ANGPTL4基因在重症急性胰腺炎肺损伤大鼠肺微血管内皮细胞中的表达和作用
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摘要
目的：重症急性胰腺炎（severe acute pancreatitis, SAP）具有发病急剧，病情凶险等特点，早期即可出现急性肺损伤（acute lung injury, ALI）并导致死亡。而其确切的发病机制较为复杂，有研究报道以细胞因子和炎症介质的过度释放而引起的肺微血管内皮细胞通透性增加导致的肺水肿是急性肺损伤的主要病理改变。因此，肺微血管内皮细胞的通透性的改变及其机制探讨尤为重要。血管生成素样蛋白4（Angptl4）是一个重要的调节糖代谢、脂代谢和胰岛素敏感性的蛋白,目前被确定为过氧化物体增殖体激活受体γ血管生成素相关蛋白（PPAR-γ）的靶基因。目前的资料显示，Angptl4基因除了参与脂肪脂质代谢外，其在肿瘤方面的作用的研究较多，但关于Angptl4在炎症反应中的作用特别是其在重症急性胰腺炎导致的肺损伤中的作用的研究鲜有报道。
由于SAP诱发ALI的机制复杂，涉及到胰酶激活、过氧化损伤、全身炎症反应、内毒素血症等多个方面，故目前尚未有一种特效的治疗方法，综合治疗方法仍为首选。有研究发现，Angptl4基因在全身炎症反应中可能对集体具有保护性作用。本课题通过观察Angptl4在重症急性胰腺炎大鼠肺组织及肺微血管内皮细胞上的表达变化，以及应用药物干预及转染技术观察其在炎症反应过程中的自身变化及对下游炎症因子的影响。本实验试图从急性胰腺炎肺损伤的动物模型及更直接的向肺微血管内皮细胞中转染Angptl4基因以致其高表达，并应用脂多糖刺激，观察其变化特点，及炎症因子和细胞形态的改变。旨在从更全面的新角度探讨SAP诱发ALI的发病机制，为有效防治急性胰腺炎肺损伤提供新的方法和实验依据。
方法：实验一：健康雄性（Spraghe-Dawley，SD)大鼠32只，体重180g-220g，随机分为4组:假手术组(CON), SAP模型组(SAP)，罗格列酮治疗组(ROSI/ROZ)，GW9662治疗组(GW9662)每组8只。SAP动物模型采用1.5%的去氧胆酸钠溶液(lml/kg)逆行胰胆管注射法。罗格列酮治疗组（剂量:5mg/kg）及GW9662治疗组（剂量5mg/kg）于造模后10分钟立即静脉注射药物一次。假手术组开腹后，仅轻翻动胰腺后关腹。模型建立24h后，各组大鼠麻醉后开腹，取胰腺、肺组织及动静脉采血。观察胰腺和肺组织的病理改变，采用全自动生化分析仪行血气分析，并对血淀粉酶的含量进行测定，双抗体夹心法(enzyme linked immuno sorbent assay，ELISA)检测血清TNF-α和RAF-1含量，采用反转录-聚合酶链式反应法（RT-PCR）测定肺组织中Angptl4和PPAR-γmRNA的表达，Western-Blot法测定肺组织中Angptl4和PPAR-γ蛋白的表达。HE染色法观察肺组织及胰腺组织的病理改变，免疫组化法检测肺微血管壁上VEGF的表达和胰腺细胞的BCL-2的表达。
实验二：应用Pricells公司提供的大鼠肺微血管内皮细胞系、经鉴定后，于第三代开始用于实验。培养大鼠肺微血管内皮细胞后将其分为4组：正常组，LPS（100ng/mL）刺激组，LPS+罗格列酮（50g/mL）组，LPS+GW9662（50g/mL）组，药物作用24h后，以Realtime-PCR和Western bloting法检测肺微血管内皮细胞中Angptl4的表达。应用脂多糖LPS（100ng/ml）分别刺激大鼠肺微血管内皮细胞6h,12h,24h,以MTT检测法观察细胞存活情况，并应用罗丹明-鬼笔环肽染色标记细胞骨架F-actin蛋白，观察大鼠肺微血管内皮细胞的形态结构学改变。
实验三：基于实验一与实验二，使用美国Sourcebioscience公司提供的大鼠Angptl4基因为模板，通过重组构建pcDNA3.1-eGFP-Angptl4质粒，用于转染大鼠肺微血管内皮细胞。转染48h后经LPS作用24h，以Realtime-PCR和Westernbloting法检测肺微血管内皮细胞中Angptl4表达变化。培养大鼠肺微血管内皮细胞后将其分为8组：正常组，LPS（100ng/mL）刺激组，LPS+罗格列酮（50g/mL）组，LPS+GW9662（50g/mL）组，pcDNA3.1–eGFP组，pcDNA3.1–Angptl4-eGFP组，LPS+pcDNA3.1-eGFP组，LPS+pcDNA3.1-Angptl4-eGFP组。Western bloting法检测细胞信号通路上的p-MEK1/2, p-AKT/AKT, Bax, casapase8,9蛋白的变化，并ELISA法检测TNF-α含量变化。再次应用罗丹明-鬼笔环肽染色标记细胞骨架F-actin蛋白，观察大鼠肺微血管内皮细胞的形态结构学改变。
结果：1．实验一：与假手术组相比，SAP组血清淀粉酶、TNF-α含量、肺组织中Angptl4mRNA和蛋白表达水平明显增高，而PPAR-γmRNA基因和蛋白的表达却明显降低，胰、肺组织病理损伤明显，具有明显的统计学意义（P<0.05）。与SAP组相比罗格列酮药物干预组的胰、肺病理损伤较轻，血清淀粉酶及TNF-α和RAF-1含量降低，肺组织Angptl4和PPAR-γ表达水平明显上升，肺血管内皮细胞上的VEGF和胰腺腺泡上的BCL-2明显受抑制。而GW9662干预组却不同程度降低，具有显著的统计学意义（P<0.05）。
2．实验二：CD31抗体鉴别原代大鼠肺微血管内皮细胞。LPS组（100ng/mL）刺激24h后Angptl4蛋白表达增加，而同样应用Angptl4促进剂罗格列酮后，Angptl4蛋白表达增加明显（P<0.01）。并且LPS组培养基的TNF-α水平升高。而应用罗格列酮后TNF-α水平下降明显，具有显著差异（P<0.01）。而单纯应用LPS刺激后，24h细胞减少达到高峰。罗格列酮组细胞存活率明显高于GW9662组。（P<0.01）罗丹明-鬼笔环肽和DAPI分别染色细胞骨架F-actin和细胞核后，激光共聚焦显微镜下观察单纯LPS刺激组，细胞核周围的胞骨架解聚，而罗格列酮应用组的细胞核中央部分解聚明显减少，细胞形态稳定。（P<0.05）
3．实验三：pcDNA3.1-eGFP-Angptl4质粒转染48小时后Realtime-PCR和Westernbloting检测肺微血管内皮细胞中Angptl4表达明显比pcDNA3.1-eGFP转染组增加。（P<0.01）与实验一、二的结果一致，LPS（100ng/mL）刺激后，肺微血管内皮细胞存活率随时间增加而减少，24h达到高峰（P<0.01）转染目的基因后，大鼠肺微血管内皮细胞存活延长。凋亡通路的促凋亡因子Bax蛋白与casapase8,9蛋白在LPS组明显增加，而在应用罗格列酮组与转染目的基因组明显降低（P<0.01）。LPS+pcDNA3.1-eGFP-Angptl4组凋亡通路上的调节蛋白p-AKT/AKT和p-mek1/2蛋白明显下调。罗丹明-鬼笔环肽和DAPI分别染色细胞骨架F-actin和细胞核后，激光共聚焦显微镜下观察转染目的组的细胞核中央部分解聚明显减少，细胞形态稳定。（P<0.05）
结论：Angptl4是在正常的肺微血管内皮细胞低表达的一种分泌性蛋白，其功能是参与脂质及脂肪的代谢，Angptl4对细胞膜的通透性影响较大，所以其对肺微血管内皮细胞的稳定尤其重要。实验一的结果得出，随着胰腺炎肺损伤的出现、肺水肿的加重，肺组织Angptl4的mRNA表达和蛋白表达水平上调，说明了Angptl4参与了急性炎症反应。而其上游基因PPAR-γ的降低，反应了Angptl4参与的炎症反应并不是直接单靠上游靶基因PPAR-γ的影响。实验二的模仿急性肺损伤的细胞实验结果与动物实验一致，应用罗格列酮药物可以减轻LPS刺激肺微血管内皮细胞导致的肺损伤。实验三进一步应用转染Angptl4基因，观察其对肺微血管内皮细胞的保护作用及在炎症损伤情况下对炎症因子的影响作用。
SAP诱发ALI的发病机制较为复杂，目前研究多认为是由于炎症介质和细胞因子的过度释放，增加了肺微血管内皮细胞的通透性而发生的肺水肿，因此本文选择肺微血管内皮细胞作为靶细胞进行研究。在炎症反应过程中TNF-α是重要的介质之一，它的出现及表达水平高低可被作为SAP预后的标准。而本实验结果SAP组与LPS组血清和培养基中的TNF-α升高，肺水肿加重，炎症反应加重。而罗格列酮的应用Angptl4在肺组织中的表达上调，说明Angptl4的水平与炎症因子TNF-α的变化成反比。同样转染增加了Angptl4的表达后抑制TNF-α的通路上的p-AKT/AKT的表达，减少炎症因子的生成。并且抑制p-mek1/2表达，影响了细胞骨架的F-actin的解聚，抑制细胞收缩，维持细胞形态，减少炎症因子的进一步渗出；抑制促凋亡因子casapase8,9和Bax的生成，拮抗了肺微血管内皮细胞的凋亡。
因此我们推测，Angptl4是炎症反应时的一种正性蛋白，它的增加能干预炎症因子的生成，并且维持肺微血管内皮细胞形态的稳定，对抗炎症反应导致的细胞凋亡，保护肺功能从而减轻SAP诱发的ALI，为SAP时ALI的防治提供新的的思路和方法。
Background: Severe acute pancreatitis associated lung injury is an inflammatorydisease which closely resembles the severe acute pancreatitis (SAP), whichcharacterized by tissue injury and a systemic inflammatory response, but themechanisms are unknown. Pulmonary microvascular endothelial cells (PMVECs)possess both highly proliferative and angiogenic capacities, and lined at the criticalinterface between the blood and microvessel are primary targets of inflammatorycytokines during lung inflammation. Angiopoietin-like4(Angptl4) is a circulatingprotein that has recently been implicated in the regulation of angiogenesis andmetastasis. This study aimed to investigate the effect of Angptl4on RPMVECs andsevere acute pancreatitis-associated lung injury of rats.
Methods: SAP animal model was administrated as previously method andadministrated by Rosiglitazone (ROSI, ROZ) and GW9662. The cell culture wasadministrated by LPS (100ng/mL). The PCR product was recombined topcDNA3.1-eGFP vector and pcDNA3.1-eGFP-Angptl4vector, which were transfectedinto RPMVECs with SuperFect Transfection Reagent (QIAGEN). Vascular endothelialgrowth factor (VEGF) was detected from vascular endothelial cells of lung byimmunohistochemistry. Pancreatitis tissue was stained with hematoxylin-eosin andimmunohistochemistry analysis with BCL-2antibodies was performed.Angptl4mRNAlevels, protein level and cell morphology of RPMVECs in experiment group weredetected with RT-PCR, real time-PCR, Western-blotting, MTT, ELISA and Confocaldevelopment methods, respectively.
Results: Angptl4expression vector pcDNA3.1-eGFP-Angptl4was successfullyconstructed. The Angptl4mRNA level in LPS-pcDNA3.1-eGFP was slightly increasedand experiment group was significantly higher than that of empty vector group and blank control group with obviously differences. The pro-apoptosis casapase8,9andBax protein was inhibited, while p-AKT/AKT and p-Mek1/2protein expression wasalso decreased. Angptl4protein was increased after induced by deoxycholic acidsodium salt, expansion with PPAR-γagonist rosiglitazone treatment, whereas, it wasobviously decreased with the PPAR-γantagonist GW9662(p<0.01). The rosiglitazonegroup had obviously decreased levels of the inflammatory cytokine TNF-α(p<0.01)and inhibit expression of VEGF in the vascular endothelial cells of lung associatedpancreatitis. Overexpression of Angptl4can inhibit that LPS cause the increase ofpermeability of RPMVEC, which relates to the depolymerization of central F-actin inRPMVECs.
Conclusions: In summary, our study demonstrated that overexpression of Angptl4may induce protective, anti-inflammatory and antiangiogenic effectiveness. It representsa novel therapeutic target gene for the therapy of severe acute pancreatitis-associatedlung injury and ALI induced by LPS.
由于SAP诱发ALI的机制复杂，涉及到胰酶激活、过氧化损伤、全身炎症反应、内毒素血症等多个方面，故目前尚未有一种特效的治疗方法，综合治疗方法仍为首选。有研究发现，Angptl4基因在全身炎症反应中可能对集体具有保护性作用。本课题通过观察Angptl4在重症急性胰腺炎大鼠肺组织及肺微血管内皮细胞上的表达变化，以及应用药物干预及转染技术观察其在炎症反应过程中的自身变化及对下游炎症因子的影响。本实验试图从急性胰腺炎肺损伤的动物模型及更直接的向肺微血管内皮细胞中转染Angptl4基因以致其高表达，并应用脂多糖刺激，观察其变化特点，及炎症因子和细胞形态的改变。旨在从更全面的新角度探讨SAP诱发ALI的发病机制，为有效防治急性胰腺炎肺损伤提供新的方法和实验依据。
方法：实验一：健康雄性（Spraghe-Dawley，SD)大鼠32只，体重180g-220g，随机分为4组:假手术组(CON), SAP模型组(SAP)，罗格列酮治疗组(ROSI/ROZ)，GW9662治疗组(GW9662)每组8只。SAP动物模型采用1.5%的去氧胆酸钠溶液(lml/kg)逆行胰胆管注射法。罗格列酮治疗组（剂量:5mg/kg）及GW9662治疗组（剂量5mg/kg）于造模后10分钟立即静脉注射药物一次。假手术组开腹后，仅轻翻动胰腺后关腹。模型建立24h后，各组大鼠麻醉后开腹，取胰腺、肺组织及动静脉采血。观察胰腺和肺组织的病理改变，采用全自动生化分析仪行血气分析，并对血淀粉酶的含量进行测定，双抗体夹心法(enzyme linked immuno sorbent assay，ELISA)检测血清TNF-α和RAF-1含量，采用反转录-聚合酶链式反应法（RT-PCR）测定肺组织中Angptl4和PPAR-γmRNA的表达，Western-Blot法测定肺组织中Angptl4和PPAR-γ蛋白的表达。HE染色法观察肺组织及胰腺组织的病理改变，免疫组化法检测肺微血管壁上VEGF的表达和胰腺细胞的BCL-2的表达。
实验二：应用Pricells公司提供的大鼠肺微血管内皮细胞系、经鉴定后，于第三代开始用于实验。培养大鼠肺微血管内皮细胞后将其分为4组：正常组，LPS（100ng/mL）刺激组，LPS+罗格列酮（50g/mL）组，LPS+GW9662（50g/mL）组，药物作用24h后，以Realtime-PCR和Western bloting法检测肺微血管内皮细胞中Angptl4的表达。应用脂多糖LPS（100ng/ml）分别刺激大鼠肺微血管内皮细胞6h,12h,24h,以MTT检测法观察细胞存活情况，并应用罗丹明-鬼笔环肽染色标记细胞骨架F-actin蛋白，观察大鼠肺微血管内皮细胞的形态结构学改变。
实验三：基于实验一与实验二，使用美国Sourcebioscience公司提供的大鼠Angptl4基因为模板，通过重组构建pcDNA3.1-eGFP-Angptl4质粒，用于转染大鼠肺微血管内皮细胞。转染48h后经LPS作用24h，以Realtime-PCR和Westernbloting法检测肺微血管内皮细胞中Angptl4表达变化。培养大鼠肺微血管内皮细胞后将其分为8组：正常组，LPS（100ng/mL）刺激组，LPS+罗格列酮（50g/mL）组，LPS+GW9662（50g/mL）组，pcDNA3.1–eGFP组，pcDNA3.1–Angptl4-eGFP组，LPS+pcDNA3.1-eGFP组，LPS+pcDNA3.1-Angptl4-eGFP组。Western bloting法检测细胞信号通路上的p-MEK1/2, p-AKT/AKT, Bax, casapase8,9蛋白的变化，并ELISA法检测TNF-α含量变化。再次应用罗丹明-鬼笔环肽染色标记细胞骨架F-actin蛋白，观察大鼠肺微血管内皮细胞的形态结构学改变。
结果：1．实验一：与假手术组相比，SAP组血清淀粉酶、TNF-α含量、肺组织中Angptl4mRNA和蛋白表达水平明显增高，而PPAR-γmRNA基因和蛋白的表达却明显降低，胰、肺组织病理损伤明显，具有明显的统计学意义（P<0.05）。与SAP组相比罗格列酮药物干预组的胰、肺病理损伤较轻，血清淀粉酶及TNF-α和RAF-1含量降低，肺组织Angptl4和PPAR-γ表达水平明显上升，肺血管内皮细胞上的VEGF和胰腺腺泡上的BCL-2明显受抑制。而GW9662干预组却不同程度降低，具有显著的统计学意义（P<0.05）。
2．实验二：CD31抗体鉴别原代大鼠肺微血管内皮细胞。LPS组（100ng/mL）刺激24h后Angptl4蛋白表达增加，而同样应用Angptl4促进剂罗格列酮后，Angptl4蛋白表达增加明显（P<0.01）。并且LPS组培养基的TNF-α水平升高。而应用罗格列酮后TNF-α水平下降明显，具有显著差异（P<0.01）。而单纯应用LPS刺激后，24h细胞减少达到高峰。罗格列酮组细胞存活率明显高于GW9662组。（P<0.01）罗丹明-鬼笔环肽和DAPI分别染色细胞骨架F-actin和细胞核后，激光共聚焦显微镜下观察单纯LPS刺激组，细胞核周围的胞骨架解聚，而罗格列酮应用组的细胞核中央部分解聚明显减少，细胞形态稳定。（P<0.05）
3．实验三：pcDNA3.1-eGFP-Angptl4质粒转染48小时后Realtime-PCR和Westernbloting检测肺微血管内皮细胞中Angptl4表达明显比pcDNA3.1-eGFP转染组增加。（P<0.01）与实验一、二的结果一致，LPS（100ng/mL）刺激后，肺微血管内皮细胞存活率随时间增加而减少，24h达到高峰（P<0.01）转染目的基因后，大鼠肺微血管内皮细胞存活延长。凋亡通路的促凋亡因子Bax蛋白与casapase8,9蛋白在LPS组明显增加，而在应用罗格列酮组与转染目的基因组明显降低（P<0.01）。LPS+pcDNA3.1-eGFP-Angptl4组凋亡通路上的调节蛋白p-AKT/AKT和p-mek1/2蛋白明显下调。罗丹明-鬼笔环肽和DAPI分别染色细胞骨架F-actin和细胞核后，激光共聚焦显微镜下观察转染目的组的细胞核中央部分解聚明显减少，细胞形态稳定。（P<0.05）
结论：Angptl4是在正常的肺微血管内皮细胞低表达的一种分泌性蛋白，其功能是参与脂质及脂肪的代谢，Angptl4对细胞膜的通透性影响较大，所以其对肺微血管内皮细胞的稳定尤其重要。实验一的结果得出，随着胰腺炎肺损伤的出现、肺水肿的加重，肺组织Angptl4的mRNA表达和蛋白表达水平上调，说明了Angptl4参与了急性炎症反应。而其上游基因PPAR-γ的降低，反应了Angptl4参与的炎症反应并不是直接单靠上游靶基因PPAR-γ的影响。实验二的模仿急性肺损伤的细胞实验结果与动物实验一致，应用罗格列酮药物可以减轻LPS刺激肺微血管内皮细胞导致的肺损伤。实验三进一步应用转染Angptl4基因，观察其对肺微血管内皮细胞的保护作用及在炎症损伤情况下对炎症因子的影响作用。
SAP诱发ALI的发病机制较为复杂，目前研究多认为是由于炎症介质和细胞因子的过度释放，增加了肺微血管内皮细胞的通透性而发生的肺水肿，因此本文选择肺微血管内皮细胞作为靶细胞进行研究。在炎症反应过程中TNF-α是重要的介质之一，它的出现及表达水平高低可被作为SAP预后的标准。而本实验结果SAP组与LPS组血清和培养基中的TNF-α升高，肺水肿加重，炎症反应加重。而罗格列酮的应用Angptl4在肺组织中的表达上调，说明Angptl4的水平与炎症因子TNF-α的变化成反比。同样转染增加了Angptl4的表达后抑制TNF-α的通路上的p-AKT/AKT的表达，减少炎症因子的生成。并且抑制p-mek1/2表达，影响了细胞骨架的F-actin的解聚，抑制细胞收缩，维持细胞形态，减少炎症因子的进一步渗出；抑制促凋亡因子casapase8,9和Bax的生成，拮抗了肺微血管内皮细胞的凋亡。
因此我们推测，Angptl4是炎症反应时的一种正性蛋白，它的增加能干预炎症因子的生成，并且维持肺微血管内皮细胞形态的稳定，对抗炎症反应导致的细胞凋亡，保护肺功能从而减轻SAP诱发的ALI，为SAP时ALI的防治提供新的的思路和方法。
Background: Severe acute pancreatitis associated lung injury is an inflammatorydisease which closely resembles the severe acute pancreatitis (SAP), whichcharacterized by tissue injury and a systemic inflammatory response, but themechanisms are unknown. Pulmonary microvascular endothelial cells (PMVECs)possess both highly proliferative and angiogenic capacities, and lined at the criticalinterface between the blood and microvessel are primary targets of inflammatorycytokines during lung inflammation. Angiopoietin-like4(Angptl4) is a circulatingprotein that has recently been implicated in the regulation of angiogenesis andmetastasis. This study aimed to investigate the effect of Angptl4on RPMVECs andsevere acute pancreatitis-associated lung injury of rats.
Methods: SAP animal model was administrated as previously method andadministrated by Rosiglitazone (ROSI, ROZ) and GW9662. The cell culture wasadministrated by LPS (100ng/mL). The PCR product was recombined topcDNA3.1-eGFP vector and pcDNA3.1-eGFP-Angptl4vector, which were transfectedinto RPMVECs with SuperFect Transfection Reagent (QIAGEN). Vascular endothelialgrowth factor (VEGF) was detected from vascular endothelial cells of lung byimmunohistochemistry. Pancreatitis tissue was stained with hematoxylin-eosin andimmunohistochemistry analysis with BCL-2antibodies was performed.Angptl4mRNAlevels, protein level and cell morphology of RPMVECs in experiment group weredetected with RT-PCR, real time-PCR, Western-blotting, MTT, ELISA and Confocaldevelopment methods, respectively.
Results: Angptl4expression vector pcDNA3.1-eGFP-Angptl4was successfullyconstructed. The Angptl4mRNA level in LPS-pcDNA3.1-eGFP was slightly increasedand experiment group was significantly higher than that of empty vector group and blank control group with obviously differences. The pro-apoptosis casapase8,9andBax protein was inhibited, while p-AKT/AKT and p-Mek1/2protein expression wasalso decreased. Angptl4protein was increased after induced by deoxycholic acidsodium salt, expansion with PPAR-γagonist rosiglitazone treatment, whereas, it wasobviously decreased with the PPAR-γantagonist GW9662(p<0.01). The rosiglitazonegroup had obviously decreased levels of the inflammatory cytokine TNF-α(p<0.01)and inhibit expression of VEGF in the vascular endothelial cells of lung associatedpancreatitis. Overexpression of Angptl4can inhibit that LPS cause the increase ofpermeability of RPMVEC, which relates to the depolymerization of central F-actin inRPMVECs.
Conclusions: In summary, our study demonstrated that overexpression of Angptl4may induce protective, anti-inflammatory and antiangiogenic effectiveness. It representsa novel therapeutic target gene for the therapy of severe acute pancreatitis-associatedlung injury and ALI induced by LPS.
引文
[1] Kim, I. et al. Hepatic expression, synthesis and secretion of a novelfibrinogen/angiopoietin-related protein that prevents endothelial-cell apoptosis.Biochem.J2000;346:603–610
[2] Ge H, Yang G, Yu X,et al. Oligomerization state-dependent hyperlipidemic effectof angiopoietin-like protein4. J Lipid Res.2004;45:2071–2079.
[3] Xu A, Lam MC, Chan KW, et al. Angiopoietin-like protein4decreases bloodglucose and improves glucose tolerance but induces hyperlipidemia and hepaticsteatosis in mice. Proc Natl Acad Sci USA.2005;102:6086–6091.
[4] Sukonina V, Lookene A, Olivecrona T, et al. Angiopoietin-likeprotein4convertslipoprotein lipase to inactive monomers and modulates lipaseactivity in adiposetissue. Proc Natl Acad Sci USA2006;103:17450–17455.
[5] Mandard S, Zandbergen F, VanStraten E, et al. The fasting-induced adiposefactor/angiopoietin-like protein4is physically associated with lipoproteins andgoverns plasma lipid levels and adiposity. J Biol Chem2006;281:934–944.
[6] Yoon, J. C., Chickering, T. W., Rosen, E. D., et al. Peroxisomeproliferator-activated receptor γ target gene encoding a novelangiopoietin-related protein associated with adipose differentiation. Mol. Cell.Biol.2000;20:5343–5349.
[7] Kersten, S., Mandard, S., Tan, N. S., et al.Characterization of the fasting-inducedadipose factor FIAF, a novel peroxisome proliferator activated receptor target gene.J. BiolChem2000;275:28488–28493
[8] Mandard, S., Zandbergen, F., Tan, N.S., et al. J.Biol.Chem.2004;279:34411–34420.
[9] Halonen KI, Pettila V, Leppaniemi AK, et al. Multiple organ disfunction associatedwith severe acute pancreatitis. Crit Care Med.2002;30(6):1274-1279.
[10]Harting W, Wemer J, Muller CA, Uhl M, Buchler MW. Surgical management ofsevere pancreatitis including sterile necrosis. J Hepatobaliary. Pancrea Surg.2002;9:429-435.
[11]Tiscornia OM, Hamamura S, Lehmann ES,Otero G, Waisman H,TiscorniaWasserman P, Bank S. Biliary acute pancreatitis:a review. World JGastroenterol.2000;6:157-168.
[12]Yousaf M, Mc Callion K, Diamond T. Management of severe acute pancreatitis.BrJ Surg.2003;90:407-420.
[13]刘学民，潘承恩，刘清光等.重症急性胰腺炎合并肺损伤的诊治探讨.中华肝胆外科杂志.2002;8(2):116-117
[14]Faffe DS, Rocco PRM, Negri EM, et al. Comparison of rat and mouse pulmonarytissue mechanical properties and histology. Journal of Applied Physiology2002;92:230-4.
[15]Koishi, R. et al. Angptl3regulates lipid metabolism in mice. Nat. Genet.2002;30:151–157
[16]Oike, Y. et al. Angiopoietin-related growth factor (AGF) promotes epidermalproliferation, remodeling and regeneration. Proc. Natl. Acad. Sci. U. S. A.2003;100:9494–9499.
[17]Oike, Y. et al. Angiopoietin-related/like protein (ARPs/Angptls) regulatesangiogenesis. Int. J. Hematol.2004;80:21–28.
[18]Wang F．Gong Y．Qin W X．el a1．Large-scale eDNA trans—fection screeningfor genes related to cancer development and progression[J]．Proc Natl Acad SciUSA，2004，101(44)：15724—15729．
[19]Ge H．Yang G，Huang L． a1．ligornerizatiol1and regulated proteolytic processingof angiopoietin-like protein4[J]．J Biol Chem，2004,27(9)：2038—2045．
[20]Davis S，Aldrich TH，Johes PF，et a1．holation of angiopoietin．1，a ligand forthe Tie2receptor，by secretion trap expression cloning．Cell，1996，87：l161-1l69．
[21]Suri C，Jones PF，Patan S，et a1．Requisite role of angiopoietin-l，a ligand for theTie2receptor，during embryonic anglogenesis．Cell，1996，87：l171-1180．
[22]Maisonpierre PC，Suri C，Johes PF，et a1．Angiopoietin-2，a natural antagonistTie-2that disrupts in vivo anglogenesis．Science，1997,277：55-60．
[23]ValenzuelaDM，Griffiths JA，Rojas J，et a1．Angiopoiefins3and4：diverging genecounterparts in mice and humans．Proc Natl Acad Sci U S A，l999，96：l904-l909．
[24]Asahara T，Chen D，1ahashi T，et a1．Tie2receptor ligands，angiopoietin-1andangiopoietin-2， modulate VEGF-induced postnatal neovascularization． CircRes．1998，83：233-240．
[25]I. Kim, H.G. Kim, H. Kim, et al. Hepatic expression, synthesis and secretion of anovel fibrinogen angiopoietin-related protein that prevents endothelial-cellapoptosis Biochem. J.2000;346(Pt.3):603–610.
[26]Camenisch, G. et al. ANGPTL3stimulates endothelial cell adhesion and migrationvia Integrin avb3and induces blood vessel formation in vivo. J.Biol.Chem.2002;277:17281–17290.
[27]Dhanabal, M. et al. Angioarrestin: an antiangiogenic protein with tumor-inhibitingproperties. Cancer Res.2002;62:3834–3841.
[28]Le Jan, S. et al. Angiopoietin-like4is a proangiogenic factor produced duringischemia and in conventional renal cell carcinoma. Am. J. Pathol.2003;162:1521–1528.
[29]Ito Y, Oike Y, Yasunaga K, et al. Inhibition of angiogenesis and vascular leakinessby angiopoietin-related protein4. Cancer Res2003;63:6651–6657.
[30]Jiang C, Ting AT, Seed B. PPAR-gamma agonists inhibit production of monocyteinflammatory cytokines. Nature1998;391:82–86.
[31]Ricote M, Li AC, Willson TM, et al. The peroxisome proliferator-activatedreceptor-gamma is a negative regulator of macrophage activation. Nature.1998;391:79–82.
[32]Naito Y, Yoshikawa T. Thiazolidinediones: A new class of drugs for the therapy ofischemia-reperfusion injury. Drugs Today (Barc).2004;40:423–430.
[33]Yuji Naito, Tomohisa Takagi, Kazuhiro Katada, et al. Gastric peroxisomeproliferator activator receptorγ expression and cytoprotective actions of its ligandsagainst ischemiareperfusion injury in rats. J Clin Biochem Nutr.2011Mar;48(2):170-7.
[34]L.M. Hermann, M. Pinkerton, K. Jennings, et al. Angiopoietin-like-4is a potentialangiogenic mediator in arthritis. Clinical Immunology2005;115:93–101.
[35]Le Jan S, Amy C, Cazes A, et al. Angiopoietin-like4is a proangiogenic factorproduced during ischemia and in conventional renal cell carcinoma. Am J Pathol2003;162:1521–1528.
[36]Cazes A, Galaup A, Chomel C, et al. Extracellular matrix-bound angiopoietin-like4inhibits endothelial cell adhesion, migration, and sprouting and alters actincytoskeleton. Circ Res.2006;99:1207–1215.
[37]Li KQ, Li WL, Peng SY, et al. Anti-tumor effect of recombinant retroviralvector-mediated human ANGPTL4gene transfection. Chin Med J (Engl)2004;117:1364–1369.
[38]Galaup A, Cazes A, Le Jan S, et al. Angiopoietin-like4prevents metastasis throughinhibition of vascular permeability and tumor cell motility and invasiveness. ProcNatl Acad Sci USA2006;103:18721–18726.
[39]Ying-Hua Yang, Yu Wang, Karen S.L, et al. Suppression of the Raf/MEK/ERKSignaling Cascade and Inhibition of Angiogenesis by the Carboxyl Terminus ofAngiopoietin-Like Protein4. Arterioscler Thromb Vasc Biol2008;28:835-840.
[40]Dhillon AS, Kolch W. Untying the regulation of the Raf-1kinase. Arch BiochemBiophys2002;404:3–9.
[41]Gomez G, Lee HM, He Q. Acutepancreatitis signals activation ofapoptosis-associated and survival genes in mice [J]. ExpBiol Med (Maywood),2001;226(7):692-700.
[42]Masamune A, Watanabe T, Kikuta K, et al. Roles of pancreatic stellate cells inpancreatic inflammation and fibrosis. Clinical Gastroenterology and Hepatology2009;7:48-54.
[43]肖贞良，钱贵生，孙耕耘. TNF-a对大鼠肺微血管内皮细胞-受体及其相关GRKs的影响.第三军医大学学报，2004，26(10):859一862。
[44]蔡栩栩，韩玉昆.肺血管内皮细胞与急性肺损伤.国外医学儿科学分册，2002，29(l):34-36。
[45]金惠铭，刘清行，曹翔等.TNF-a引起的微血管内皮细胞功能障碍及其细胞分子机制.微循环学杂志，2000，10(3):5-6。
[46]Norman JG, Fink GW, Franz MG. Acute pancreatitis induces intra pancreatic tumornecrosis factor gene expression. Arch Surg.1995;130:966-970.
[47]Makhija R, Kingsnorth AN. Cytokine storm in acute pancreatitis.Journal of Hepato–Biliary–Pancreatic Surgery2002;9:401-10.
[48]Nagar AB, Gorelick FS. Acute pancreatitis Current Opinion in Gastroenterology2002;18:552-7.
[49]Rollins MD, Sudarshan S, Firpo MA, et al. Anti-inflammatory effects of PPAR-γagonists directly correlates with PPAR-gamma expression during acute pancreatitis.J Gastrointest Surg2006;10:1120-1130.
[50]Kaneda K, Miyamoto K, Nomura S, et al. Intercellular localization of occludins andZO-1as a solute transport barrier of the mesothelial monolayer. J Artif Organs,2006;9(4):241-50.
[51]Siflinger-Birnboim A, Johnson A. Protein kinase C modulates pulmonaryendothelial permeability: a paradigm for acute lung injury. Am J Physiol Lung CellMol Physiol,2003;284(3):L435-51.
[52]Kuebler WM. Inflammatory pathways and microvascular responses in the lung.Pharmacol Rep,2005;57Suppl:196-205.
[53]Mehta D, Malik AB. Signaling mechanisms regulating endothelial permeability.Physiol Rev,2006;86(1):279-367.
[54]Birukova AA, Adyshev D, Gorshkov B, et al. ALK5and Smad4are involved inTGF-beta1-induced pulmonary endothelial permeability. FEBS Lett,2005;579(18):4031-7.
[55]Clements RT, Minnear FL, Singer HA, et al. RhoA and Rho-kinase dependent andindependent signals mediate TGF-beta-induced pulmonary endothelial cytoskeletalreorganization and permeability. Am J P hysiol Lung Cell Mol Physiol,2005;288(2):L294-306.
[56]Petrache I, Verin AD, Crow MT, et al. Differential effect of MLC kinase inTNF-alpha-induced endothelial cell apoptosis and barrier dysfunction. Am JPhysiol Lung Cell Mol Physiol,2001;280(6):L1168-78.
[57]Gao G, Kapushoc ST, Simpson AM, Thiemann OH, Simpson L: Guide RNAs ofthe recently isolated LEM125strain of Leishmania tarentolae: an unexpectedcomplexity. RNA2001,7(9):1335-1347.
[58]Essler M, Staddon JM, Weber PC, Aepfelbacher M: Cyclic AMP blocks bacteriallipopolysaccharide-induced myosin light chain phosphorylation in endothelial cellsthrough inhibition of Rho/Rho kinase signaling. J Immunol2000,164(12):6543-6549.
[59]Harhaj NS, Antonetti DA: Regulation of tight junctions and loss of barrier functionin pathophysiology. Int J Biochem Cell Biol2004,36(7):1206-1237.
[60]张明，金惠铭，曹翔.低浓度H2O2对肺微血管内皮细胞的迟发效应—凋亡.中国病理生理杂志,1999,15(1).
[61]王应灯，孙耕耘.山莨菪碱对血小板活化因子诱导肺微血管内皮细胞形态和骨架变化的影响.安徽医科大学学报,2004,39(1):32-36.
[62]Orlikowsky T，Wang ZQ，Dudhane A，et a1．Two distinct pathways of humanmacrophage differentiation are mediated by interferon-gamma and interleukin-10[J]．Immunology，1997，91(1)：104-108．
[63]雷宇华,闫芝芬,严玉平,等.微丝骨架与信号转导研究进展.华北农学报,2000,15:37-41.
[64]Albert AP, LiuM, LargeWA. Dual effect of calmodulinonstoreoperatedCa2+-permeable cation channels in rabbit portal vein myoeytes. Br J Pharmaco,J2006,148:1001-l011.
[65]Hermanns MI, Fuchs S, Bock M, et al. Primary human coculture model ofalveolo-capillary unit to study mechanisms of injury to peripheral lung. Cell TissueRes,2009;336(1):91-105.
[66]Ofori-Acquah SF, King J, Voelkel N, et al. Heterogeneity of barrier function in thelung reflects diversity in endothelial cell junctions. Microvasc Res,2008;75(3):391-402.
[67]Lim MJ, Chiang ET, Hechtman HB, et al. Inflammation-induced subcellularredistribution of VE-cadherinactin and gamma-catenin in cultured human lungmicrovessel endothelial cells. Microvasc Res,2001;62(3):366-82.
[68]Gong P, Angelini DJ, Yang S, et al. TLR4signaling is coupled to SRC familykinase activation, tyrosine phosphoryla tion of zonula adherens pr oteins, andopening of the paracellular pathway in human lung microvascular endothelia. J BiolChem,2008;283(19):13437-49.
[69]Koss M, Pfeiffer GR,2nd, Wang Y, et al. Ezrin/radi xin/moesin proteins arephosphorylated by TNF-alpha and modulat e permeability increases in humanpulmonary microvascular endothelial cells. J Immunol,2006;176(2):1218-27.
[70]Tinsley JH, Breslin JW, T easdale NR, et al. PKC-dependent, burn-inducedadherens junction reorganization and barrier dys function in pulmonarymicrovascular endothelial cells. Am J Physiol Lung Cell Mol Physiol,2005;289(2):L217-23.
[71]Tinsley JH, Teasdale NR, Yuan SY. Involvement of PKC delta and PKD inpulmonary microvascular endothelial cell hyperpermeability.Am J Physiol CellPhysiol,2004;286(1):C105-11.
[72]Yang S, Yip R, Polena S, et al. Reac tive oxygen species increased focal adhesionkinase production in pulmonary microvascular endothelial cells. Proc WestPharmacol Soc,2004;47:54-6.
[73]Liu T, Guevara OE, Warburton RR, et al. Modulation of HSP27altershypoxia-induced endothelial permeability and related signaling pathways. J CellPhysiol,2009;220(3):600-10.
[74]Angelini DJ, Hyun SW, Grigoryev DN, et al. TNF-alpha increases tyrosinephosphorylation of vascular endothelial cadherin and opens the paracellularpathway through fyn activation in human lung endothelia. Am J Physiol Lung CellMol Physiol,2006;291(6):L1232-45.
[75]An SS, Pennella CM, Gonnabathula A, et al. Hypoxia alters biophysical propertiesof endothelial cells via p38MAPK and Rho kinase-dependent pathways. Am JPhysiol Cell Physiol,2005;289(3):C521-30.
[76]Tiruppathi C, Ahmmed GU, Vogel SM, et al. Ca2+signaling, TRP channels andendothelial permeability. Microcirculation,2006;13(8):693-708.
[77]Cliona M. Stapleton, Joung Hyuck Joo, Yong-Sik Kim, Grace Liao, Reynold A.Panettieri Jr., Anton M. Jetten. Induction of ANGPTL4expression in human airwaysmooth muscle cells by PMA through activation of PKC and MAPK pathways.Experimental Cell Research,2010;316,507–516
[78]Ying-Hua Yang, Yu Wang, Karen S.L, et al. Suppression of the Raf/MEK/ERKSignaling Cascade and Inhibition of Angiogenesis by the Carboxyl Terminus ofAngiopoietin-Like Protein4. Arterioscler Thromb Vasc Biol2008;28:835-840.
[79]van der Poll T. Immunotherapy of sepsis. Lancet Infect Dis,2001;1(3):165-74.
[80]Alba-Loureiro TC, Martins EF, Miyasaka CK, et al. Evidence that arachidonic acidderived from neutrophils and prostaglandin E2are associated with the induction ofacute lung inflammation by lipopolysaccharide of Escherichia coli. Inflamm Res,2004;53(12):658-63.
[81]Lv T, Shen X, Shi Y, et al. TLR4is essential in acute lung injury induced byunresuscitated hemorrhagic shock. J Trauma,2009;66(1):124-31.
[82]Wu SH, Liao PY, Dong L, et al. Signal pathway involved in inhibition by lipoxinAof production of interleukins induced in endothelial cells by lipopolysaccharide.Inflamm Res,2008;57(9):430-7.
[83]Koss M, Pfeiffer GR, and, Wang Y, et al. Ezrin/radi xin/moesin proteins arephosphorylated by TNF-alpha and modulat e permeability increases in humanpulmonary microvascular endothelial cells. J Immunol,2006;176(2):1218-27.
[84]Angelini DJ, Hyun SW, Grigoryev DN, et al. TNF-alpha increases tyrosinephosphorylation of vascular endothelial cadherin and opens the paracellularpathway through fyn activation in human lung endothelia. Am J Physiol Lung CellMol Physiol,2006;291(6):L1232-45.
[85]Sedgwick JB, Menon I, Gern JE, et al. Effects of inflammatory cytokines on thepermeability of human lung microvascular endothelial cell monolayers anddifferential eosinophil transmigration. J Allergy Clin Immunol,2002;110(5):752-6.
[86]Farley KS, Wang L, Mehta S. Septic pulmonary microvascular endothelial cellinjury: role of alveolar macrophage NADPH oxidase. Am J Physiol Lung Cell MolPhysiol,2009;296(3):L480-8.
[87]Tinsley JH, Hunter FA, Childs EW. PKC and MLCK-Dependent,Cytokine-Induced Rat Coronary Endothelial Dysfunctio n. J Surg Res,2009;152(1):76-83.
[88]肖贞良，孙耕耘，夏前明，等．肿瘤坏死因子致肺微血管内皮细胞单层通透性损伤的实验研究[J]．中国应用生理学杂志，2001，17(1)：79—81．
[89]Liu F, Verin AD, Borbiev T, et al. Role of cAMP-dependent protein kinaseAactivity in endothelial cell cytoskeleton rearrangement. Am J Physiol Lung CellMol Physiol,2001;280(6):L1309-17.
[1] H. Baumann, J. Gauldie, The acute phase response, Immunol. Today15(1994)74–80.
[2] C. Gabay, I. Kushner, Acute-phase proteins and other systemic responses toinflammation, N. Engl. J. Med.340(1999)448–454
[3] G.S. Hotamisligil, Inflammation and metabolic disorders, Nature444(2006)860–867.
[4] P. Libby, Inflammation in atherosclerosis, Nature420(2002)868–874.
[5] J.C. Pickup, Inflammation and activated innate immunity in the pathogenesis oftype2diabetes, Diabetes Care27(2004)813–823.
[6] S. Schenk, M. Saberi, J.M. Olefsky, Insulin sensitivity: modulation by nutrients andinflammation, J. Clin. Invest.118(2008)2992–3002.
[7] Kim I. Kim HG．Kim H．et a1．H epatic expression，synthesis and secretion of anovel fibrinogen angiopoietin-related prorein that preventsendothelial-ce1lapoptosis [J]．Biochem，2000，346(3)：603-610．
[8] Kersten S，Mandard S．Fan NS．et a1．Characterization of the fasting-inducedadipose factor FIAF．a novel peroxisome proliferator-activated receptor targetgene[J]．J Biol Chem，2000，275(37)：28488-28493．
[9] Yoon J C．Chickering T W，Rosen E D，el a1．Pcroxisome proliferator-activatedreceptor gammma target gene encoding a novel angiopoietin-relatcd proteinassociated with adipose differentiation[J]．Mol Cell Biol,2000,20(14)：5343-5349．
[10]Wang F．Gong Y．Qin W X．el a1．Large scale eDNA transfection screening forgenes related to cancer development and progression[J]．Proc Natl Acad Sci USA，2004，101(44)：15724-15729．
[11]朱洪新，李锦军，覃文新，等．新基因ANGPTL4的克隆及在血管新生中的功能研究[J].中华医学杂志，2002，82(2)；94-99
[12]Mandard S，Zandbergen F，van Straten E，et a1．The fasting-indueed adiposefactor/angiopoietin-like protein4is physically associated with lipoproteins andgoverns plasma lipid levels and adiposity[J]．J Biol Chem，2006，281(2)；934-944。
[13]Merkel M，Eckel RH，Goldberg IJ．Lipoprotein lipase：genetics,lipid uptake,andregulation[J]．J Lipid Res，2002，43(12)；1997-2006．
[14]Le Jan S，Amy C，Cazes A，et a1.Angiopoietin-like4is a proangiogenic factorproduced during ischemia and in conventional renal cell carcinoma[J]．Am JPathol，2003，162(5)：1521-1528．
[15]Hermann LM，Pinkerton M，Jennings K，et a1．Angiopoietin-Iike4is a potentialangiogenic mediator in arthritis[J]．Clin Immunol，2005，115(1)：93-101．
[16]Ito Y，Oike Y, Yasunaga K, et a1. Inhibition of angiogenesis and vascular leakinessby angiopoietin-related protein4[J]．Cancer Ras，2003，63(20)；6651-6657．
[17]YamakawaM, LiuLX, DateT, et al. Hypoxia-induciblefactor-1mediatesactivationofcultured vascular endothelial cells by inducing multiple angiogenic factors [J].Circul Res,2003,93(7):664-673.
[18]陈愉,吴炳绪,彭娜,等. Ang-4在大肠癌的表达及其临床意义[J].中国误诊学杂志,2010,31(10):7564-7566.
[19]Brunckhorst MK, WangH, LuR, et al. Angiopoietin-4promotes glioblastomaprogression by enhancing tumor cell viability and angiogenesis [J]. CancerRes,2010,70(18):7283-7293.
[20]Galaup A，Cazes A，Le Jan S，et a1．Angiopoietin-like4prevents metastasisthrough inhibition of vascular permeability and tumor cell motility andinvasiveness[J]．Proc Natl Acad Sci USA,2006，103(49)：18721-18726．
[21]Gentil C．Le Jan S．Philippe J，et a1．Is oxygen a key factor in the fipodystrophyphenotype[J]．Lipids Health Dis，2006，28(5)：27．
[22]Ge H，Cha J Y，Gopal H．et a1．Differential regulation and properties ofangiopoietin-like proteins3and4[J]．J Lipid Res，2005，46(7)：1484-1490．
[23]Klopper J P．Berenz A．Hays W R，et a1．In vivo and microarray analysis ofrexinoid-responsive anaplastic thyroid carcinoma[J]．Clin Cancer Res．2008．14(2)：589-596．
[24]Yamada T．Ozaki N．Kato Y，et a1．insulin downregulates angiopoietin-like protein4mRNA in3T3-L1adipocytes[J]．Biochem Biophys Res Commun，2006，347(4)：1138-1144．
[25]Belanger A J．Lu H，Date T．Hypoxia up-regulates expression of peroxisomeproliferator-activated receptor gamma angiopoietin-related gene(PGAR)incardiomyocytes：role of hypoxia inducible factor lalpha[J]．J Mol Cell Cardiol，2002，34(7)：765-774．
[26]Schmuth M，Haqq C M，Cairns W J，et a1．Peorxisome proliferators-activatedreceptor(PPAR) beta/delta stimulates differentiation and lipid accumulation inkcratinocytes[J]．J Invest Dermatol，2004.122(6)：971-983．
[27]Akiyama T E，Lambert G．Nicol C J，e1．a1．Peroxisome proliferator-activatedreceptor beta／delta regulates very low density lipoprotdn production andcatabolism in mice on a Westem diet[J]．J Biol Chem．2004．279(4)：20874-20881．
[28]Carmeliet P，Jain R K．Angiogenesis in cancer and other disease[J]．Nature，2000，407(6)：249-257．
[29]Le Jan S, Amy C, Cazes A．Angiopoietin-like4is a proangiogenic factor producedduring ischemia and in conventional renal cel carcinoma[J]．Am J Patho1．2003，162(5)：1521-1528．
[30]Biao Lu, Arthur Moser, Judy K. Shigenaga, Carl Grunfeld, Kenneth R. Feingold.The acute phase response stimulates the expression of angiopoietin like protein4[J]． Biochemical and Biophysical Researc Communications，2010，391：1737–1741
[31]Pengcheng Zhu，Ming Jie Tan,Royston-Luke Huang, e1.a1．Angiopoietin-like4Protein Elevates the Prosurvival Intracellular O–2: H2O2Ratio and Confers AnoikisResistance to Tumors
[32]刘轲,韩向辉.血管生成素及其受体对脑缺血后微血管生成作用机制研究进展[J].国外医学老年医学分册,2009,11(6):250-251.
[33]WongAL, HaroonZA, WernerS, et al. Tie2expression and phos-phorylation inangiogenic and quiescent adult tissues [J]. CircRes,1997,81(4):567-574.
[34]Jones N, IljinK, Dumont DJ, et al. Tie receptors: new modulators of angiogenic andlymphangiogenic responses [J]. Nat RevMol Cell Biol,2001,2(4):257-267.
[35]WardNL, Dumont DJ. Theangiopoietins and Tie2/Tek: adding to the complexity ofcardiovascular development [J]. SeminCell Dev Biol,2002,13(1):19-27.
[36]KohGY, KimI, KwakHJ, et al. Biomedical significanceof endothelial cell specificgrowthfactor, angiopoietin [J]. ExpMol Med,2002,34(1):1-11.
[37]SatoA, LwamaA, TakakuraN, et al. Characterization of TEK Receptor tyrosinekinase and its ligands, Angiop oietins inhuman hematopoietic progenitor cells [J].Int Immunol,1998,10(8):1217-1227.
[38]Cliona M. Stapleton, Joung Hyuck Joo, Yong-Sik Kim, et al. Induction ofANGPTL4expression in human airway smooth muscle cells by PMA throughactivation of PKC and MAPK pathways [J]. Experimental Cell Research,2010,316:507–516
[39]Ying-Hua Yang, Yu Wang, Karen S.L. Lam, et al. Suppression of theRaf/MEK/ERK signaling cascade and inhibition of Angiogenesis by the CarboxylTerminus of Angiopoietin-Like Protein4[J].Arterioscler Thromb VascBiol,2008,5:835-840
[40]于冬梅,裴凌.血管生成素1与肺损伤研究进展[J].沈阳部队医药,2009,22(5):349-351.
[41]韩沙沙,王晓芝.血管生成素4的研究进展[J].医学综述,2011,17(6):807-809
[2] Ge H, Yang G, Yu X,et al. Oligomerization state-dependent hyperlipidemic effectof angiopoietin-like protein4. J Lipid Res.2004;45:2071–2079.
[3] Xu A, Lam MC, Chan KW, et al. Angiopoietin-like protein4decreases bloodglucose and improves glucose tolerance but induces hyperlipidemia and hepaticsteatosis in mice. Proc Natl Acad Sci USA.2005;102:6086–6091.
[4] Sukonina V, Lookene A, Olivecrona T, et al. Angiopoietin-likeprotein4convertslipoprotein lipase to inactive monomers and modulates lipaseactivity in adiposetissue. Proc Natl Acad Sci USA2006;103:17450–17455.
[5] Mandard S, Zandbergen F, VanStraten E, et al. The fasting-induced adiposefactor/angiopoietin-like protein4is physically associated with lipoproteins andgoverns plasma lipid levels and adiposity. J Biol Chem2006;281:934–944.
[6] Yoon, J. C., Chickering, T. W., Rosen, E. D., et al. Peroxisomeproliferator-activated receptor γ target gene encoding a novelangiopoietin-related protein associated with adipose differentiation. Mol. Cell.Biol.2000;20:5343–5349.
[7] Kersten, S., Mandard, S., Tan, N. S., et al.Characterization of the fasting-inducedadipose factor FIAF, a novel peroxisome proliferator activated receptor target gene.J. BiolChem2000;275:28488–28493
[8] Mandard, S., Zandbergen, F., Tan, N.S., et al. J.Biol.Chem.2004;279:34411–34420.
[9] Halonen KI, Pettila V, Leppaniemi AK, et al. Multiple organ disfunction associatedwith severe acute pancreatitis. Crit Care Med.2002;30(6):1274-1279.
[10]Harting W, Wemer J, Muller CA, Uhl M, Buchler MW. Surgical management ofsevere pancreatitis including sterile necrosis. J Hepatobaliary. Pancrea Surg.2002;9:429-435.
[11]Tiscornia OM, Hamamura S, Lehmann ES,Otero G, Waisman H,TiscorniaWasserman P, Bank S. Biliary acute pancreatitis:a review. World JGastroenterol.2000;6:157-168.
[12]Yousaf M, Mc Callion K, Diamond T. Management of severe acute pancreatitis.BrJ Surg.2003;90:407-420.
[13]刘学民，潘承恩，刘清光等.重症急性胰腺炎合并肺损伤的诊治探讨.中华肝胆外科杂志.2002;8(2):116-117
[14]Faffe DS, Rocco PRM, Negri EM, et al. Comparison of rat and mouse pulmonarytissue mechanical properties and histology. Journal of Applied Physiology2002;92:230-4.
[15]Koishi, R. et al. Angptl3regulates lipid metabolism in mice. Nat. Genet.2002;30:151–157
[16]Oike, Y. et al. Angiopoietin-related growth factor (AGF) promotes epidermalproliferation, remodeling and regeneration. Proc. Natl. Acad. Sci. U. S. A.2003;100:9494–9499.
[17]Oike, Y. et al. Angiopoietin-related/like protein (ARPs/Angptls) regulatesangiogenesis. Int. J. Hematol.2004;80:21–28.
[18]Wang F．Gong Y．Qin W X．el a1．Large-scale eDNA trans—fection screeningfor genes related to cancer development and progression[J]．Proc Natl Acad SciUSA，2004，101(44)：15724—15729．
[19]Ge H．Yang G，Huang L． a1．ligornerizatiol1and regulated proteolytic processingof angiopoietin-like protein4[J]．J Biol Chem，2004,27(9)：2038—2045．
[20]Davis S，Aldrich TH，Johes PF，et a1．holation of angiopoietin．1，a ligand forthe Tie2receptor，by secretion trap expression cloning．Cell，1996，87：l161-1l69．
[21]Suri C，Jones PF，Patan S，et a1．Requisite role of angiopoietin-l，a ligand for theTie2receptor，during embryonic anglogenesis．Cell，1996，87：l171-1180．
[22]Maisonpierre PC，Suri C，Johes PF，et a1．Angiopoietin-2，a natural antagonistTie-2that disrupts in vivo anglogenesis．Science，1997,277：55-60．
[23]ValenzuelaDM，Griffiths JA，Rojas J，et a1．Angiopoiefins3and4：diverging genecounterparts in mice and humans．Proc Natl Acad Sci U S A，l999，96：l904-l909．
[24]Asahara T，Chen D，1ahashi T，et a1．Tie2receptor ligands，angiopoietin-1andangiopoietin-2， modulate VEGF-induced postnatal neovascularization． CircRes．1998，83：233-240．
[25]I. Kim, H.G. Kim, H. Kim, et al. Hepatic expression, synthesis and secretion of anovel fibrinogen angiopoietin-related protein that prevents endothelial-cellapoptosis Biochem. J.2000;346(Pt.3):603–610.
[26]Camenisch, G. et al. ANGPTL3stimulates endothelial cell adhesion and migrationvia Integrin avb3and induces blood vessel formation in vivo. J.Biol.Chem.2002;277:17281–17290.
[27]Dhanabal, M. et al. Angioarrestin: an antiangiogenic protein with tumor-inhibitingproperties. Cancer Res.2002;62:3834–3841.
[28]Le Jan, S. et al. Angiopoietin-like4is a proangiogenic factor produced duringischemia and in conventional renal cell carcinoma. Am. J. Pathol.2003;162:1521–1528.
[29]Ito Y, Oike Y, Yasunaga K, et al. Inhibition of angiogenesis and vascular leakinessby angiopoietin-related protein4. Cancer Res2003;63:6651–6657.
[30]Jiang C, Ting AT, Seed B. PPAR-gamma agonists inhibit production of monocyteinflammatory cytokines. Nature1998;391:82–86.
[31]Ricote M, Li AC, Willson TM, et al. The peroxisome proliferator-activatedreceptor-gamma is a negative regulator of macrophage activation. Nature.1998;391:79–82.
[32]Naito Y, Yoshikawa T. Thiazolidinediones: A new class of drugs for the therapy ofischemia-reperfusion injury. Drugs Today (Barc).2004;40:423–430.
[33]Yuji Naito, Tomohisa Takagi, Kazuhiro Katada, et al. Gastric peroxisomeproliferator activator receptorγ expression and cytoprotective actions of its ligandsagainst ischemiareperfusion injury in rats. J Clin Biochem Nutr.2011Mar;48(2):170-7.
[34]L.M. Hermann, M. Pinkerton, K. Jennings, et al. Angiopoietin-like-4is a potentialangiogenic mediator in arthritis. Clinical Immunology2005;115:93–101.
[35]Le Jan S, Amy C, Cazes A, et al. Angiopoietin-like4is a proangiogenic factorproduced during ischemia and in conventional renal cell carcinoma. Am J Pathol2003;162:1521–1528.
[36]Cazes A, Galaup A, Chomel C, et al. Extracellular matrix-bound angiopoietin-like4inhibits endothelial cell adhesion, migration, and sprouting and alters actincytoskeleton. Circ Res.2006;99:1207–1215.
[37]Li KQ, Li WL, Peng SY, et al. Anti-tumor effect of recombinant retroviralvector-mediated human ANGPTL4gene transfection. Chin Med J (Engl)2004;117:1364–1369.
[38]Galaup A, Cazes A, Le Jan S, et al. Angiopoietin-like4prevents metastasis throughinhibition of vascular permeability and tumor cell motility and invasiveness. ProcNatl Acad Sci USA2006;103:18721–18726.
[39]Ying-Hua Yang, Yu Wang, Karen S.L, et al. Suppression of the Raf/MEK/ERKSignaling Cascade and Inhibition of Angiogenesis by the Carboxyl Terminus ofAngiopoietin-Like Protein4. Arterioscler Thromb Vasc Biol2008;28:835-840.
[40]Dhillon AS, Kolch W. Untying the regulation of the Raf-1kinase. Arch BiochemBiophys2002;404:3–9.
[41]Gomez G, Lee HM, He Q. Acutepancreatitis signals activation ofapoptosis-associated and survival genes in mice [J]. ExpBiol Med (Maywood),2001;226(7):692-700.
[42]Masamune A, Watanabe T, Kikuta K, et al. Roles of pancreatic stellate cells inpancreatic inflammation and fibrosis. Clinical Gastroenterology and Hepatology2009;7:48-54.
[43]肖贞良，钱贵生，孙耕耘. TNF-a对大鼠肺微血管内皮细胞-受体及其相关GRKs的影响.第三军医大学学报，2004，26(10):859一862。
[44]蔡栩栩，韩玉昆.肺血管内皮细胞与急性肺损伤.国外医学儿科学分册，2002，29(l):34-36。
[45]金惠铭，刘清行，曹翔等.TNF-a引起的微血管内皮细胞功能障碍及其细胞分子机制.微循环学杂志，2000，10(3):5-6。
[46]Norman JG, Fink GW, Franz MG. Acute pancreatitis induces intra pancreatic tumornecrosis factor gene expression. Arch Surg.1995;130:966-970.
[47]Makhija R, Kingsnorth AN. Cytokine storm in acute pancreatitis.Journal of Hepato–Biliary–Pancreatic Surgery2002;9:401-10.
[48]Nagar AB, Gorelick FS. Acute pancreatitis Current Opinion in Gastroenterology2002;18:552-7.
[49]Rollins MD, Sudarshan S, Firpo MA, et al. Anti-inflammatory effects of PPAR-γagonists directly correlates with PPAR-gamma expression during acute pancreatitis.J Gastrointest Surg2006;10:1120-1130.
[50]Kaneda K, Miyamoto K, Nomura S, et al. Intercellular localization of occludins andZO-1as a solute transport barrier of the mesothelial monolayer. J Artif Organs,2006;9(4):241-50.
[51]Siflinger-Birnboim A, Johnson A. Protein kinase C modulates pulmonaryendothelial permeability: a paradigm for acute lung injury. Am J Physiol Lung CellMol Physiol,2003;284(3):L435-51.
[52]Kuebler WM. Inflammatory pathways and microvascular responses in the lung.Pharmacol Rep,2005;57Suppl:196-205.
[53]Mehta D, Malik AB. Signaling mechanisms regulating endothelial permeability.Physiol Rev,2006;86(1):279-367.
[54]Birukova AA, Adyshev D, Gorshkov B, et al. ALK5and Smad4are involved inTGF-beta1-induced pulmonary endothelial permeability. FEBS Lett,2005;579(18):4031-7.
[55]Clements RT, Minnear FL, Singer HA, et al. RhoA and Rho-kinase dependent andindependent signals mediate TGF-beta-induced pulmonary endothelial cytoskeletalreorganization and permeability. Am J P hysiol Lung Cell Mol Physiol,2005;288(2):L294-306.
[56]Petrache I, Verin AD, Crow MT, et al. Differential effect of MLC kinase inTNF-alpha-induced endothelial cell apoptosis and barrier dysfunction. Am JPhysiol Lung Cell Mol Physiol,2001;280(6):L1168-78.
[57]Gao G, Kapushoc ST, Simpson AM, Thiemann OH, Simpson L: Guide RNAs ofthe recently isolated LEM125strain of Leishmania tarentolae: an unexpectedcomplexity. RNA2001,7(9):1335-1347.
[58]Essler M, Staddon JM, Weber PC, Aepfelbacher M: Cyclic AMP blocks bacteriallipopolysaccharide-induced myosin light chain phosphorylation in endothelial cellsthrough inhibition of Rho/Rho kinase signaling. J Immunol2000,164(12):6543-6549.
[59]Harhaj NS, Antonetti DA: Regulation of tight junctions and loss of barrier functionin pathophysiology. Int J Biochem Cell Biol2004,36(7):1206-1237.
[60]张明，金惠铭，曹翔.低浓度H2O2对肺微血管内皮细胞的迟发效应—凋亡.中国病理生理杂志,1999,15(1).
[61]王应灯，孙耕耘.山莨菪碱对血小板活化因子诱导肺微血管内皮细胞形态和骨架变化的影响.安徽医科大学学报,2004,39(1):32-36.
[62]Orlikowsky T，Wang ZQ，Dudhane A，et a1．Two distinct pathways of humanmacrophage differentiation are mediated by interferon-gamma and interleukin-10[J]．Immunology，1997，91(1)：104-108．
[63]雷宇华,闫芝芬,严玉平,等.微丝骨架与信号转导研究进展.华北农学报,2000,15:37-41.
[64]Albert AP, LiuM, LargeWA. Dual effect of calmodulinonstoreoperatedCa2+-permeable cation channels in rabbit portal vein myoeytes. Br J Pharmaco,J2006,148:1001-l011.
[65]Hermanns MI, Fuchs S, Bock M, et al. Primary human coculture model ofalveolo-capillary unit to study mechanisms of injury to peripheral lung. Cell TissueRes,2009;336(1):91-105.
[66]Ofori-Acquah SF, King J, Voelkel N, et al. Heterogeneity of barrier function in thelung reflects diversity in endothelial cell junctions. Microvasc Res,2008;75(3):391-402.
[67]Lim MJ, Chiang ET, Hechtman HB, et al. Inflammation-induced subcellularredistribution of VE-cadherinactin and gamma-catenin in cultured human lungmicrovessel endothelial cells. Microvasc Res,2001;62(3):366-82.
[68]Gong P, Angelini DJ, Yang S, et al. TLR4signaling is coupled to SRC familykinase activation, tyrosine phosphoryla tion of zonula adherens pr oteins, andopening of the paracellular pathway in human lung microvascular endothelia. J BiolChem,2008;283(19):13437-49.
[69]Koss M, Pfeiffer GR,2nd, Wang Y, et al. Ezrin/radi xin/moesin proteins arephosphorylated by TNF-alpha and modulat e permeability increases in humanpulmonary microvascular endothelial cells. J Immunol,2006;176(2):1218-27.
[70]Tinsley JH, Breslin JW, T easdale NR, et al. PKC-dependent, burn-inducedadherens junction reorganization and barrier dys function in pulmonarymicrovascular endothelial cells. Am J Physiol Lung Cell Mol Physiol,2005;289(2):L217-23.
[71]Tinsley JH, Teasdale NR, Yuan SY. Involvement of PKC delta and PKD inpulmonary microvascular endothelial cell hyperpermeability.Am J Physiol CellPhysiol,2004;286(1):C105-11.
[72]Yang S, Yip R, Polena S, et al. Reac tive oxygen species increased focal adhesionkinase production in pulmonary microvascular endothelial cells. Proc WestPharmacol Soc,2004;47:54-6.
[73]Liu T, Guevara OE, Warburton RR, et al. Modulation of HSP27altershypoxia-induced endothelial permeability and related signaling pathways. J CellPhysiol,2009;220(3):600-10.
[74]Angelini DJ, Hyun SW, Grigoryev DN, et al. TNF-alpha increases tyrosinephosphorylation of vascular endothelial cadherin and opens the paracellularpathway through fyn activation in human lung endothelia. Am J Physiol Lung CellMol Physiol,2006;291(6):L1232-45.
[75]An SS, Pennella CM, Gonnabathula A, et al. Hypoxia alters biophysical propertiesof endothelial cells via p38MAPK and Rho kinase-dependent pathways. Am JPhysiol Cell Physiol,2005;289(3):C521-30.
[76]Tiruppathi C, Ahmmed GU, Vogel SM, et al. Ca2+signaling, TRP channels andendothelial permeability. Microcirculation,2006;13(8):693-708.
[77]Cliona M. Stapleton, Joung Hyuck Joo, Yong-Sik Kim, Grace Liao, Reynold A.Panettieri Jr., Anton M. Jetten. Induction of ANGPTL4expression in human airwaysmooth muscle cells by PMA through activation of PKC and MAPK pathways.Experimental Cell Research,2010;316,507–516
[78]Ying-Hua Yang, Yu Wang, Karen S.L, et al. Suppression of the Raf/MEK/ERKSignaling Cascade and Inhibition of Angiogenesis by the Carboxyl Terminus ofAngiopoietin-Like Protein4. Arterioscler Thromb Vasc Biol2008;28:835-840.
[79]van der Poll T. Immunotherapy of sepsis. Lancet Infect Dis,2001;1(3):165-74.
[80]Alba-Loureiro TC, Martins EF, Miyasaka CK, et al. Evidence that arachidonic acidderived from neutrophils and prostaglandin E2are associated with the induction ofacute lung inflammation by lipopolysaccharide of Escherichia coli. Inflamm Res,2004;53(12):658-63.
[81]Lv T, Shen X, Shi Y, et al. TLR4is essential in acute lung injury induced byunresuscitated hemorrhagic shock. J Trauma,2009;66(1):124-31.
[82]Wu SH, Liao PY, Dong L, et al. Signal pathway involved in inhibition by lipoxinAof production of interleukins induced in endothelial cells by lipopolysaccharide.Inflamm Res,2008;57(9):430-7.
[83]Koss M, Pfeiffer GR, and, Wang Y, et al. Ezrin/radi xin/moesin proteins arephosphorylated by TNF-alpha and modulat e permeability increases in humanpulmonary microvascular endothelial cells. J Immunol,2006;176(2):1218-27.
[84]Angelini DJ, Hyun SW, Grigoryev DN, et al. TNF-alpha increases tyrosinephosphorylation of vascular endothelial cadherin and opens the paracellularpathway through fyn activation in human lung endothelia. Am J Physiol Lung CellMol Physiol,2006;291(6):L1232-45.
[85]Sedgwick JB, Menon I, Gern JE, et al. Effects of inflammatory cytokines on thepermeability of human lung microvascular endothelial cell monolayers anddifferential eosinophil transmigration. J Allergy Clin Immunol,2002;110(5):752-6.
[86]Farley KS, Wang L, Mehta S. Septic pulmonary microvascular endothelial cellinjury: role of alveolar macrophage NADPH oxidase. Am J Physiol Lung Cell MolPhysiol,2009;296(3):L480-8.
[87]Tinsley JH, Hunter FA, Childs EW. PKC and MLCK-Dependent,Cytokine-Induced Rat Coronary Endothelial Dysfunctio n. J Surg Res,2009;152(1):76-83.
[88]肖贞良，孙耕耘，夏前明，等．肿瘤坏死因子致肺微血管内皮细胞单层通透性损伤的实验研究[J]．中国应用生理学杂志，2001，17(1)：79—81．
[89]Liu F, Verin AD, Borbiev T, et al. Role of cAMP-dependent protein kinaseAactivity in endothelial cell cytoskeleton rearrangement. Am J Physiol Lung CellMol Physiol,2001;280(6):L1309-17.
[1] H. Baumann, J. Gauldie, The acute phase response, Immunol. Today15(1994)74–80.
[2] C. Gabay, I. Kushner, Acute-phase proteins and other systemic responses toinflammation, N. Engl. J. Med.340(1999)448–454
[3] G.S. Hotamisligil, Inflammation and metabolic disorders, Nature444(2006)860–867.
[4] P. Libby, Inflammation in atherosclerosis, Nature420(2002)868–874.
[5] J.C. Pickup, Inflammation and activated innate immunity in the pathogenesis oftype2diabetes, Diabetes Care27(2004)813–823.
[6] S. Schenk, M. Saberi, J.M. Olefsky, Insulin sensitivity: modulation by nutrients andinflammation, J. Clin. Invest.118(2008)2992–3002.
[7] Kim I. Kim HG．Kim H．et a1．H epatic expression，synthesis and secretion of anovel fibrinogen angiopoietin-related prorein that preventsendothelial-ce1lapoptosis [J]．Biochem，2000，346(3)：603-610．
[8] Kersten S，Mandard S．Fan NS．et a1．Characterization of the fasting-inducedadipose factor FIAF．a novel peroxisome proliferator-activated receptor targetgene[J]．J Biol Chem，2000，275(37)：28488-28493．
[9] Yoon J C．Chickering T W，Rosen E D，el a1．Pcroxisome proliferator-activatedreceptor gammma target gene encoding a novel angiopoietin-relatcd proteinassociated with adipose differentiation[J]．Mol Cell Biol,2000,20(14)：5343-5349．
[10]Wang F．Gong Y．Qin W X．el a1．Large scale eDNA transfection screening forgenes related to cancer development and progression[J]．Proc Natl Acad Sci USA，2004，101(44)：15724-15729．
[11]朱洪新，李锦军，覃文新，等．新基因ANGPTL4的克隆及在血管新生中的功能研究[J].中华医学杂志，2002，82(2)；94-99
[12]Mandard S，Zandbergen F，van Straten E，et a1．The fasting-indueed adiposefactor/angiopoietin-like protein4is physically associated with lipoproteins andgoverns plasma lipid levels and adiposity[J]．J Biol Chem，2006，281(2)；934-944。
[13]Merkel M，Eckel RH，Goldberg IJ．Lipoprotein lipase：genetics,lipid uptake,andregulation[J]．J Lipid Res，2002，43(12)；1997-2006．
[14]Le Jan S，Amy C，Cazes A，et a1.Angiopoietin-like4is a proangiogenic factorproduced during ischemia and in conventional renal cell carcinoma[J]．Am JPathol，2003，162(5)：1521-1528．
[15]Hermann LM，Pinkerton M，Jennings K，et a1．Angiopoietin-Iike4is a potentialangiogenic mediator in arthritis[J]．Clin Immunol，2005，115(1)：93-101．
[16]Ito Y，Oike Y, Yasunaga K, et a1. Inhibition of angiogenesis and vascular leakinessby angiopoietin-related protein4[J]．Cancer Ras，2003，63(20)；6651-6657．
[17]YamakawaM, LiuLX, DateT, et al. Hypoxia-induciblefactor-1mediatesactivationofcultured vascular endothelial cells by inducing multiple angiogenic factors [J].Circul Res,2003,93(7):664-673.
[18]陈愉,吴炳绪,彭娜,等. Ang-4在大肠癌的表达及其临床意义[J].中国误诊学杂志,2010,31(10):7564-7566.
[19]Brunckhorst MK, WangH, LuR, et al. Angiopoietin-4promotes glioblastomaprogression by enhancing tumor cell viability and angiogenesis [J]. CancerRes,2010,70(18):7283-7293.
[20]Galaup A，Cazes A，Le Jan S，et a1．Angiopoietin-like4prevents metastasisthrough inhibition of vascular permeability and tumor cell motility andinvasiveness[J]．Proc Natl Acad Sci USA,2006，103(49)：18721-18726．
[21]Gentil C．Le Jan S．Philippe J，et a1．Is oxygen a key factor in the fipodystrophyphenotype[J]．Lipids Health Dis，2006，28(5)：27．
[22]Ge H，Cha J Y，Gopal H．et a1．Differential regulation and properties ofangiopoietin-like proteins3and4[J]．J Lipid Res，2005，46(7)：1484-1490．
[23]Klopper J P．Berenz A．Hays W R，et a1．In vivo and microarray analysis ofrexinoid-responsive anaplastic thyroid carcinoma[J]．Clin Cancer Res．2008．14(2)：589-596．
[24]Yamada T．Ozaki N．Kato Y，et a1．insulin downregulates angiopoietin-like protein4mRNA in3T3-L1adipocytes[J]．Biochem Biophys Res Commun，2006，347(4)：1138-1144．
[25]Belanger A J．Lu H，Date T．Hypoxia up-regulates expression of peroxisomeproliferator-activated receptor gamma angiopoietin-related gene(PGAR)incardiomyocytes：role of hypoxia inducible factor lalpha[J]．J Mol Cell Cardiol，2002，34(7)：765-774．
[26]Schmuth M，Haqq C M，Cairns W J，et a1．Peorxisome proliferators-activatedreceptor(PPAR) beta/delta stimulates differentiation and lipid accumulation inkcratinocytes[J]．J Invest Dermatol，2004.122(6)：971-983．
[27]Akiyama T E，Lambert G．Nicol C J，e1．a1．Peroxisome proliferator-activatedreceptor beta／delta regulates very low density lipoprotdn production andcatabolism in mice on a Westem diet[J]．J Biol Chem．2004．279(4)：20874-20881．
[28]Carmeliet P，Jain R K．Angiogenesis in cancer and other disease[J]．Nature，2000，407(6)：249-257．
[29]Le Jan S, Amy C, Cazes A．Angiopoietin-like4is a proangiogenic factor producedduring ischemia and in conventional renal cel carcinoma[J]．Am J Patho1．2003，162(5)：1521-1528．
[30]Biao Lu, Arthur Moser, Judy K. Shigenaga, Carl Grunfeld, Kenneth R. Feingold.The acute phase response stimulates the expression of angiopoietin like protein4[J]． Biochemical and Biophysical Researc Communications，2010，391：1737–1741
[31]Pengcheng Zhu，Ming Jie Tan,Royston-Luke Huang, e1.a1．Angiopoietin-like4Protein Elevates the Prosurvival Intracellular O–2: H2O2Ratio and Confers AnoikisResistance to Tumors
[32]刘轲,韩向辉.血管生成素及其受体对脑缺血后微血管生成作用机制研究进展[J].国外医学老年医学分册,2009,11(6):250-251.
[33]WongAL, HaroonZA, WernerS, et al. Tie2expression and phos-phorylation inangiogenic and quiescent adult tissues [J]. CircRes,1997,81(4):567-574.
[34]Jones N, IljinK, Dumont DJ, et al. Tie receptors: new modulators of angiogenic andlymphangiogenic responses [J]. Nat RevMol Cell Biol,2001,2(4):257-267.
[35]WardNL, Dumont DJ. Theangiopoietins and Tie2/Tek: adding to the complexity ofcardiovascular development [J]. SeminCell Dev Biol,2002,13(1):19-27.
[36]KohGY, KimI, KwakHJ, et al. Biomedical significanceof endothelial cell specificgrowthfactor, angiopoietin [J]. ExpMol Med,2002,34(1):1-11.
[37]SatoA, LwamaA, TakakuraN, et al. Characterization of TEK Receptor tyrosinekinase and its ligands, Angiop oietins inhuman hematopoietic progenitor cells [J].Int Immunol,1998,10(8):1217-1227.
[38]Cliona M. Stapleton, Joung Hyuck Joo, Yong-Sik Kim, et al. Induction ofANGPTL4expression in human airway smooth muscle cells by PMA throughactivation of PKC and MAPK pathways [J]. Experimental Cell Research,2010,316:507–516
[39]Ying-Hua Yang, Yu Wang, Karen S.L. Lam, et al. Suppression of theRaf/MEK/ERK signaling cascade and inhibition of Angiogenesis by the CarboxylTerminus of Angiopoietin-Like Protein4[J].Arterioscler Thromb VascBiol,2008,5:835-840
[40]于冬梅,裴凌.血管生成素1与肺损伤研究进展[J].沈阳部队医药,2009,22(5):349-351.
[41]韩沙沙,王晓芝.血管生成素4的研究进展[J].医学综述,2011,17(6):807-809