK pathway is involved in the PHSML-induced pulmonary endothelial barrier dysfunction remains unclear. In the present study, permeability changes of pulmonary capillaries were found in vivo, and activation of the ASK1-p38 MAPK pathway was determined in vitro. PMVEC barrier dysfunction was determined by measuring TEER. Furthermore, junctional and cytoskeletal protein expressions were analyzed. The results showed that hemorrhagic shock led to a marked increase in the permeability of pulmonary capillaries in vivo, which was markedly alleviated by PHSML drainage. In cultured pulmonary microvascular endothelial cells (PMVECs), PHSML reduced the endothelial barrier function accompanied by upregulated p-ASK1 and p-p38 MAPK protein expression, impaired the cytoskeletal protein structure, and down-regulated junction protein expression. These adverse effects were eliminated by applying either Trx1 (ASK1 inhibitor) or SB203580 (p38 MAPK inhibitor). These results indicated that the ASK1-p38 MAPK pathway mediates PHSML-induced pulmonary vascular endothelial barrier dysfunction during hemorrhagic shock.

The return of post-hemorrhagic shock mesenteric lymph (PHSML) induces pulmonary vascular endothelial barrier dysfunction, which results in acute lung injury.