Role of p38 mitogen-activated protein kinase in ozone-induced airway hyperresponsiveness and inflammation

Ozone is a potent oxidant and causes airway hyperresponsiveness and neutrophilia. To determine the role of p38 mitogen-activated protein kinase (MAPK) activation, we studied the effect of a p38α inhibitor SD-282 (Scios Inc, Fremont, CA USA) on ozone-induced airway hyperresponsiveness and neutrophilia. Balb/c mice received SD-282 (30 or 90 mg/kg i.p) or vehicle 1 h before exposure to either ozone (3 ppm, 3 h) or air. Three hours after exposure, lungs were analysed for cytokine levels and bronchoalveolar lavage was performed. Another set of mice were dosed 6 h after exposure and 1 h before assessing airway hyperresponsiveness. SD-282 (90 mg/kg) significantly inhibited ozone-induced airway hyperresponsiveness (− LogPC₁₅₀: SD-282: − 1.73 ± 0.14 vs. vehicle: − 0.99 ± 0.15, P < 0.05). Bronchoalveolar lavage neutrophil numbers were time-dependently increased in vehicle-dosed, ozone-exposed mice, greatest at 20–24 h after exposure. SD-282 (30 and 90 mg/kg) significantly inhibited ozone induced neutrophil numbers at 3 h and 20–24 h after ozone SD-282 significantly inhibited ozone-induced increases in phosphorylated p38 MAPK expression, and in cyclooxygenase-2 (COX-2), interleukin-6 (IL-6) and IL-1β but not MIP-1α gene expression. We conclude that p38 MAPK is involved in ozone-induced airway hyperresponsiveness and lung neutrophilia. Inhibition of p38 MAPK with small molecule kinase inhibitors may be a means of reducing ozone-induced inflammation and airway hyperresponsiveness.     

Involvement of p38 mitogen-activated protein kinase in PLL-AGE-induced cyclooxgenase-2 expression

In the present study, murine RAW 264.7 macrophages were incubated with poly-L-lysine-derived advanced glycosylation end products (PLL-AGEs) to examine cyclooxygenase-2 protein expression. Treatment of RAW 264.7 cells with PLL-AGEs caused the dose-dependent expression of cylooxygenase-2 but not cylooxygenase-1 and an increase in cylooxygenase activity. Increased cylooxygenase-2 expression was seen at 6 h and reached a maximum at 24 h. The tyrosine kinase inhibitor, genistein, and the p38 mitogen-activated protein kinase (MAPK) inhibitor, [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole] (SB 203580), inhibited PLL-AGE-induced cylooxygenase-2 expression, while the Ras inhibitor, FPT inhibitor II, and the MAP kinase kinase inhibitor, (2'-amino-3'-methoxyflavone) (PD 98059), had no effect on PLL-AGE-induced cylooxygenase-2 expression. Incubation of RAW 264.7 cells with PLL-AGEs resulted in activation of p38 MAPK, and this activation was suppressed by genistein and SB 203580. Taken together, our results suggest that activation of protein tyrosine kinase and p38 MAPK is involved in AGE-induced cyclooxygenase-2 expression in RAW 264.7 macrophages.     

地塞米松抑制哮喘大鼠肺组织p38蛋白激酶的表达

目的:探讨支气管哮喘大鼠肺组织p38蛋白激酶(p38 MAPK)表达的变化以及地塞米松对其影响.方法:复制大鼠哮喘模型,随机分成3组:正常对照组、哮喘对照组和地塞米松(DEX)干预组.分别采用酶联免疫吸附法(ELISA)和蛋白质印迹检测支气管肺泡灌洗液(BALF)IL-5含量和肺组织磷酸化p38 MAPK表达的变化,并观察气道阻力、BALF中EOS计数以及肺组织病理学变化.结果:哮喘对照组大鼠肺组织磷酸化p38 MAPK表达水平及气道阻力、BALF中IL-5含量和EOS计数均较正常对照组显著增加(P＜0.01);DEX干预组上述指标较哮喘对照组显著降低(P＜0.01),肺组织病理学损伤程度明显减轻.肺组织磷酸化p38 MAPK表达水平与气道阻力、BALF中IL-5含量和EOS计数之间分别呈显著正相关(r=0.77、0.63、0.65,P＜0.01).结论:p38 MAPK可能参与了支气管哮喘的发病过程.DEX对哮喘的治疗作用至少部分与抑制磷酸化p38 MAPK的表达有关.     

New inhibitors of p38 kinase

In the short time since the 1994 report that the molecular target for the 4-aryl-5-pyridin-4-yl imidazole class of cytokine suppressive anti-inflammatory agents (exemplified by SB-203580) was the human homologue of the stress-induced kinase p38, there has been an explosion of patent literature disclosing related inhibitor analogues. These compounds fall into the general structural class of vicinal aryl/pyridin-4-yl heterocycles. Compounds of this class have been claimed as p38 inhibitors or inhibitors of cytokine biosynthesis. Since cytokines mediate a variety of disease processes, inhibition of cytokine biosynthesis has potential as a therapeutic target. The SAR of binding to p38 for this intensively studied class of compounds is now understandable on the basis of recent x-ray crystallographic and mutagenesis studies. The inhibitors can be sub-classified based upon a variety of structural characteristics. Recently new inhibitor structural classes have been disclosed. Although distinctly different structurally, several of these new compounds appear to bind with the same key interactions as the vicinal aryl/pyridin-4-yl heterocycles.     

通心络胶囊对糖尿病小鼠视网膜 p38 MAPK信号通路的影响

目的：观察通心络胶囊对糖尿病小鼠视网膜p38丝裂原活化蛋白激酶（ p38 MAPK）信号通路的影响,探讨其视网膜保护作用的可能机制。方法 KK／Upj-Ay小鼠40只随机分为糖尿病模型组、通心络低、中、高剂量组,每组10只,另设C57BL／6（C57）小鼠10只作为对照组。按照分组给予不同剂量处理因素,疗程3个月,观察体质量,测定空腹血糖（FBG）,取眼球行HE 染色,Western-blot 检测视网膜p38MAPK、JNK、ERK 总蛋白及磷酸化p38MAPK、JNK、ERK（ p-p38MAPK、p-JNK、p-ERK）的表达。结果与对照组比较,模型组体质量、FBG及p-p38MAPK、p-JNK、p-ERK表达均显著增高,通心络胶囊能够减轻视网膜病理损伤,降低p-p38 MAPK表达（ P ＜0?．05）,而不影响体质量、FBG及p-JNK、p-ERK表达（ P ＞0．05）;且各组p38MAPK、JNK、ERK 总蛋白表达差异无统计学意义（ P ＞0．05）。结论 p38 MAPK信号通路可能参与了糖尿病视网膜损害的发生发展。通心络胶囊可减轻糖尿病小鼠视网膜病理损伤,其机制可能与降低p38MAPK蛋白磷酸化水平有关。     

In vitro metabolite identification of ML3403, a 4-pyridinylimidazole-type p38 MAP kinase inhibitor by LC-Qq-TOF-MS and LC-SPE-cryo-NMR/MS

Prediction of the metabolic profile of a potential new drug is recommended at an early stage in industrial drug discovery process to determine whether or not any potentially reactive or toxic metabolites are formed. In the present study, we investigated the in vitro metabolism of ML3403 ({4-[5-(4-Fluorophenyl)-2-methylsulfanyl-3H-imidazol-4-yl]-pyridin-2-yl}-(1-phenylethyl)-amine), a potent and selective p38 MAP kinase inhibitor using mouse liver microsomes. The combination of LC-ESI-Qq-TOF (tandem quadrupole time-of-flight)-MS (mass spectrometer) and LC-SPE (solid phase extraction)-cryo-NMR (nuclear magnetic resonance)/MS at 600?MHz has been applied for comprehensive and straightforward structural elucidation of ML3403 metabolites. It was possible to determine the metabolic profile of ML3403, revealing eight different metabolites formed by N-desalkylation, S-mono- and di-oxidation, aliphatic hydroxylation and pyridine-N-oxidation. The ESI-Qq-TOF-MS data yielded elemental compositions of all metabolites and their fragments by evaluation of the accurate mass and isotopic pattern information using the sigma-fit algorithm. Evaluation of 2D NMR spectra obtained from pure ML3403 an its major metabolite ML3603 allowed the unequivocal assignment of the resonances in 1D NMR spectra obtained directly from the microsomal incubation by LC-SPE-cryo-NMR/MS. The presented method significantly decreases the time required for a complete structural assignment of metabolites from microsomal in vitro assays.     

Endothelin-1 induces contraction via a Syk-mediated p38 mitogen-activated protein kinase pathway in rat aortic smooth muscle

Although spleen tyrosine kinase (Syk) has crucial roles in various cells, its function on vascular smooth muscle contraction has not been determined. In the present study, we performed experiments to determine if Syk contributes to the endothelin-1 (ET-1)-mediated contraction in rat aortic smooth muscle. ET-1-induced contraction of aortic strips was inhibited by piceatannol, PD98059, and SB203580, inhibitors of Syk, extracellular signal-regulated kinase 1/2 (ERK1/2), and p38 mitogen-activated protein kinase (MAPK), respectively. Piceatannol also attenuated high K(+)-induced contraction. ET-1 dose-dependently enhanced the activity of Syk and this was inhibited by piceatannol in both rat aortic strip and rat aortic smooth muscle cells. The phosphorylation of p38 MAPK and heat shock protein 27 (HSP27), but not that of ERK1/2, in response to ET-1 was inhibited by both piceatannol and SB203580. These results suggest that Syk may play an important role in the regulation of aortic smooth muscle contraction induced by ET-1, which may be mediated by the p38 MAPK/HSP27 signaling pathway.     

Anti-inflammatory effects of LASSBio-998, a new drug candidate designed to be a p38 MAPK inhibitor, in an experimental model of acute lung inflammation

We investigated the effects of LASSBio-998 (L-998), a compound designed to be a p38 MAPK (mitogen-activated protein kinase) inhibitor, on lipopolysaccharide (LPS)-induced acute lung inflammation in vivo. BALB/c mice were challenged with aerosolized LPS inhalation (0.5 mg/ml) 4 h after oral administration of L-998. Three hours after LPS inhalation, bronchoalveolar lavage fluid was obtained to measure the levels of the proinflammatory cytokines TNF-α (tumor necrosis factor-α) and IL-1 (interleukin-1) and the chemokines MCP-1 (monocyte chemoattractant protein-1) and KC (keratinocyte chemoattractant). In addition, neutrophil infiltration and p38 MAPK phosphorylation was measured. L-998 inhibited LPS-induced production of TNF-α and IL-1β and did not alter KC and MCP-1 levels. Furthermore, L-998 also significantly decreased neutrophil accumulation in lung tissues. As expected, L-998 diminished p38 MAPK phosphorylation and reduced acute lung inflammation. Inhibition of p38 MAPK phosphorylation by L-998 was also demonstrated in LPS-challenged murine C57BL/6 peritoneal macrophages in vitro, with concentration-dependent effects. L-998 suppressed LPS-induced lung inflammation, most likely by inhibition of the cytokine-p38 MAPK pathway, and we postulate that L-998 could be a clinically relevant anti-inflammatory drug candidate.     

Involvement of p38 mitogen-activated protein kinase in the regulation of platelet-derived growth factor induced cell migration

The aim of this study was to investigate the role of p38 mitogen-activated protein kinase (MAPK) in cell migration induced by platelet-derived growth factor (PDGF). Western blot was performed to detect the phosphorylation of p38 in NIH3T3 cells treated with PDGF. A Transwell cell migration system was used to determine the effects of PDGF treatment on the migration of NIH3T3 cells and the influence of p38 deficiency on this process in a p38 gene knockout (p38^−/−) mouse embryonic fibroblast cell line. On the stimulation of PDGF, the migration of NIH3T3 cells was significantly increased (P < 0.001) compared to the control and p38 MAP kinase was simultaneously phosphorylated. Furthermore, the PDGF-induced cell migration was significantly blocked in p38 gene knockout (p38^−/−) mouse embryonic fibroblasts (MEFs) (P < 0.001) as compared with the wild type cells (p38^+/+). p38 MAPK plays an important role in the regulation of cell migration induced by PDGF. Translated from Medical Journal of Chinese People’s Liberation Army, 2007, 32(3): 205–207 [译自: 解放军医学杂志]     

腰椎间盘退变组织中P-p38 MAPK的表达

目的探讨腰退变椎间盘组织中丝裂原活化蛋白激酶(P-p38 MAPK)的表达。方法应用免疫组织化学方法和ELISA检测10例正常腰椎间盘组织和30例腰退变椎间盘组织中P-p38MAPK的表达量。结果腰退变椎间盘组织中P-p38 MAPK的表达量明显高于正常腰椎间盘组织[(0.657±0.086)μg/L vs.(0.165±0.024)μg/L](P<0.05)。结论退变椎间盘中P-p38 MAPK含量明显高于正常椎间盘组织,提示其可能参与了腰椎间盘的退变过程。     

Rapamycin reduces orofacial nociceptive responses and microglial p38 mitogen-activated protein kinase phosphorylation in trigeminal nucleus caudalis in mouse orofacial formalin model

The mammalian target of rapamycin (mTOR) plays a role in various cellular phenomena, including autophagy, cell proliferation, and differentiation. Although recent studies have reported its involvement in nociceptive responses in several pain models, whether mTOR is involved in orofacial pain processing is currently unexplored. This study determined whether rapamycin, an mTOR inhibitor, reduces nociceptive responses and the number of Fos-immunoreactive (Fos-ir) cells in the trigeminal nucleus caudalis (TNC) in a mouse orofacial formalin model. We also examined whether the glial cell expression and phosphorylated p38 (p-p38) mitogen-activated protein kinases (MAPKs) in the TNC are affected by rapamycin. Mice were intraperitoneally given rapamycin (0.1, 0.3, or 1.0 mg/kg); then, 30 min after, 5% formalin (10 µl) was subcutaneously injected into the right upper lip. The rubbing responses with the ipsilateral forepaw or hindpaw were counted for 45 min. High-dose rapamycin (1.0 mg/kg) produced significant antinociceptive effects in both the first and second phases of formalin test. The number of Fos-ir cells in the ipsilateral TNC was also reduced by high-dose rapamycin compared with vehicle-treated animals. Furthermore, the number of p-p38-ir cells the in ipsilateral TNC was significantly decreased in animals treated with high-dose rapamycin; p-p38 expression was co-localized in microglia, but not neurons and astrocytes. Therefore, the mTOR inhibitor, rapamycin, reduces orofacial nociception and Fos expression in the TNC, and its antinociceptive action on orofacial pain may be associated with the inhibition of p-p38 MAPK in the microglia.     

p38 MAPK及其抑制剂在子宫内膜异位症中的作用

子宫内膜异位症(EMs)是与炎症有关的雌激素依赖性疾病。p38丝裂原活化蛋白激酶(p38MAPK)受性激素、炎症因子等因素的激活,在细胞凋亡、增殖、炎症、应激等多种细胞反应中起着重要的作用,并直接参与子宫内膜异位症发生发展过程的调控。p38MAPK信号转导通路在性激素和炎症之间的特殊调节作用,将有助于更好地理解子宫内膜异位症错综复杂的病理假说。p38MAPK抑制剂在子宫内膜异位症的研究中发挥重要作用,且前景广阔。在信号通路水平上阻断和调控p38MAPK的表达和活性,有望成为防治子宫内膜异位症的新策略。     

氯沙坦对糖尿病大鼠肾脏结构、功能及肾组织p38MAPK的影响

目的　探讨特异性血管紧张素ⅡⅠ型受体拮抗剂氯沙坦对糖尿病大鼠肾脏结构、功能的保护机制及p38MAPK信号转导通路对此过程的作用。方法　♂Wister大鼠行右肾切除术 2wk后 ,随机分为 3组 ,右肾切除对照组、糖尿病组 ,氯沙坦治疗组。腹腔注射链脲佐菌素 (STZ ,6 5mg·kg-1)诱发糖尿病模型 ,氯沙坦 4 0mg·kg-1·d-1灌胃。分别于注射STZ后 4wk后各组选取 6只大鼠 ,收集尿液 ,测定尿蛋白(Upro) ,尿肌酐 (Ucr) ;股动脉放血分离血清 ,测定血糖(Glu)、血尿素氮 (BUN) ,血肌酐 (Scr)并计算肌酐清除率(Ccr)。免疫组化检测肾皮质磷酸化p38蛋白激酶 (p p38MAPK)及磷酸化cAMP反应元件结合蛋白 (p CREB)的表达特征 ,纤维粘连蛋白 (fibronectin ,FN )及层粘连蛋白(laminin ,LN)的表达 ,应用图像分析系统进行半定量分析。Westernblot及流式细胞术定量检测 p p38MAPK和 p CREB蛋白的表达。结果　与对照组相比 ,4wk时糖尿病模型组肾小球基底膜轻度增厚 ,细胞外基质 (ECM )增多 ,系膜区扩大 ,肾脏肥大指数升高 ,肾功能轻度受损 ,p p38MAPK、p CREB、FN及LN表达明显升高 ;而与糖尿病模型组相比 ,氯沙坦组肾脏结构 ,功能及各指标的表达有不同程度的降低。结论　氯沙坦对糖尿病大鼠肾脏结构和功能具有保护作用 ,可能是通过调     

Simultaneous determination of a p38 MAP kinase inhibitor and its amide hydrolyzed metabolite in Cynomolgus monkey plasma by LC-MS/MS, and its application to a toxicokinetic study

A LC-MS/MS method was developed for the determination of a p38 MAP kinase inhibitor (Compound I) and its amide hydrolyzed metabolite (M7) in Cynomolgus monkey plasma over the concentration range of 1.00-1000ng/mL. Stable isotope labeled compounds (d(3)-Compound I and d(3)-M7) were used as internal standards (IS). Samples were prepared using protein precipitation in the 96-well format with a 30μL plasma sample volume. Chromatographic separation was performed with reversed-phase liquid chromatography on a Varian Monochrom C(18) (100mm×2.00mm, 5μm) analytical column. The mobile phases were 5mM ammonium formate in acetonitrile/water (95/5, v/v) pH 7.0 and 5mM ammonium formate in acetonitrile/water (5/95, v/v) pH 7.0. Gradient elution, at a flow rate of 550μL/min, was used to separate Compound I and M7. Positive atmospheric pressure chemical ionization was utilized with detection by multiple reaction monitoring (MRM). Total run time was about 3.2min. This method was validated following the current Food and Drug Administration (FDA) guidance for bioanalytical method validation. The intra- and inter-day precision (% CV) and accuracy (% bias) at all concentrations tested were below 15% for both analytes. The mean recoveries for Compound I, M7, d(3)-Compound I, and d(3)-M7 were 106%, 107%, 108% and 105%, respectively. The method was successfully applied to support a GLP toxicokinetic study in Cynomolgus monkeys after oral administration of Compound I. A total of 48 samples (～12.5% of the total number of samples) were selected for incurred sample reanalysis (ISR). The % difference between the reassay concentrations and the original concentrations were all less than 20% of their mean values and met the acceptance criteria for ISR.     

p38 Inhibitors: beyond pyridinylimidazoles

Since the discovery of p38 mitogen-activated protein kinase (MAPK) as a potential intracellular modulator that regulates the crucial biosynthesis and functions of pro-inflammatory cytokines (e.g., TNF-α and IL-1β), numerous groups have disclosed their efforts to find small-molecule p38 inhibitors as potential therapeutic agents for the treatment of inflammatory diseases such as rheumatoid arthritis (RA), Crohn’s disease (CD) and psoriasis. Although greater selectivity has been achieved with these newly disclosed series, their safety profile after chronic treatment remains a question to be answered in human clinical trials. The p38 inhibitors that have been disclosed in the recent patent literature (2000 – 2004) are summarised here. These compounds will be classified into series based on their intrinsic structures and by their binding modes, as revealed by either crystallography or molecular modelling.     

穴位注射黄芪对哮喘大鼠p38MAPK及Th1/Th2因子的影响

目的 观察哮喘大鼠肺组织p38蛋白激酶（p38 MAPK）和Th1/Th2类细胞因子（IFN-γ/IL-4）表达的变化,探讨穴位注射黄芪对其影响及可能机制.方法 SD大鼠随机分成4组（10只/组）,即正常对照组、哮喘模型组、地塞米松组和黄芪穴位注射组.应用卵蛋白（OVA）致敏激发法制备哮喘大鼠模型,分别采用酶联免疫吸附法（ELlSA）和蛋白质印迹检测血清中IL-4、IFN-γ含量和磷酸化p38 MAPK的变化,并观察肺组织病理学改变.结果 ①与正常对照组相比,哮喘模型组大鼠肺组织磷酸化p38 MAPK表达水平升高,血清IL-4含量升高、IFN-γ含量降低（P＜0.05）;②与哮喘模型组相比,黄芪穴位注射组大鼠血清IL-4含量、磷酸化p38 MAPK表达水平降低,血清IFN-γ含量升高（P＜0.05）;③黄芪穴位注射组与地塞米松组比较血清IL-4含量升高,IFN-γ含量降低,磷酸化p38 MAPK表达水平降低,差异有统计学意义（P＜0.05）;④在肺组织病理学方面,穴位注射黄芪注射液能明显改变哮喘大鼠病理变化;⑤肺组织磷酸化p38 MAPK的表达与IL-4比较呈显著正相关（r=0.596,P＜0.05）,与IFN-y比较呈显著负相关（r=-0.634,P＜0.05）.结论 p38 MAPK可能调控支气管哮喘的发病机制;穴位注射黄芪与糖皮质激素比较,对哮喘大鼠具有保护作用,偏重不一,其治疗作用与抑制p38 MAPK磷酸化、下调IL-4、上升IFN-γ表达水平有关.     

New small-molecule inhibitors of mitogen-activated protein kinase kinase

Background: Overexpression of the Ras/Raf/MEK/ERK (extracellular-signal-regulated kinase) pathway is associated with the formation, progression and survival of tumours and has also been implicated in a diverse range of therapeutic areas such as arthritis, organ transplant rejection, asthma and developmental disorders. One approach to down regulation of this pathway is through the inhibition of mitogen-activated protein kinase kinase 1/2 (MEK1/2). Objective: The importance of the mitogen-activated protein kinase (MAPK) pathway, MEK1/2 as a therapeutic target and early MEK1/2 inhibitors is discussed, followed by an overview of recent patent activity in the area. Methods: The patent literature was searched for inhibitors of MEK1/2 published within the last three years; these results are described. Other relevant publications that provide further insight into the discovery and development of these compounds are also discussed. Conclusion: The determination of a crystal structure with inhibitor bound has allowed the design of exquisitely selective and potent inhibitors of MEK1/2. Several allosteric inhibitors have advanced to clinical trial and shown some efficacy in cancer as single agents, but the future application of MEK1/2 inhibitors is likely to be either in combination with other therapies or in disorders which are genetically defined as being dependent on the MAPK pathway.     

普伐他汀对高糖培养肾小球系膜细胞P38促分裂原活化蛋白激酶信号通路的影响

目的探讨普伐他汀对高糖培养大鼠肾小球系膜细胞(MC)p38促分裂原活化蛋白激酶(p38MAPK)信号传导通路的影响。方法大鼠MC分别培养在正常糖5.5mmol·L-1(正常对照组),高糖25mmol·L-1(高糖组),葡萄糖25mmo.lL-1+p38MAPK特异性抑制剂SB203580(SB)10μmol.L-1,及葡萄糖25mmol·L-1+普伐他汀(PV)100μmol·L-1。ELISA法检测培养上清液Ⅳ型胶原(Col-Ⅳ)、纤连蛋白(FN)含量;Phospho-ELISA法检测胞浆及胞核内p38MAPK和磷酸化p38MAPK(p-p38MAPK)蛋白的表达;以及RT-PCR法检测p38MAPK mRNA的表达。结果与正常对照组比较,高糖组MC合成基质蛋白Col-Ⅳ,FN增多;胞浆及胞核内p-p38MAPK的表达增加。SB或PV干预能部分或完全逆转这一变化。与高糖组比较,SB干预后,上清液中Col-Ⅳ含量下降〔48h:(21.19±3.21)vs(16.75±1.93)μg·L-1,n=6,P<0.05〕、FN减少〔48h:(13.47±1.27)vs(12.01±0.85)μg·L-1,n=6,P<0.05〕;胞浆及胞核内p-p38MAPK表达显著下调。PV干预后,上清液中Col-Ⅳ含量下降〔48h:(21.19±3.21)vs(14.97±3.04)μg·L-1,n=6,P<0.05〕、FN减少〔48h:(13.57±1.27)vs(11.99±0.98)μg·L-1,n=6,P<0.05〕;胞核内p-p38MAPK表达显著下调,但对胞浆内p-p38MAPK的表达则无显著影响。各组总p38MAPK蛋白水平及p38MAPK mRNA表达则没有明显改变。结论PV能够显著下调高糖培养的MC胞核内p38MAPK信号传导通路的活化,进而减少胞外基质合成,达到对糖尿病肾病的治疗作用。     

Role of p38 mitogen-activated protein kinase in cardiac remodelling

BACKGROUND AND PURPOSE: Mitogen-activated protein kinases (MAPK) are centrally involved in several mechanisms important for heart failure such as apoptosis, activation of inflammatory responses and cell proliferation. We therefore evaluated the effect of the selective p38 MAPK inhibitor SB 239063 on progression of left ventricular remodelling after myocardial infarction (MI) in rats. EXPERIMENTAL APPROACH: Rats were treated for 9 weeks with placebo or SB 239063 by gavage (15 mg kg(-1)) twice daily starting 7 days after ligation of the left anterior descending artery. Serial transthoracic echocardiography was performed at days 7, 36 and 70. KEY RESULTS: Over the 9 weeks, mortality was not different between the groups. On echocardiography, animals after myocardial infarction exhibited significant left ventricular dilatation as expected (week 10, end-systolic diameter, placebo sham 5.21+/- 0.34 vs. placebo MI 8.44+/- 0.57 mm). However, there was no difference between placebo and SB 239063-treated rats (week 10, end-systolic diameter, SB MI 7.76+/- 0.74 mm, not significantly different from placebo MI). Haemodynamics changed accordingly. Moreover, SB 239063 had no effect on left ventricular hypertrophy. Treatment with SB 239063 significantly reduced cytokine expression of tumour necrosis factor and interleukin-1beta after myocardial infarction. However, collagen content was not influenced by the treatment. CONCLUSION: Despite a reduction of inflammation, treatment with the p38 inhibitor SB 239063 does not affect cardiac remodelling and cardiac function when treatment is started 7 days after myocardial infarction.