NK2 tachykinin receptors mediate contraction of the pig intravesical ureter: tachykinin-induced enhancement of non-adrenergic non-cholinergic excitatory neurotransmission

The current study was designed to characterize the functionally active tachykinin receptors involved in tachykinin-elicited contractions in the pig intravesical ureter, and to investigate the possible modulation exerted by the natural tachykinins substance P (SP) and neurokinin A (NKA) on the non-adrenergic non-cholinergic (NANC) excitatory ureteral neurotransmission. In pig intravesical ureteral strips pretreated with phosphoramidon (10(-5) mol/L) to block the endopeptidase activities, isometric force recordings showed that SP, NKA, and the NK2 receptor selective agonist [beta-Ala(8)]-NKA (4-10), all three induced contractions, with the following potency order: NKA > [beta-Ala(8) ]-NKA (4-10) > SP. [Sar(9), Met(O(2))(11)]-SP and senktide, selective agonists of the NK1 and NK3 receptors, respectively, failed to modify the ureteral tone. Urothelium removal and incubation with tetrodotoxin (10(-6) mol/L), phentolamine (10(-7) mol/L), propranolol (3 x 10(-6) mol/L), atropine (10(-7) mol/L) and indomethacin (3 x 10(-6) mol/L), did not alter the contraction induced by a submaximal (10(-7) mol/L) dose of [beta-Ala(8)]-NKA (4-10). MEN 10,376 (10(-8)-10(-7) mol/L), a NK2 receptor antagonist, reduced the contraction to 3 x 10(-8) mol/L NKA. GR 82334 (10(-6) -10(-5) mol/L) and SR 142801 (10(-8)-10(-7) mol/L), selective antagonists of the NK1 and NK3 receptors, respectively, did not modify that contraction. In pig intravesical ureteral strips in NANC conditions, SP and NKA induced a potentiation of the contractions to electrical field stimulation (EFS) and to exogenous ATP. The results suggest that the tachykinins evoke a direct contraction of pig intravesical ureteral strips through NK2 receptors located in the smooth muscle. SP and NKA exert an enhancement of the NANC excitatory neurotransmission of the pig intravesical ureter.     

乌司他丁对油酸致家兔急性肺损伤的保护作用

目的探讨乌司他丁对油酸致家兔急性肺损伤的保护作用及其可能的机制。方法健康成年新西兰大耳白兔16只随机均分为两组:油酸损伤组(A组),乌司他丁保护组(B组)。A组由颈总静脉缓慢注射分析纯油酸0·12ml/kg;B组先静脉给予乌司他丁50000U/kg,并随之以微量泵5000U·kg-1·h-1持续给予乌司他丁至实验结束,20min后缓慢注射分析纯油酸0·12ml/kg。两组均于给予油酸前(T0)及油酸后30、60、120、180、240min(T1、T2、T3、T4、T5)分别检查血气分析、中性粒细胞蛋白酶活性,实验结束测定肺湿重,计算肺系数。结果A组在注射油酸后PaO2呈进行性下降,B组PaO2保持平稳,各时点PaO2值与B组比较明显降低(P<0·01),A组PaCO2则呈进行性上升,与B组比较明显升高(P<0·01)。两组中性粒细胞弹性蛋白酶水平在注射油酸后均有不同程度升高,各时点比较A组明显高于B组(P<0·01),A组肺系数值明显高于B组(P<0·01),两组心率、pH值比较无显著性差异(P>0·05)。结论乌司他丁能有效地保护油酸致家兔急性肺损伤,可通过抑制血清中中性粒细胞弹性蛋白酶活性而达到肺保护作用。     

Inhibition of the vanilloid receptor subtype-1 attenuates tnbs-colitis

Primary sensory neurons are important in regard to the initiation and propagation of intestinal in.ammation. The vanilloid receptor subtype-1 (VR-1) is a cation channel located on the sensory nerves that, when stimulated, release proinflammatory peptides. Previous reports have indicated that inhibition of VR-1 with capsazepine (CPZ), a VR-1 antagonist, attenuates dextran sodium sulfate (DSS) colitis in rats. DSS-induced colitis resembles ulcerative colitis with regard to its pathologic features. In this study, we examined the effect of CPZ on trinitrobenzene sulfonic acid (TNBS)-induced colitis, an experimental model of intestinal inflammation that most closely resembles the histologic and microscopic features of Crohn’s disease. Colitis was induced by administering a single enema of 100 mg/ kg TNBS in 50% ethanol via catheter to lightly anesthetized rats. Subsets of rats were treated with either 1 μmol/kg/ml of CPZ or CPZ-vehicle via enema for 6 days. Seven days after TNBS administration, rats were sacrificed and inflammation was assessed using a validated macroscopic damage score (MDS) and by measuring myeloperoxidase (MPO) activity. In addition, histologic examination was performed. TNBS administration resulted in reproducible chronic erosive lesions extending into the muscularis propria and extensive recruitment of neutrophils in the distal colon. MDS and MPO scores were considerably elevated in the TNBS colons when compared with the TNBS vehicle animals. TNBS rats treated with CPZ enemas exhibited a substantial reduction in MDS and MPO scores and demonstrated dramatically improved pathologic findings. Topical CPZ resulted in considerable attenuation of TNBSinduced colitis. These results support the role of VR-1 and sensory neurons with regard to intestinal inflammation. Presented at the Forty-Fifth Annual Meeting of The Society for Surgery of the Alimentary Tract, New Orleans, Louisiana, May 15–19, 2004 (oral presentation). This work was supported by the American Surgical Association Fellowship Award and a Career Development Award from the American Society of Colon and Rectum Surgery (C.R.M.).     

胱天蛋白酶募集域蛋白9在大鼠急性胰腺炎相关肺损伤中的作用及其机制

目的:探讨胱天蛋白酶募集域蛋白9(CARD9)在大鼠急性胰腺炎相关性肺损伤(APALI)中的作用及机制。方法:30只雄性Sprague Dawley大鼠采用随机数字表法分成对照组(6只)、APALI组(12只)、腺病毒干扰组(12只)。通过胰管注射牛磺胆酸钠建立重症急性胰腺炎(SAP)大鼠模型,造模后3、6 h处死动物...     

The kinetics of autophagy in the lung following acute spinal cord injury in rats

Background Context

Lung injury is a major cause of respiratory complications following an acute spinal cord injury (ASCI), which are associated with a high mortality rate. Autophagy has been shown to be involved in a variety of lung diseases; however, whether autophagy is activated in the lung following ASCI remains unknown.

Mechanisms of neurokinin A- and substance P-induced contractions in rat detrusor smooth muscle in vitro

OBJECTIVE: To investigate the mechanisms of neurokinin A- and substance P-induced contractions of rat urinary bladder smooth muscle, and to compare them with those of the muscarinic agonist carbachol. MATERIALS AND METHODS: Rat urinary bladder strips were suspended under 1 g of tension in a physiological buffer at 37 degrees C, gassed with 95% O(2)/5% CO(2). Mechanical activity was recorded isometrically during exposure to neurokinin A and substance P. RESULTS: Both agents produced concentration-dependent contractions of smooth muscle strips which were unaffected by tetrodotoxin (1 micro mol/L), peptidase inhibitors (captopril, thiorphan and bestatin; 1 micro mol/L each) or piroxicam (10 micro mol/L). The rank order of potency of agonists was neurokinin A > substance P > carbachol. Contractile responses to neurokinin A and substance P, like the contractile responses to carbachol, were abolished in a nominally Ca(2+)-free medium and significantly reduced by nifedipine (1 micro mol/L). SKF-96365 (60 micro mol/L), an inhibitor of receptor-mediated Ca(2+) entry, abolished the nifedipine-resistant response to substance P and carbachol, and significantly attenuated the response to neurokinin A. Depleting intracellular Ca(2+) stores with thapsigargin (1 micro mol/L) significantly attenuated neurokinin A-induced contractions but had no effect on substance P- or carbachol- induced contractions. The Rho-kinase inhibitor, Y-27632 (10 micro mol/L), significantly reduced both phasic and tonic components of the contractile responses to neurokinin A, substance P and carbachol. CONCLUSION: The contractile responses induced by tachykinins in rat urinary bladder smooth muscle strips involve a direct action on smooth muscle and are not modulated by peptidases or prostanoids. Neurokinin A and substance P, like carbachol-induced contractions, depend on extracellular Ca(2+) influx largely through voltage-operated and partly through receptor-operated Ca(2+) channels. Intracellular Ca(2+) release contributes to the contractile response to neurokinin A but appears to have no involvement in substance P- and carbachol-induced contractions. Rho-kinase activation contributes to contractions induced by substance P, neurokinin A and carbachol.     

热休克蛋白27在垂盆草提取物改善大鼠重症急性胰腺炎相关的肺损伤中的作用

目的研究垂盆草提取物(Sedum sarmentosum Bunge extraction,SSBE)对大鼠重症急性胰腺炎(severe acute pancreatitis,SAP)相关的急性肺损伤(acute lung injury,ALI)的改善作用及其机制。方法 42只健康成年SD大鼠随机分成3组:假手术组(C)、胰腺炎组(SAP)、垂盆草提取物治疗组(SSBE),每组14只。逆行胰胆管注射5%牛磺胆酸钠(1 m L/kg)建立SAP模型,SSBE组在SAP模型基础上给予SSBE(100 mg/kg)治疗,C组和SAP组给予等量生理盐水。建模成功后12 h、24 h检测肺组织湿干比重、肺组织髓过氧化物酶(myeloperoxidase,MPO)活性、肺组织病理评分及肺组织磷酸化的热休克蛋白27(phospho-heat shock protein 27,p-Hsp27)蛋白的表达。结果在12 h及24 h时间点,SSBE组肺组织病理学评分(2.10±0.012,1.92±0.215)、肺组织湿干比重(2.80±0.12,2.83±0.15)、肺组织MPO活性(69.32±9.03,72.20±5.93)均明显低于SAP组肺组织病理学评分(3.49±0.212,2.85±0.210)、肺组织湿干比重(3.45±0.10,3.48±0.12)、肺组织MPO活性(87.51±4.03,89.33±3.75),具有统计学差异(P0.05)。肺组织中p-Hsp27蛋白表达SSBE组低于SAP组(P0.05),两组均高于C组(P0.05)。结论垂盆草提取物对大鼠重症急性胰腺炎相关的肺损伤的保护作用可能与减少肺组织中性粒细胞浸润有关,其机制可能与下调肺组织内p-Hsp27的表达有关。     

环磷酸腺苷/蛋白激酶A信号转导通路在重症急性胰腺炎肺损伤中的作用

目的 探讨环磷酸腺苷/蛋白激酶A(cAMP/PKA)信号转导通路在重症急性胰腺炎肺损伤的作用机制.方法 健康雄性SD大鼠72只,按完全随机法分为假手术(SO)组、重症急性胰腺炎组(SAP组)、SAP+ H89(cAMP抑制剂)组,后两组按取材时间不同又分为3、6、12及24 h四个亚组,共9组,每组8只.采用酶联免疫吸附法检测血清TNF-α、IL-1β,同时观察胰腺和肺组织的病理变化,免疫组织化学蛋白方法检测cAMP依赖PKA催化亚基C(PKA C)和磷酸化的血管扩张刺激磷蛋白(p-VASP),荧光定量聚合酶链反应检测肺组织VSAP mRNA表达水平.结果 与SO组比较,SAP组各时间点血清TNF-α 、IL-1β明显上升(P＜0.05),胰腺、肺病理学改变明显,肺组织PKA C蛋白、VASP磷酸化水平及VASPmRNA表达水平明显增强(P＜0.05),12 h达高峰[TNF-α(266.07±17.14) pg/mL、IL-1β (169.17±25.92) pg/mL、PKA C(210.69 ±6.32)×103、p-VASP(56.62 ±0.57)×103、VASPmRNA(2.06 ±0.21)],且与TNF-α、IL-1β之间存在明显的正相关性.与SAP组比较,SAP+ H89组各时间点胰腺、肺病理学改变明显减轻,肺组织PKA C蛋白、VASP磷酸化水平及VSAP mRNA表达水平明显下降(P＜0.05).结论 cAMP/PKA信号转导通路的活化参与了重症急性胰腺炎肺损伤的病理过程,可能与TNF-α及IL-1β水平上调及VASP磷酸化而发挥作用有关.     

血管外肺水指数与氧合指数评估急性肺损伤程度准确性的比较

目的 比较血管外肺水指数(EVLWI)与氧合指数(PaO2/FiO2)评估急性肺损伤(ALI)程度的准确性.方法 创伤后(创伤时间＜48 h)ALI行机械通气患者16例,性别不限,年龄18～80岁,采用PiCCO监测仪监测EVLWI,建立PiCCO监测后每隔24 h采集动脉血样,测定PaO2,计算PaO2/FiO2;同时记录EVLWI,并进行肺损伤评分(LIS).分别在建立HCCO监测后24、48、72 h时按PaO2/FiO2将患者分为PaO2/FiO2≤300组(200 mm Hg＜PaO2/FiO2≤300 mm Hg)和PaO2/FiO2≤200组(PaO2/FiO2≤200 mm Hg),按EVLWI将患者分为EVLWI＜10组(EVLWI＜10 ml/kg)和EVLWI≥10组(EVLWI≥10 ml/kg).结果 与PaO2/FiO2≤300组比较,PaO2/FiO2≤200组建立PiCCO监测后24、48 h时LIS评分差异无统计学意义(P＞0.05),建立PiCCO监测后72 h时LIS评分升高(P＜0.01).与EVLWI＜10组比较,EVLWI≥10组各时点LIS评分均升高(P＜0.05或0.01).结论 临床中PaO2/FiO2作为评估ALI程度的指标存在局限性,而EVLWI在评估ALI程度方面可能比PaO2/FiO2更准确.

Abstract：

Objective To compare extravascular lung water index (EVLWI) and oxygenation index (PaO2/FiO2) in estimation of acute lung injury(ALI) .Methods Sixteen patients with post traumatic ALI (within 48 h) of both sexes, aged 18-80 yr, were studied. The patients were mechanically ventilated. Right internal jugular vein and femoral artery were catheterized and connected to PiCCO monitor (IntelliVue MP50, Philips, Netherlands).EVLWI was monitored with the PiCCO system. PaO2 was determined every 24 h. ALI was diagnosed based on the following criteria:(1)PaO2/FiO2≤300 mm Hg; (2)X-ray chest film-patchy shadows in the bilateral lungs and (3) CVP≤12 mm Hg.Lung injury score(LIS) was recorded. The patients were divided into PaO2/FiO2≤ 300 group and ≤200 group and EVLWI ≥ 10 group and ＜ 10 group. Results There was no significant difference in LIS between PaO2/FiO2 ≤300 group and PaO2/FiO2 ≤200 group at 24 and 48 h of PiCCO monitoring. At 72 h of PiCCO monitoring LIS was significantly increased in PaO2/FiO2 ≤200 group as compared with PaO2/FiO2 ≤300 group, LIS was significantly higher in EVLWI≥ 10 group than in EVLWI ＜ 10 group at 24, 48 and 72 h of PiCCO monitoring. Conclusion EVLWI is more accurate than PaO2 /FiO2 in estimation of severity of ALI.     

Open blunt crush injury of different severity determines nature and extent of local tissue regeneration and repair

Insufficiency of skeletal muscle regeneration is often accompanied with functional deficiencies. The goal of our study was to assess the restoration of peripheral muscle upon injury of different severity. Blunt crush injury of the soleus muscle in rats was induced by a clamp and stepwise amplified in severity by rising the locking level of the clamp, resulting in three different groups (1× lock; 2× lock; 3× lock; n = 30 animals per group). After assessment of the fast twitch and tetanic contraction capacity at days 1, 4, 7, 14, and 42 postinjury sampling of muscle tissue served for analysis of cell proliferation, including satellite cells, apoptosis, and leukocyte infiltration. Contraction force analysis demonstrated significantly higher values of relative muscle strength in the 1× lock group compared to the two other groups over 42 days. Calculation of the twitch‐to‐tetanic force ratio revealed significantly higher mean values at days 1, 7, and 14 in the animals of group 2× lock and 3× lock, indicating a transformation toward a fast‐twitching muscular phenotype. Moreover, cell proliferation during the first 4 days was found dependent on the severity of muscle injury in that the higher the severity the higher the proliferation. At the same time, cell apoptosis was found increased, and at day 1 the local leukocyte infiltration was significantly higher in the 3× lock compared to the 1× lock group. These data indicate that severity of injury correlates with local repair responses, which, however, are not necessarily sufficient to fully restore muscle function. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:950–957, 2010     

血管生成素-1在急性肺损伤治疗中的作用

急性肺损伤(acute lung injury,ALI)的典型特征是肺泡毛细血管的损伤以及伴随而来的肺水肿,血管生成素-1(angiopoietin-1,Ang1)可以减轻炎症反应,抑制内皮细胞凋亡及降低血管通透性,因此能通过减小肺泡毛细血管的损伤而在肺损伤治疗中发挥一定的作用并已在动物实验中得到证实.进一步认识并了解Ang1可能为肺损伤的预防及治疗提供一种新的手段.现就Ang1的功能及其在ALI预防与治疗中的进展作一综述.     

西维来司钠对大鼠重症急性胰腺炎肺损伤的作用

目的 探讨西维来司钠(sivelestat sodium)对SD大鼠重症急性胰腺炎(severe acute pancreatitis,SAP)肺损伤的作用及其可能机制.方法 健康成年SD大鼠24只随机分成3组:对照组、模型组、药物组,每组8只.逆行胰胆管注射5%牛磺胆酸钠建立SAP模型.药物组在模型基础上给予西维来司钠干预,对照组和模型组给予等量生理盐水.建模成功6h后处死大鼠,检测各组大鼠血清淀粉酶(AMS)、血清中性粒细胞弹性蛋白酶(NE)活性以及肺脏组织湿干比重(W/D)、髓过氧化物酶(MPO)活性、核因子-κB(NF-κB)活性,光镜下观察肺脏病理改变,并进行病理学评分.结果 与对照组比较,模型组肺组织MPO、NF-κB含量显著升高(P<0.05),W/D比值显著升高(P<0.05),血清AMS、NE显著升高(P<0.05),光镜下可见肺组织出现明显的病理损伤(P<0.05).与模型组相比,药物组的血清NE以及肺组织MPO、W/D、NF-κB含量显著降低(P<0.05),但是AMS却没有显著降低(P>0.05).光镜下肺组织病理损害显著减轻(P<0.05),其损伤程度介于对照组和模型组之间.结论 早期应用西维来司钠对减轻大鼠急性胰腺炎肺损伤程度具有一定的作用.其作用机制可能是:西维来司钠通过抑制NF-κB活性来抑制炎症反应,从而起到减轻重症急性胰腺炎肺损伤的作用.     

血管生成素-1在急性肺损伤治疗中的作用

急性肺损伤(acute lung injury,ALI)的典型特征是肺泡毛细血管的损伤以及伴随而来的肺水肿,血管生成素-1(angiopoietin-1,Ang1)可以减轻炎症反应,抑制内皮细胞凋亡及降低血管通透性,因此能通过减小肺泡毛细血管的损伤而在肺损伤治疗中发挥一定的作用并已在动物实验中得到证实.进一步认识并了解Ang1可能为肺损伤的预防及治疗提供一种新的手段.现就Ang1的功能及其在ALI预防与治疗中的进展作一综述.     

The role of HMGB1 in inflammation-mediated organ injury

HMGB1 is a chromosome-binding protein that also acts as a damage-associated molecular pattern molecule. It has potent proinflammatory effects and is one of key mediators of organ injury. Evidence from research has revealed its involvement in the signaling mechanisms of Toll-like receptors and the receptor for advanced glycation end-products in organ injury. HMGB1-mediated organ injuries are acute damage including ischemic, mechanical, allograft rejection and toxicity, and chronic diseases of the heart, kidneys, lungs, and brain. Strategies against HMGB1 and its associated cellular signal pathways need to be developed and may have preventive and therapeutic potentials in organ injury.     

利多卡因减轻内毒素诱导兔肺损伤炎症反应的实验研究

静脉注射内毒素引起的急性肺损伤与临床脓毒血症引起的急性肺损伤相似，是全身的过度炎症反应引起的急性损伤。肺由于其组织结构及功能的特殊性，往往成为受累最先及最严重的一个器官。近年，大量的动物及体外实验证明，利多卡因具有抑制中性粒细胞黏附、趋化，抑制氧自由基和蛋白水解酶释放，稳定细胞膜，调节细胞因子和抑制过度的炎症反应等作用。动物实验已经证实利多卡因预防性及打击后早期给药可以减轻多种因素诱发急性肺损伤的程度（包括高氧、盐酸吸入、胰酶及蛋白酶诱导、内毒素诱导及缺血再灌注损伤等）。但利多卡因剂量与减轻急性肺损伤程度的关系尚不清楚。本研究探讨利多卡因是否能减轻内毒素诱导兔肺部的炎症反应，最终减轻肺损伤及量效关系。