炎调方对脓毒症急性肺损伤大鼠肺组织热休克蛋白70 mRNA和p38丝裂原活化蛋白激酶的影响

目的 探讨炎调方对脓毒症急性肺损伤（ALI）大鼠肺组织热休克蛋白70（HSP70）mRNA和p38丝裂原活化蛋白激酶（p38 MAPK）的调控作用。方法 将清洁级健康雄性SD大鼠随机分为假手术组、模型组、炎调方（生药量9.9 g/kg）组、谷氨酰胺组、槲皮素组,采用盲肠结扎穿孔术法（CLP）建立脓毒症ALI模型。观察大鼠一般状况,各组分别于术后4、6、8、10、12、18、24 h采集肺组织标本,HE染色观察肺组织病理学改变;实时荧光定量PCR法检测肺组织HSP70 mRNA的表达水平;Western Blotting法检测肺组织p38 MAPK的蛋白表达水平。结果 炎调方组、谷氨酰胺组大鼠与模型组比较,术后不同时间点的精神状态、活动量等明显好转,可见少量稀便;肺组织损伤程度明显减轻,腔内出血较少,肺实变较轻。炎调方组不同时间点的肺组织HSP70 mRNA表达水平显著高于假手术组、模型组（除24 h时间点外）、槲皮素组（P<0.01）,在8、12、18、24 h时间点显著低于谷氨酰胺组（P<0.01）;炎调方组不同时间点的肺组织p38 MAPK的蛋白表达量显著低于模型组、槲皮素组（P<0.01）,在4、6、10 h时间点明显低于谷氨酰胺组（P<0.05、0.01）。结论 炎调方可通过上调肺组织HSP70 mRNA的表达,下调肺组织p38 MAPK的蛋白表达,改善肺组织损伤,对脓毒症ALI发挥保护作用。     

丝裂原活化蛋白激酶抑制剂对急性肺损伤影响

目的探讨p38MAPK抑制剂SB203580对大鼠急性肺损伤影响。方法采用LPS建立SD大鼠急性肺损伤模型，随机分为对照组、LPS组、SB203580组。造模后注射p38MAPK抑制剂SB203580，在1h、3h、6h及12h时，剖杀大鼠，观察肺组织病理改变，ELISA法测血清中的TNF—α及IL-6；免疫组化检测肺组织中的p38MAPK及其磷酸化-p38MAPK。结果注射LPS后，SB203580治疗组较LPS组血清中的TNF—α及IL-6显著减少（P〈0．05 or 0.01）；肺组织中的磷酸化-p38MAPK的表达显著减轻，而p38丝裂原活化蛋白激酶未明显减轻。结论p38MAPK抑制剂SB203580可减轻血清中的TNF-α及IL-6和肺组织中的磷酸化-p38MAPK的表达，从而减轻LPS诱导的急性肺损伤。     

p38丝裂原活化蛋白激酶在类风湿关节炎治疗中的可能作用

类风湿关节炎(RA)是一种慢性进展性炎性疾病,常引起慢性滑膜炎、关节损伤、关节功能减退和过早死亡.     

抑制P38丝裂原活化蛋白激酶信号通路对急性重症胰腺炎大鼠大脑皮层诱导型一氧化氮合酶表达的影响

目的观察P38丝裂原活化蛋白激酶信号通路抑制剂SB203580对急性重症胰腺炎(SAP)大鼠大脑皮层诱导型一氧化氮合酶(iNOS)蛋白表达的影响。方法将45只SD大鼠按随机数字法分3组。模型组:将5%牛磺胆酸钠经胰胆管逆行注入胰腺制备;抑制剂组:造模后于大鼠尾静脉注射SB203580;对照组开腹后翻动胰腺数次立即缝合腹壁,尾静脉注射0.9%氯化钠注射液。造模成功后24h,检测血清淀粉酶;应用免疫组织化学、蛋白印迹法观察及检测各组神经元中iNOS和磷酸化P38表达的变化,并进行图像分析和统计学处理。结果模型组大鼠p-P38、iNOS阳性神经元显著增加及蛋白水平升高;给予注射SB203580后,抑制剂组较模型组均明显减轻(P<0.05)。结论 P38丝裂原活化蛋白激酶信号通路抑制剂SB203580具有调控SAP大鼠大脑皮层iNOS蛋白表达的作用,减轻神经元的变性丢失,对于SAP大鼠大脑起到保护作用     

p38丝裂原活化蛋白激酶与骨代谢

丝裂原活化蛋白激酶（mitogen-activated protein kinases,MAPK）是机体广泛表达的丝氨酸/酪氨酸激酶,在哺乳动物细胞多种信号转导通路中起重要作用。p38MAPK信号通路是MAPK通路的一个重要分支,在细胞增殖、分化、凋亡和细胞周期调控等多种生理和病理过程中发挥重要作用。近年来,有关p38MAPK信号通路在与骨代谢相关的破骨细胞、成骨细胞、软骨细胞生长、代谢及功能方面的研究倍受关注。本文就p38MAPK与骨代谢相关研究进展进行综述,旨在探讨p38MAPK在骨代谢相关疾病中的作用机制。     

姜黄素对结核小鼠复发及p38丝裂原活化蛋白激酶信号通路的影响

目的 研究姜黄素对结核小鼠复发及p38丝裂原活化蛋白激酶(p38 MAPK)信号通路的影响.方法 将45只C57BL/6小鼠随机分为模型组(n=15)、实验组(n=15)和对照组(n=15),所有小鼠均尾静脉注射结核分枝杆菌H37RV(1×107 CFU·mL-1)0.1 mL.4周后,实验组腹腔注射异烟肼10 mg·...     

p38丝裂原活化蛋白激酶在骨肉瘤的作用机制研究进展

骨肉瘤是临床上常见的一种恶性骨肿瘤,它的特点是肿瘤细胞可直接产生于骨样组织,造成机体骨组织细胞病变,影响患者的骨健康,降低免疫力,威胁患者的生命健康。目前,有调查研究资料显示骨肉瘤好发于青少年人群,且约65%的骨肉瘤患者年龄在25岁以下,男性多于女性。骨肉瘤多发于股骨远端、胫骨近端以及肱骨近端的干骺端部位,常于骨头表面呈现梭形的瘤体,并且多伤及骨膜、骨皮质以及髓腔等部位,影响股骨头的健康,对患者的关节活动范围造成很大的影响。p38丝裂原活化蛋白激酶（p38 mitogen-activated protein kinase,p38 MAPK）是人体内重要的信号物质,能够被MAPK激酶3和MKK6磷酸化从而被激活,进而磷酸化并激活MAPK相关蛋白激酶等,最终激活机体内的转录因子,如ATF-2、Max和MEF2等转录因子,参与调节细胞生长、分化以及炎症反应等重要的细胞生理和病理过程。在骨肉瘤方面,p38 MAPK信号通路能够参与到骨肉瘤的发生、侵袭和转移的过程。本文着重对p38MAPK信号通路在骨肉瘤中的作用机制进行综述。     

p38丝裂原活化蛋白激酶选择性抑制剂对难治性癫痫模型大鼠神经细胞的保护作用及其机制研究

目的:研究p38丝裂原活化蛋白激酶(p38MAPK)选择性抑制剂SB202190对难治性癫痫模型大鼠神经细胞的保护作用及其机制。方法:取大鼠随机分为空白对照组、模型组、阳性对照组(卡马西平5 mg.kg-1)和SB202190低、中、高剂量组(7.5、15、30mg.kg-1),每组10只,除空白对照组外,其余各组腹腔注射海仁酸(KA)10 mg.kg-1建立难治性癫痫模型,阳性对照组和SB202190各剂量组建模前30 min腹腔注射相应药物。建模给药后按Racine分级标准对各组大鼠进行行为学评价,观察建模给药后1 h内各组大鼠的脑电图(EEG)变化,采用免疫组化法和蛋白免疫印迹法检测建模给药后3 h各组大鼠脑组织中p38MAPK蛋白的表达。结果:空白对照组无癫痫发作,EEG无明显节律性;模型组癫痫大发作,发作程度为5级,EEG出现癫痫样放电,与空白对照组比较,模型组p38MAPK阳性细胞数明显增加,其表达明显增强(P<0.01);与模型组比较,阳性对照组和SB202190 3个剂量组发作程度、EEG癫痫样放电、p38MAPK阳性细胞数及其蛋白表达均明显降低(P<0.05或P<0.01)。结论:SB202190对KA诱导的难治性癫痫模型大鼠神经细胞具有保护作用,可能与其抑制p38MAPK蛋白的表达有关。     

p38促丝裂原活化蛋白激酶对疾病调控作用的研究进展

近来研究发现,p38促丝裂原活化蛋白激酶(p38MAPK)在疾病的发生、发展过程中具有明显的调控作用。特别是在介导炎症、应激等细胞反应方面,其特异性和选择性抑制剂亦已被广泛应用到各类疾病的研究中来。本文结合近年国内、外相关文献,对p38MAPK的结构特征、家族成员、激活与效应在疾病中的调控作用及研究中存在的问题等进行综述,旨在为今后p38MAPK的研究提供参考。1对p38MAPK的认识1·1p38MAPK的发现1993年,Brewster JL等[1]发现,细菌脂多糖(Lipopolysac_charide,LPS)刺激巨噬细胞后有3个蛋白快速发生酪氨酸磷酸化;1994年,Han JH…     

p38 MAPK抑制剂对重症胰腺炎大鼠急性肺损伤的保护作用

目的探究p38MAPK抑制剂对重症胰腺炎大鼠急性肺损伤的保护作用。方法采用随机数字表法将60只大鼠分为三组,A组为假手术组,B组为重症胰腺炎模型组,C组为重症胰腺炎模型加p38MAPK抑制剂组;检测三组大鼠的肺组织病理学切片、肺组织湿干重比、髓过氧化物酶活性以及p38MAPK mRNA的表达水平。结果 B组大鼠与A组大鼠相比,其肺组织损伤病理评分、肺组织湿干重比、肺组织髓过氧化物酶(MPO)活性以及肺组织p38MAPK mRNA的表达水平均显著升高,而C组大鼠与B组大鼠相比上述指标均有所下降,P<0.05。结论 p38MAPK抑制剂能减少TNF-α的释放,降低炎症反应,为临床上治疗重症急性胰腺炎并发急性肺损伤的提供新的方向。     

p38MAPK inhibition attenuates LPS-induced acute lung injury involvement of NF-kappaB pathway

The pathogenesis of acute lung injury/acute respiratory distress syndrome (ARDS) is complex and involves multiple signal transduction processes. It is believed that p38MAPK (mitogen-activated protein kinase) is one of the most kinases in inflammatory signaling. At present study, we demonstrated the role of p38MAPK in lipopolysaccharide (LPS)-induced acute lung injury with pharmacologic p38MAPK inhibition by SB203580. SB203580, p38MAPK specific inhibitor, was injected (10 mg/kg, i.v.) 30 min before LPS administration (5 mg/kg, i.v.). The hematoxylin-eosin staining of lung tissues showed that p38MAPK inhibition significantly attenuated the pulmonary inflammatory responses induced by LPS. Moreover, SB203580 can also inhibit the inflammatory cytokine release, and reduce the mortality rate of LPS-induced acute lung injury. Further, western blot analysis that showed SB203580 administration can inhibit the activation of NF-kappaB, which was associated with the inhibition of IkappaBalpha degradation in cytoplasm. These data suggest that p38MAPK signaling may be involved in the activation of NF-kappaB, and activation of p38MAPK signaling may be one of the mechanisms of acute lung injury.     

Ly-6Chigh inflammatory-monocyte recruitment is regulated by p38 MAPK/MCP-1 activation and promotes ventilator-induced lung injury

Lymphocyte antigen 6Chigh (Ly-6C^high) inflammatory monocytes, as novel mononuclear cells in the innate immune system, participate in infectious diseases. In this study, we investigated the potential role of these monocytes in ventilator-induced lung injury (VILI) and the possible mechanism involved in their migration to lung tissue. Our results showed that mechanical ventilation with high tidal volume (HTV) increased the accumulation of Ly-6C^high inflammatory monocytes in lung tissues and that blocking C‑C chemokine receptor 2 (CCR2) could significantly reduce Ly-6C^high inflammatory-monocyte migration and attenuate the degree of inflammation of lung tissues. In addition, inhibition of p38 mitogen-activated protein kinase (p38 MAPK) activity could decrease the secretion of monocyte chemoattractant protein 1 (MCP-1), which in turn decreased the migration of Ly-6C^high inflammatory monocytes into lung tissue. We also demonstrated that high ventilation caused Ly-6C^high inflammatory monocytes in the bone marrow to migrate into and aggregate in the lungs, creating inflammation, and that the mechanism was quite different from that of infectious diseases. Ly-6C^high inflammatory monocytes might play a pro-inflammatory role in VILI, and blocking their infiltration into lung tissue might become a new target for the treatment of this injury.     

p38MAPK在大鼠胃缺血再灌注损伤中的表达

目的:探讨p38MAPK在大鼠胃缺血再灌注损失中的作用.方法:30只SD大鼠随机分为假手术组和胃缺血再灌注损伤组,分别在胃缺血再灌注损伤的0、0.5、1、3、6、12 h处死大鼠,切除胃组织标本做病理检查;用免疫组化方法检查p38MAPK在胃组织中的表达.结果:p38MAPK在胃缺血再灌注损伤中表达增强;胃缺血再灌注损伤后0.5 h表达即明显增加,1h达高峰,再灌注3h有所下降,而后又上升并维持在相对较高水平再灌注12h.结论:p38MAPK缺血再灌注损伤的发展过程中发挥着不同程度的作用.     

p38MAPK在纳洛酮减轻大鼠心肌缺血再灌注损伤中的作用

目的 研究大鼠心肌缺血再灌注损伤后p38 MAPK的变化及纳洛酮对其的影响.方法SD大鼠24只随机均分为假手术组(sham)、缺血再灌注组(IR)、纳洛酮组(Nal).采用结扎左冠状动脉左前降支30 min,再灌注2h制作心肌缺血再灌注模型.观察心电图J点电位的变化;Western Bloting检测p38 MAPK、...     

p38 Mitogen-activated protein kinase up-regulates LPS-induced NF-kappaB activation in the development of lung injury and RAW 264.7 macrophages

Clarification of the key regulatory steps that lead to nuclear factor-kappa B (NF-kappaB) under cellular and pathological conditions is very important. The action of p38 mitogen-activated protein kinase (MAPK) on the upstream of NF-kappaB activation remains controversial. To examine this issue using an in vivo lung injury model, SB203580, a p38 MAPK inhibitor was given intraorally 1h prior to lipopolysaccharide (LPS) treatment (intratracheally). The mice were sacrificed 4 h after LPS treatment. SB203580 substantially suppressed LPS-induced rises in p38 MAPK phosphorylation, neutrophil recruitment, total protein content in bronchoalveolar lavage fluid, and apoptosis of bronchoalveolar cells. Furthermore, SB203580 blocked LPS-induced NF-kappaB activation in lung tissue through down-regulation of serine phosphorylation, degradation of IkappaB-alpha, and consequent translocation of the p65 subunit of NF-kappaB to the nucleus. It is likely that, in cultured RAW 264.7 macrophages, SB203580 also blocked LPS-induced NF-kappaB activation in a dose-dependent manner. SB203580 inhibited LPS-induced serine phosphorylation, degradation of IkappaB-alpha, and tyrosine phosphorylation of p65 NF-kappaB. These data indicate that p38 MAPK acts upstream of LPS-induced NF-kappaB activation by modulating the phosphorylation of IkappaB-alpha and p65 NF-kappaB during acute lung injury. Because LPS-stimulated macrophages may contribute to inflammatory lung injury, the inhibition of the p38 MAPK-mediated intracellular signaling pathway leading to NF-kappaB activation represents a target for the attenuation of lung inflammation and parenchymal damage.     

表没食子儿茶素没食子酸酯对小鼠油酸型肺损伤的保护作用

目的研究表没食子儿茶素没食子酸酯(EGCG)对油酸型小鼠肺损伤的保护作用，并探讨其作用机制。方法以油酸型小鼠为研究对象，利用光镜、电镜观察肺部形态学变化，称重法计算肺指数及湿/干重比(w/d)，应用酶联免疫吸附法(ELISA)检测血清中TNF-α含量及Western blotting法测定肺组织中p38 MAPK的磷酸化程度。结果EGCG可明显减轻油酸组小鼠肺组织病理学改变，降低肺指数及肺湿/干重比，降低血清中炎症因子TNF-α的含量，抑制肺组织中p38 MAPK的磷酸化。结论EGCG有明显的抗油酸型小鼠肺损伤的作用，其作用机制可能与抑制p38 MAPK的磷酸化，并最终导致TNF-α的合成与释放减少有关。     

The role of p38 MAPK in acute paraquat-induced lung injury in rats

Abstract

Context: Paraquat (PQ; 1,1'-dimethyl-4,4'-bipyridinium dichloride) is highly toxic and accounts for a large proportion of the herbicide poisonings seen in clinic. The major cause of mortality is respiratory failure. The p38 mitogen-activated protein kinase (MAPK) signal transduction pathway coordinates various cellular stress responses that have been shown to participate in the pathogenesis of PQ-induced lung injury.

Objective: To evaluate the effect of the specific p38 MAPK inhibitor SB203580 on PQ-induced lung injury and cytokine secretion.

Methods: In groups of 24, rats were treated with PQ, PQ and SB203580 (SB?+?PQ), SB203580 alone (SB) or normal saline (control group). Six rats from each group were euthanized at 1, 3, 5 or 7?d. Pathology of lung specimens was scored through hematoxylin and eosin staining. Edema in the lung was quantified from wet-to-dry weight ratios. p38 and p-p38MAPK proteins were measured via electrochemiluminescent Western blots. tumor necrosis factor (TNF)-alpha and interleukin-1 beta (IL-1β) concentrations in lung specimens and bronchoalveolar lavage fluid (BALF) were quantified via enzyme-linked immunosorbent assay.

Results: The mortality rate of the SB?+?PQ group (16.7%) was significantly lower than that of the PQ group (33.3%; p?<?0.05). The PQ group had significantly higher pulmonary histology scores, wet-to-dry weight ratios and phosphorylated p-p38 MAPK levels, as well as higher IL-1β and TNF-alpha levels in BALF and lung tissues, that did the SB?+?PQ and control groups (p?<?0.05, all).

Conclusion: The data suggest that the p38 MAPK signaling pathway has an important role in regulating the production of IL-1β and TNF-alpha in PQ-induced lung injury in rats.     

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。     

The p38 MAPK inhibitors for the treatment of inflammatory diseases and cancer

Background: The p38 mitogen-activated protein kinase (MAPK) is activated by various pro-inflammatory and stressful stimuli. Mounting evidence suggests that the p38 MAPK signaling cascade is involved in various biological responses other than inflammation such as cell proliferation, differentiation, apoptosis and invasion, suggesting that the p38 MAPK can serve as a potential therapeutic target for the treatment of not only inflammatory diseases but also cancer. Methods: The unique characteristics of p38 MAPK are summarized with regard to activation and function of p38 MAPK signaling cascades. We then discuss the involvement of p38 MAPK in diseases and the implications of the possible therapeutic use of p38 MAPK inhibitors. The p38 MAPK inhibitors that have been used in the in vitro/in vivo systems as well as in the clinical trials are summarized. Results/conclusion: The p38 MAPK plays an important role in key cellular processes related to inflammation and cancer. Understanding the signal transduction mechanisms and gene regulation by p38 MAPK provides useful information in the development of p38 MAPK inhibitors with therapeutic benefits with reduced side effects. In this review, we summarize and present the list of p38 MAPK inhibitors in in vitro/in vivo studies as well as in clinical trials.