重症急性胰腺炎肝损伤的研究进展

重症急性胰腺炎(severeacute pancreatitis,SAP)是临床常见的急腹症,具有发病急、病情重、进展快等特点。常常引起胰外器官损伤,肝脏是主要受损器官之一,其损害的不断加重可导致胰腺炎病情恶化,甚至导致全身炎症反应综合征(systemic inflammatory response syndrome,SIRS)和多器官功能障碍综合征(multiple organ dysfunction syndrome,MCDS)。肝损伤后主要通过影响毒素代谢、释放大量炎症介质等途径进一步加重全身炎症反应,增加病死率。目前对重症急性胰腺炎肝损伤的发病机制尚无统一确切结论,开展对Kupffer细胞、细胞因子、氧化应激对SAP肝损伤的相关细胞信号调控机制研究,既能发现相应的干预靶点,还能为临床治疗提供新思路。文中就重症急性胰腺炎并发肝损伤的病因及发病机制作一综述。     

NF-kB在急性胰腺炎治疗研究中的进展及前景

急性胰腺炎是胰酶激活后引起胰腺组织自身消化所致的急性炎性介质反应,可诱发全身炎性介质反应,并恶化为多脏器功能衰竭,导致患者死亡.核转录因子κB在急性胰腺炎的发展中占据核心地位,它凋节了炎性因子和免疫蛋白的基因表达.本文就基于NF-κB的胰腺炎治疗作一综述.     

NF-κB在急性胰腺炎治疗研究中的进展及前景

急性胰腺炎是胰酶激活后引起胰腺组织自身消化所致的急性炎性介质反应,可诱发全身炎性介质反应,并恶化为多脏器功能衰竭,导致患者死亡.核转录因子κB在急性胰腺炎的发展中占据核心地位,它凋节了炎性因子和免疫蛋白的基因表达.本文就基于NF-κB的胰腺炎治疗作一综述.     

重症急性胰腺炎患者肠内营养的研究进展

重症急性胰腺炎是一种较常见的外科疾病.重症急性胰腺炎患者处于高分解代谢状态,需要加强营养支持.早期肠内营养支持能改善重症急性胰腺炎患者的营养状况,保护肠屏障功能,减少肠道细菌移位调节炎性介质反应,降低住院费用.有关重症急性胰腺炎的肠内营养时机,目前尚有争论.我们现结合近年来国内外相关文献,对重症急性胰腺炎肠内营养治疗的可行性及具体实施予以综述.     

急性胰腺炎分期的沿革

急性胰腺炎是多种病因导致胰酶激活后引起胰腺组织自身消化、水肿、出血甚至坏死的炎性介质反应,是比较常见的一种急腹症,发病率占急腹症的第3～5位.急性胰腺炎病变程度轻重不等,约80％临床病例为轻症,以胰腺水肿为主,病情常呈自限性,预后良好.重症胰腺炎常继发局部及全身并发症,临床病死率为10％～24％,其治疗也多需要借助微创手段或手术干预[1-3].因此,对急性胰腺炎进行恰当的分期,既可以判断病情严重程度,还可以指导临床干预的时机和方式,更重要的是能以此为平台,荟萃分析各医疗机构对于急性胰腺炎的治疗方案和临床结局,从而加深对该疾病的认识,提高治疗水平.     

重症急性胰腺炎并发肝损伤的研究进展

重症急性胰腺炎病情凶险、进展迅速,并发症多、死亡率高,其中并发症肝损伤的发生率高达88.9%。肝损伤后可通过影响毒素代谢、释放大量炎症介质等途径进一步加重全身炎症反应,增加死亡率。文中就重症急性胰腺炎并发肝损伤发病机制中炎症介质、细胞因子、血管活性物质、氧自由基、核因子-κB、细胞凋亡、胰酶的作用机制,以及其诊断、防治作一综述。     

p38MAPK信号传导通路与重症急性胰腺炎

丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)信号传导通路是细胞外信号引起细胞反应的共同通路,其中p38MAPK在介导炎症、应激等细胞反应中最为引人注目.本文综述了p38MAPK这一信号传导通路的结构特征、激活与生物学效应,及其在重症急性胰腺炎发病机制中的作用,旨在为重症急性胰腺炎的诊治研究提供新的思路.     

血液滤过治疗中的营养支持

血液滤过(hemofiltration,HF),特别是连续性血液滤过治疗可大量清除体内炎性介质,对全身炎性反应综合征(SIRS)、多器官功能障碍综合征和多器官功能衰竭(MODS/MOF)、急性重症胰腺炎等疾病的病理生理能够产生积极影响,其应用范围已经从急性肾功能衰竭抢救逐渐扩展到临床常见危重症的治疗上.     

坏死性胰腺炎与感染出血的防治

80%～90%的急性胰腺炎病人仅表现为轻度的水肿性胰腺炎,一般通过非手术治疗可以痊愈;另外15%的病人表现为严重的坏死性胰腺炎.坏死性胰腺炎的自然病程包括两个时期:发病后的14 d内疾病表现为全身炎症反应综合征,炎症介质释放进入循环系统可以引起心肺及肾脏功能衰竭,但由于稳定的诊断程序和重症监护,只有少数病人死于重症急性胰腺炎的全身炎症反应综合征;发病后的2～3周,40%～70%的坏死性胰腺炎会发生胰腺坏死物的感染.由于坏死性胰腺炎合并感染可以诱发多器官功能衰竭,此类病人的死亡率可高达50%,同时坏死组织感染可以浸蚀邻近的血管和组织器官引起出血,加重病情,影响疾病的转归,因此我们应该重视急性坏死性胰腺炎感染出血的防治.     

重症急性胰腺炎并发感染治疗观念的更新

1889年Fitz首次对急性胰腺炎(acute pancreatitis,AP)作出较全面的阐述.一个多世纪以来,人类对重症急性胰腺炎(severe acute pancreatitis,SAP)的认识及治疗取得了巨大的进步. 2002年国际胰腺病学联合会制定的外科治疗急性胰腺炎的循证医学指导建议指出,SAP的病程大致分为两个阶段[1]:第一阶段即病程早期(发病最初14 d内),由于炎性介质的大量释放,以全身炎症反应综合征(systemic inflammatory response syndrome,SIRS)为特点[2];第二阶段即疾病发生2周以后,则以SAP并发感染相关的脓毒症为特点[3].     

Multiple organ failure following severe acute pancreatitis: its clinically patterns and pathogenetic factors]

To detect the clinical course and possible pathogenetic factors of multiple organ failure (MOF) after severe acute pancreatitis (SAP), we investigated retrospectively 70 consecutive patients with SAP for a 16-year period. Two different patterns of MOF were identified: rapid-single phase MOF developed early after SAP attack, and delayed tow-phase MOF developed progressively and sequentially with a lag phase. The clinical course of MOF was characterized by a severely systemic inflammatory response. Clinical variables associated with the evolution of MOF included early circulatory shock, pancreatic sepsis and severe pancreatic necrosis, which might be the leading one. It is suggested that the generalized inflammatory response triggered by the toxic focus seems to be the final common pathway linking SAP with MOF syndrome.     

Sepsis, systemic inflammatory response, and multiple organ dysfunction: the mystery continues

Human sepsis is thought to be systemic inflammatory response syndrome (SIRS) that is activated by invasive infection. The multiple organ dysfunction syndrome (MODS) is the identified failure of critical organ function in patients that have sustained SIRS. Because SIRS and MODS are consequences of the excessive activation of inflammation, extensive research and numerous clinical trials have pursued treatments that would modify the inflammatory response. This presentation reviews the normal local mechanisms of inflammation and provides a theoretical framework for the transition of the inflammatory process to a systemic level. Clinical trials with biomodulators to block or inhibit inflammation have generally failed to improve the outcomes in patients with severe sepsis, septic shock, and MODS. The role of counter-inflammatory signaling and the newer concept of the cholinergic anti-inflammatory pathway are being investigated, and newer hypotheses are focusing upon the balancing of proinflammatory and counter-inflammatory mechanisms as important directions for newer therapies. It is concluded that failure to define novel and effective treatments reflects fundamental gaps in our understanding of inflammation and its regulation.     

肿瘤坏死因子-α、Fas/FasL在急性胰腺炎肝细胞凋亡中的作用

目的 观察大鼠肝枯否细胞(KCs)产生的炎症因子肿瘤坏死因子(TNF)-α、Fas/FasL和核因子(NF)-κB在重症急性胰腺炎(SAP)肝细胞凋亡中的作用,并探讨其与全身炎症反应综合征(SIRS)之间的关系.方法 将50只SD大鼠随机分成3组:(1)假手术对照(SO)组;(2)SAP组;(3)SAP(枯否细胞抑制)组.SAP模型通过胰胆管逆行注射5%牛磺胆酸钠诱导.假手术及造模大鼠均24 h后处死,无菌条件下取肝脏组织,制作石蜡切片,免疫组织化学SP法检测TNF-α、Fas/FasL的表达,原位杂交法检测NF-κB的表达,TUNEL法检测肝细胞凋亡.结果 (1)TNF-α、Fas/FasL和NF-κB在SAP组高表达,阳性率分别为90.0%、85.0%和80.0%,与SO组比较差异均有统计学意义(P<0.05);SAP枯否细胞抑制组它们表达下降,与SAP组比较差异有统计学意义(P<0.05),与SO组比仍然高表达(P<0.05).(2)NF-κB与Fas/FasL及TNF-α的表达均密切相关,相关系数分别为r1=0.78(P<0.05),r2=0.88(P<0.05).(3)肝细胞的凋亡与TNF-α、Fas/FasL和NF-κB的表达呈正相关,相关系数分别为ra=0.72,rb=0.91,rc=0.34,差异均有统计学意义(P<0.05).结论 在SAP时TNF-α能造成肝细胞凋亡并能引起全身炎症反应,NF-κB在SAP时细胞因子基因表达中起中心作用,Fas/FasL在肝细胞凋亡中起重要作用;枯否细胞在SAP时释放炎症因子造成肝损伤引起肝细胞凋亡,抑制枯否细胞能减轻SAP时肝细胞凋亡,从而降低SAP病死率,提高SAP的治愈率.     

Signaling mechanism of TGF-beta1 in prevention of renal inflammation: role of Smad7

TGF-beta has been shown to play a critical role in anti-inflammation; however, the signaling mechanisms of TGF-beta in anti-inflammatory response remains largely unclear. This study reported that mice that overexpress latent TGF-beta1 on skin are protected against renal inflammation in a model of obstructive kidney disease and investigated the signaling mechanism of TGF-beta1 in inhibition of renal inflammation in vivo and in vitro. Seven days after urinary obstruction, wild-type mice developed severe renal inflammation, including massive T cell and macrophage infiltration and marked upregulation of IL-1beta, TNF-alpha, and intercellular adhesion molecule-1 (all P < 0.001). Surprising, renal inflammation was prevented in transgenic mice. This was associated with an increase in latent TGF-beta1 in circulation (a 10-fold increase) and renal tissues (a 2.5-fold increase). Further studies showed that inhibition of renal inflammation in TGF-beta1 transgenic mice was also associated with a marked upregulation of renal Smad7 and IkappaBalpha and a suppression of NF-kappaB activation in the diseased kidney (all P < 0.01). These in vivo findings suggested the importance of TGF-beta-NF-kappaB cross-talk signaling pathway in regulating renal inflammation. This was tested in vitro in a doxycycline-regulated Smad7-expressing renal tubular cell line. Overexpression of Smad7 was able to upregulate IkappaBalpha directly in a time- and dose-dependent manner, thereby inhibiting NF-kappaB activation and NF-kappaB-driven inflammatory response. In conclusion, latent TGF-beta may have protective roles in renal inflammation. Smad7-mediated inhibition of NF-kappaB activation via the induction of IkBalpha may be the central mechanism by which latent TGF-beta prevents renal inflammation.     

胆汁外引流对重症急性胰腺炎大鼠肺部炎症和水肿的疗效及机制研究

目的 探讨胆汁外引流对重症急性胰腺炎大鼠肺部炎症和水肿的疗效与机制。方法 24只雄性Sprague-Dawley（SD）大鼠随机分为4组（n=6）：假手术组（SS组）、重症急性胰腺炎组（SAP组）、SAP+胆汁外引流组（SAP+BTED组）、SAP+BTED+锌原卟啉组（SAP+BTED+ZnPP组）。ZnPP是血红蛋白氧合酶1（HO-1）的特异性阻断剂,抑制HO-1的表达。造模24 h后取肺组织和血液备用。采用Schmidt评分标准对肺组织进行病理评分。采用Western印迹法检测肺组织中HO-1蛋白质水平表达。采用荧光定量RT-PCR法检测肺组织中HO-1、肿瘤坏死因子α（TNF-α）和白细胞介素6（IL-6）mRNA 基因水平的表达。采用ELISA法检测肺组织中髓过氧化物酶（MPO）的含量。计算肺组织干湿比。结果 SAP+BTED组大鼠肺组织Schmidt评分显著低于SAP组大鼠（P<0.05）。BTED使肺组织中TNF-α和IL-6 mRNA 基因表达水平、MPO含量显著低于SAP组大鼠（P<0.05）。SAP+BTED组大鼠干湿比和HO-1表达水平显著高于SAP组大鼠（P<0.05）。当应用ZnPP时,BTED引起大鼠的这些效应则消失。结论 BTED通过HO-1通路减轻SAP大鼠肺部的炎症和水肿。     

STAT3在急性重症胰腺炎大鼠肠黏膜屏障功能障碍中的作用

目的　研究重症胰腺炎(SAP)时大鼠肠上皮细胞凋亡、氧化损伤及凋亡相关蛋白的激活情况。方法　Wistar大鼠4 8只,分为S(假手术)组、C(对照)组、A(急性胰腺炎)组、N(抗氧化剂)组,A组、N组采用胆胰管内逆行注入5 %牛磺胆酸钠诱导大鼠SAP模型,C组注入生理盐水。术后3h、2 4h分批处死大鼠,取胰腺组织行HE染色明确胰腺炎程度;留取血浆检测D 乳酸水平;刮取小肠黏膜检测丙二醛(MDA)、黄嘌呤氧化酶(XO)水平;小肠组织增殖细胞核抗原(PCNA)免疫组化染色;小肠组织TUNEL染色及黏膜DNA琼脂糖凝胶电泳;提取小肠黏膜蛋白行Westernblot检测Bcl 2、Bax、p STAT3表达水平。结果　A组术后3h血浆D 乳酸含量、肠上皮细胞凋亡增加,2 4h最显著(P <0 . 0 1) ,D 乳酸含量、凋亡指数分别为(3 6. 1±0 . 98) μg/ml、(4 5. 3±1. 95 ) % ,二者正相关(r =0 . 5 74 ,P <0 . 0 1) ;A组术后3h氧化应激水平高于其他各组,小肠黏膜MDA含量及XO活力分别为(4 .85±1 .0 5 )nmol/mg、(18. 1±3 .0 3)U/g ;A组术后3h肠黏膜Bax、p STAT3表达增加,2 4h最明显,二者存在相关性(r=0 . 5 91,P <0 .0 1)。结论　急性重症胰腺炎大鼠肠上皮氧化应激导致的细胞凋亡是肠黏膜通透性增加的机制之一;氧化应激可能通过激活STAT3信号传导通路调控凋亡相关蛋白的     

TWEAK Signaling Pathway Blockade Slows Cyst Growth and Disease Progression in Autosomal Dominant Polycystic Kidney Disease

BackgroundIn autosomal dominant polycystic kidney disease (ADPKD), cyst development and enlargement lead to ESKD. Macrophage recruitment and interstitial inflammation promote cyst growth. TWEAK is a TNF superfamily (TNFSF) cytokine that regulates inflammatory responses, cell proliferation, and cell death, and its receptor Fn14 (TNFRSF12a) is expressed in macrophage and nephron epithelia.MethodsTo evaluate the role of the TWEAK signaling pathway in cystic disease, we evaluated Fn14 expression in human and in an orthologous murine model of ADPKD. We also explored the cystic response to TWEAK signaling pathway activation and inhibition by peritoneal injection.ResultsMeta-analysis of published animal-model data of cystic disease reveals mRNA upregulation of several components of the TWEAK signaling pathway. We also observed that TWEAK and Fn14 were overexpressed in mouse ADPKD kidney cysts, and TWEAK was significantly high in urine and cystic fluid from patients with ADPKD. TWEAK administration induced cystogenesis and increased cystic growth, worsening the phenotype in a murine ADPKD model. Anti-TWEAK antibodies significantly slowed the progression of ADPKD, preserved renal function, and improved survival. Furthermore, the anti-TWEAK cystogenesis reduction is related to decreased cell proliferation–related MAPK signaling, decreased NF-κB pathway activation, a slight reduction of fibrosis and apoptosis, and an indirect decrease in macrophage recruitment.ConclusionsThis study identifies the TWEAK signaling pathway as a new disease mechanism involved in cystogenesis and cystic growth and may lead to a new therapeutic approach in ADPKD.     

Vitamin D, the renin-angiotensin system, and insulin resistance

Insulin resistance is characterized by the systemic impairment of insulin action and is usually the result of aging, obesity, chronic inflammation, or another factor that may contribute to the inhibition of the insulin signaling pathway. Insulin resistance is accompanied by defects in lipid metabolism and blood coagulation, hypertension, obesity, and vascular inflammation in a syndrome called syndrome X or metabolic syndrome. Metabolic syndrome is involved in the development of atherosclerosis with consequent cardiovascular complications including acute myocardial infarction, stroke, and vascular disease. Recent data have shown that vitamin D acts as a negative regulator of the renin gene and that vitamin D deficiency is followed by increased renin-angiotensin II expression. The link between the insulin signaling pathway/insulin resistance and the renin-angiotensin system has been well documented in previous studies. The present review focuses on disorders characterized by a reduction in vitamin D concentration or its receptor function and the development of insulin resistance or metabolic syndrome, and discusses also possible therapeutic interventions.