纤维状α-突触核蛋白聚集体激活NLRP3炎症小体的机制研究

目的 探索纤维状α-突触核蛋白（α-synuclein）聚集体激活NLRP3炎症小体诱导神经炎症的机制。方法 构建纤维状α-synuclein聚集体,采用纤维状α-synuclein聚集体刺激BV-2小胶质细胞,检测白介素（IL）-1β、IL-18、IL-6和肿瘤坏死因子α(TNF-α)等相关炎症因子和NLRP3、caspase-1、ASC等蛋白的表达和mRNA水平评价NLRP3炎症小体激活;采用乳酸脱氢酶释放（LDH）实验检测细胞焦亡的发生。机制研究部分,检测Toll样受体（TLR）2和TLR4的激活,并分别加入TLR2和TLR4抑制剂C29和TAK-242检测对纤维状α-synuclein聚集体诱导的NLRP3炎症小体激活的影响及核转录因子-κB(NF-κB)的入核情况。结果 Westernblot和硫黄素T染色实验结果显示,纤维状α-synuclein聚集体成功制备。纤维状α-synuclein聚集体刺激BV-2小胶质细胞24 h后可激活NLRP3炎症小体,表现为IL-1β释放增加,相关蛋白NLRP3、caspase-1表达升高,N LR P3、ASC和I L-1β的m R NA...     

心力衰竭患者核因子-kB活化与细胞因子分泌的相关性实验分析

目的：探讨充血性心力衰竭（CHF）患者外周血单个核细胞（PBMCs）核因子－kB（NF—kB）表达与肿瘤坏死因子－α（TNF-α）,白介素－1β（IL-1β）分泌的相天性。方法：将20例心力衰竭患者和11例健康对照组PBCs NF—kB表达由免疫组化染色检测,血清细胞凶子的含量由放射免疫法测定。对两组的指标进行t检验及相关分析。结果：心力衰竭患者外周血单个核细胞NF—kB／p65胞核染色率明显高于健康对照组（P〈0．01）,且NF—kB表达增高,细胞因子（TNF—β,IL-1β,IL－6）含量呈湿著正相关（P〈0．05）。结论：充血性心力衰竭患者NF—kB／p65表达增高,细胞因子（TNF一α,IL－1β,IL－6）分泌增多。充血性心力衰竭,可能通过NF—kB表达的上调促进细胞凶子（TNF—α,IL－1β,IL－6）的分泌。     

巨噬细胞移动抑制因子siRNA对肺泡上皮细胞Toll样受体及其下游信号转导通路的影响

目的:研究巨噬细胞移动抑制因子siRNA对脂多糖刺激的肺泡上皮细胞Toll样受体(TLR)及其下游信号转导通路的影响和作用机制.方法:用LPS刺激A549细胞,脂质体法分别将巨噬细胞移动抑制因子(MIF) siRNA和非特异性siRNA加入A549细胞进行干预.RTPCR法检测MIF和TLR2、TLR4 mRNA的表达,Western Blot法分析TLR下游信号转导通路元件髓样分化因子88 (MyD88)和干扰素调节因子3(IRF3)蛋白表达,细胞免疫荧光法观察NF-κB核迁移,ELISA法测定细胞培养上清炎症介质TNF-α、IL-1β、IL-6,免疫介质IFN-β分泌水平.结果:MIF siRNA对LPS刺激诱导的MIF和TLR2、TLR4 mRNA高表达有显著的下调作用和部分阻断NF-κB(p65)核迁移.LPS刺激诱导后,MIF siRNA显著降低MyD88蛋白表达和炎症介质TNF-α、IL-1β和IL-6的分泌水平,但MIF siRNA对IRF3蛋白表达和免疫介质IFN-β分泌水平无影响.结论:MIF siRNA能抑制A549细胞的炎症介质TNF-α、IL-1β、IL-6过度分泌,其机制可能是MIF siRNA降低了LPS刺激A549细胞诱导的MIF和TLR2、TLR4高表达,及阻断TLR下游信号转导通路元件MyD88和NF-κB核迁移.     

复方积雪草有效组分干预肾小管上皮细胞Toll样受体4表达的实验研究

目的：探讨复方积雪草有效组分-积雪草苷／大黄素干预肿瘤坏死因子α（TNF—α）诱导的小鼠肾小管上皮细胞（mTEC）Toll样受体4（TLR4）mRNA及蛋白的表达水平。方法：采用mTEC,模型组用TNF—α 5ng／mL诱导,治疗组在TNF-α诱导的同时,以不同浓度的积雪草苷合大黄素进行干预,于24h后分别提取细胞RNA及上清,应用逆转录．聚合酶链反应（RT-PCR）和流式细胞术（FCM）分别检测mTEC TLR4 mRNA和膜蛋白的表达。结果：正常mTEC具有TLR4 mRNA和蛋白表达,经TNF-α诱导后TLR4表达明显上调,当积雪草苷合大黄素干预浓度达4ug／mL＋0．4ug／mL时,能够抑制TLR4 mRNA及蛋白的表达水平。结论：复方积雪草有效组分能够抑制TNF-α上调所致的肾小管上皮细胞TLR4过度表达,从而缓解肾脏局部失控性炎症反应。     

五味子甲素对脂多糖诱导的小鼠RAW264.7细胞的抗炎作用

目的：探讨五味子甲素对脂多糖诱导的小鼠RAW264.7细胞的抗炎作用。方法：检测五味子甲素对于脂多糖诱导的RAW264.7细胞的增殖、凋亡、吞噬及细胞内白细胞介素-lβ（IL-lβ）、肿瘤坏死因子-α（TNF-α）、前列腺素E2（PGE2）和环氧合酶-2（COX-2）水平的影响。脂多糖诱导后加入不同浓度五味子甲素,CCK8法测定RAW264.7细胞增殖,中性红试剂检测诱导后RAW264.7细胞的吞噬能力。经酶联免疫吸附试验（ELISA）法测定细胞培养血清中IL-lβ、TNF-α、PGE2和COX-2水平的表达。Annexin V-FITC/PI双染检测五味子甲素对诱导后RAW264.7细胞凋亡的影响。结果：五味子甲素可明显抑制脂多糖诱导的RAW264.7细胞的增殖、吞噬能力及诱导刺激的细胞凋亡;ELISA结果显示,五味子甲素可以抑制细胞IL-lβ、TNF-α、PGE2和COX-2的水平。结论：五味子甲素对脂多糖诱导的小鼠RAW264.7细胞炎症具有明显的抑制作用,其机制可能与抑制炎症细胞的增殖、吞噬,减少炎症因子释放,减轻脂多糖诱导引起的细胞凋亡有关。     

头孢地嗪对中性粒细胞细胞因子分泌的影响

目的研究头孢地嗪（cefodizime，CDZ）对肺炎克雷伯菌（Klebsiella pneumoniae）感染诱导的小鼠中性粒细胞因子分泌的影响，并初步探讨其与LPS—TLR—NFKB信号传导通路的关系。方法用RT—PCR、ELISA等方法检测肺炎克雷伯菌感染诱导中性粒细胞分泌的TNF—α、IL-1β改变和Toll like receptor 4（TLR4）的表达；Western blotting检测I-κB活性，以及CDZ对上述指标的影响。结果CDZ促进了肺炎克雷伯菌感染早期小鼠中性粒细胞TNF—α、IL-1β分泌及TLR4的mRNA表达，同时伴有I—κB的降解增强；在感染后期CDZ降低了中性粒细胞TNF—α、IL-1β的分泌，但仍可促进TLR4表达。结论CDZ对肺炎克雷伯菌感染诱导的小鼠中性粒细胞有免疫调节作用，此作用可能与其调节TLR4表达和I-κB活性而影响TNF—α、IL-1β等促炎因子基因转录有关。     

Toll样受体9与溃疡性结肠炎

Toll样受体（Toll—likerecepters,TLRs）是与果蝇Toll蛋白具有同源性的表达于细胞膜上与免疫系统识别微生物有关的一类受体家族,自1997年Medzhitov等首次发现了人类的第一种Toll同源变体（即TLR4）,后又发现了至少11种人的TLR家族蛋白,分别被命名为TLR1～11。TLR9作为TLR家族的一员,主要识别细菌的非甲基化的胞嘧啶-磷酸-鸟嘌呤基序（cytidine—phosphate—guanosine,CpGDNA）。可以介导CpGDNA激活多种免疫细胞,如B细胞、T细胞、DC细胞、巨噬细胞等,导致细胞表面共刺激分子CIM0、CD80、CD86及MHCⅡ类分子等表达增多,同时分泌细胞因子如TNF—β、IL-2、IL-12、IFN-γ等,诱导免疫应答,从而在UC的发病中起了重要的作用。     

胰岛素抵抗骨骼肌细胞中P-Ser473PKB及糖原合成酶-3表达

目的探讨棕榈酸(PA)诱导的胰岛素抵抗(IR)骨骼肌细胞中P-Ser473PKB及糖原合成酶(GSK)-3的表达。方法培养大鼠骨骼肌细胞,免疫荧光鉴定原代大鼠骨骼肌细胞;设立对照组、PA组(0.6mmol/L PA),在细胞培养6、122、4 h后,胰岛素刺激15 min,葡萄糖氧化酶-过氧化物酶偶联(GOD-POD)法测定培养液中葡萄糖的浓度;Western blot检测P-Ser473PKB及P-Ser21/9GSK-3α/β的蛋白表达。结果 90%以上的肌细胞-αsarcometric actin单克隆抗体染色呈阳性,证明培养的为骨骼肌细胞;培养24 h后,PA组培养液中葡萄糖浓度高于对照组,P-Ser473PKB蛋白水平低于对照组,而P-Ser21/9GSK-3α/β高于对照组(P值均<0.05)。结论 PA作用下,胰岛素刺激的骨骼肌细胞对葡萄糖的处理能力下降,即PA可诱导骨骼肌细胞产生胰岛素抵抗,其机制可能与P-Ser473PKB蛋白表达下调,P-Ser21/9GSK-3α/β表达增加有关。     

柚皮苷对人皮肤角质细胞分泌趋化因子RANTES及其核转录因子-kB信号通路影响的实验研究

目的：研究炎症性细胞因子肿瘤坏死因子α（TNF-α）和γ干扰素（IFN-γ）对人皮肤角质细胞（HaCaT）分泌趋化因子RANTES的诱导作用;以阿维A为阳性对照药,研究柚皮苷对此诱导作用的抑制作用及其机制。方法：将HacaT分为阴性对照组、模型刺激组（TNF-α＋IFN—γ）、阿维A预处理组（TNF-α＋IFN—γ＋阿维A）和柚皮苷预处理组（TNF-α＋IFN—γ＋柚皮苷）等;采用酶联免疫吸附（ELISA）法测定HaCaT细胞经单用和合用TNF-α、IFN-γ刺激以及加入阿维A和柚皮苷后RANTES的分泌量。采用免疫细胞化学方法和Western blot法检测HaCaT中核转录因子-KB P65（NF—kB P65）蛋白的表达。结果：单用或合用TNF—α、IFN-γ可显著诱导细胞分泌RANTES,并以合用组作用最显著（P〈0．01）。柚皮苷、阿维A均能明显抑制TNF-α、IFN-γ诱导的RANTES的分泌（P〈O．01）及NF—kB P65蛋白的表达。结论：柚皮苷可以抑制TNF-α、INF-γ诱导RANTES的分泌及相关蛋白的产生,其机制可能是通过抑制NF—kB信号传导途径的活化而实现。     

西红花酸对溃疡性结肠炎大鼠模型的作用及其机制研究

目的：研究西红花酸（crocetin）对2,4,6-三硝基苯磺酸（TNBS）／乙醇诱导的大鼠溃疡性结肠炎（ulcerativecolitis,UC）的作用及可能机制。方法：采用TNBS／乙醇混合复制溃疡性结肠炎模型,用不同剂量的西红花酸进行干预。观察大鼠结肠组织形态变化;检测髓过氧化物酶（MPO）、丙二醛（MDA）和超氧化物歧化酶（SOD）活性;ELISA法测定肿瘤坏死因子-a（TNF—a）和白介素-1B（IL-1J3）含量;实时荧光定量PCR（Q—PCR）检测Toll样受体4（TLR4）和核转录因子-eBp65（NF-kBp65）基因的表达;免疫组化分析TLR4和NF-kBp65蛋白的表达。结果：西红花酸能改善UC大鼠结肠形态及组织病理学变化;西红花酸能抑制MPO活性、降低MDA含量、提高SOD活性;西红花酸能下调TNF—a和IL-1B的含量;西红花酸能降低TLR4和NF-kBp65基因与蛋白的表达。结论：西红花酸能有效改善溃疡性结肠炎大鼠的结肠炎症反应,其作用机制与抗氧化、抑制TLR4／NF—KB信号通路等有关。     

葡萄糖及细胞因子对胰岛素瘤相关蛋白-2表达水平的影响

目的探讨葡萄糖、肿瘤坏死因子(TNF)-α、干扰素(IFN)-γ对胰岛细胞自身抗原胰岛素瘤相关蛋白(IA)-2表达水平及胰岛素分泌水平的影响。方法以不同浓度的葡萄糖(3、7、11、30mmol/L)、10ng/mlIFN-γ及100ng/mlTNF-α分别刺激胰岛细胞系RIN5F24h和48h,用反转录聚合酶链反应(RT-PCR)方法检测各组RIN5F细胞中IA-2的mRNA表达水平,并用放射免疫法检测上清中胰岛素的浓度。结果RT-PCR结果显示以不同浓度葡萄糖(3、7、11、30mmol/L)分别刺激RIN5F细胞系后IA-2mRNA水平呈浓度依赖性和时间依赖性增加;TNF-α可抑制IA-2mRNA的水平,并且作用48h后IA-2表达水平显著降低(P<0.05);IFN-γ作用24h及48h均可显著抑制IA-2的表达(P<0.05)。TNF-α或IFN-γ刺激RIN5F细胞系后,上清中胰岛素水平均较基础值降低,并且作用48h后差异有统计学意义(P<0.05)。结论葡萄糖可使IA-2的mRNA水平呈剂量依赖性和时间依赖性增加,TNF-α、IFN-γ可抑制IA-2的mRNA表达和胰岛素分泌浓度。     

蒺藜提取物治疗2型糖尿病药效及其机制研究

目的：观察蒺藜提取物（NO.JL201）对自发性2型糖尿病模型KKAy小鼠空腹血糖（FPG）、血胰岛素（Ins）、TNF-α、IFN-β含量及其胰岛细胞TLR3、TLR4mRNA含量的影响,初步探讨其可能降糖机制。方法：KKAy小鼠随机分为模型组、JL201大（20mg/kg BW）、中（10mg/kg BW）、小（5mg/kg BW）剂量组和阳性药二甲双胍组（400mg/kg BW）。每周测定体质量,食、水量和FPG。给药4周后取血,测定小鼠FPG和Ins,计算小鼠Ins敏感性,Real time-PCR法测定胰岛细胞TLR2、TLR4 mRNA含量。结果：JL201不同剂量不同程度地减少了小鼠的进食、饮水量,明显降低KKAy小鼠的FPG（P〈0.05或P〈0.01）、降低血清Ins含量（P〈0.05或P〈0.01）,明显升高KKAy小鼠胰岛素敏感性（P〈0.05）,减少TNF-α、IFN-β的血中分泌量。JL201同时可降低胰岛细胞TLR2、TLR4mRNA含量。结论：JL201有较好的降血糖、增强胰岛素敏感性等作用,并能明显改善多饮、多食的临床症状,其作用可能与降低胰岛细胞TLR2、TLR4mRNA含量、抑制炎症有关。     

Discrepant roles of CpG ODN on acute alcohol-induced liver injury in mice

Increasing evidence suggests that the alcoholic liver injury is associated with activation of Toll-like receptors (TLRs) and the consequent over-production of inflammatory cytokines such as TNF-α. However, few studies have evaluated the effect of CpG ODN, a TLR9 agonist, on alcoholic liver injury. In this study, an animal model of acute alcohol-induced liver injury was established by administering the mice with alcohol at 7 g/kg intragastrically once. Using the model, 2216, an A-type CpG ODN, was found able to dramatically elevate serum ALT levels and aggravate pathological changes of liver in mice. In contrast, 2006, a B-type CpG ODN, caused elevation of serum ALT levels with no visible aggravation of liver pathological changes; YW002, a C-type CpG ODN, caused no elevation of serum ALT levels and seemed able to lessen pathological changes in the liver of the mice. Real-time RT-PCR revealed that 2216 dramatically up-regulated the expression of TLR9 and TNF-α and YW002 was unable to up-regulate expression of TLR9 and TNF-α, instead up-regulate the expression of IFN-α in the livers of the model mice. The data suggest that 2216 could aggravate alcohol-induced liver injury by inducing the up-regulation of hepatic TLR9 and TNF-α and that YW002 could alleviate the pathological changes induced by acute alcohol intake by up-regulating IFN-α, possibly.     

Miltefosine triggers a strong proinflammatory cytokine response during visceral leishmaniasis: role of TLR4 and TLR9

Visceral leishmaniasis (VL) caused by the protozoan parasite, Leishmania donovani, is associated with irregular fever, weight loss, hepatosplenomegaly and anemia. The therapeutic arsenal against VL is limited and the recent advent of a novel immunomodulatory drug, Miltefosine has shown promising results for effective treatment of VL but its dependence on Toll like receptors (TLR) has not been explored. In this study, we have shown that the non-cytotoxic dose (5 μM) of Miltefosine could render significant protection corresponding to 88% and 95% reduction in intracellular parasite load at 24 h and 48 h in L. donovani infected THP1 cells. This was accompanied by a strong proinflammatory cytokine response in the form of IFN-γ, IL-12 and TNF-α as evident by enzyme linked immunosorbent assay (ELISA) and real time PCR (RT-PCR). This Miltefosine induced proinflammatory cytokine response in infected THP1 cells was also accompanied by simultaneous 10- and 12-fold increase in TLR4 mRNA and TLR9 mRNA. These changes in cytokine response and TLR expression were also studied in peripheral blood mononuclear cells (PBMC) of VL patients treated with Miltefosine by RT-PCR which showed similar results as in THP1 cells. Thereby, suggesting a probable dependence of Miltefosine on TLR4 and TLR9 in triggering a proinflammatory response.     

Role of TLR4 and TCR or BCR against baicalin-induced responses in T and B cells

Baicalin (BA), a flavonoid compound isolated from Scutellaria baicalensis, has been shown to possess a number of pharmacological effects including antiviral, anti-inflammatory, antioxidant and immune regulation. Here, we examined its effects on human T and B cells proliferation by MTT assay and found that BA stimulated T and B cells proliferation, independently and cooperatively with Con-A (T cells) or LPS (B cells). Then, we analyzed the effects of BA treatment on the mRNA expression of Toll-like receptors (TLRs), IL-2, IFN-γ and IL-12 in T and B cells by real-time RT-PCR and attempted to observe whether blocking TLR4 had influence on mRNA expression. We found that BA treatment significantly up-regulated TLR3, 7, 8 and 9 mRNA expressions in T and B cells, IL-2 and IFN-γ in T cells and IL-12 in B cells. The increased mRNA expressions were suppressed after blocking TLR4. We further analyzed the effects of BA treatment on TCR vβ and CD79 mRNA expression levels in T and B cells and explored whether blocking TCR (αβ) or BCR mIgM F(ab′)₂ had an influence on mRNA expression. We found that BA treatment significantly improved TCR vβ and CD79 mRNA expression in T and B cells, respectively, and the improvements were all inhibited after blocking TCR (αβ) or BCR mIgM F(ab′)₂. Our results suggested that BA participates in innate and adaptive immune regulation by up-regulating the mRNA expression of TLRs (3, 7, 8 and 9), IL-2, IFN-γ and IL-12 in T and B cells, which is mediated by TLR4, and by improving the mRNA expression of TCR vβ and CD79, which is mediated by TCR (αβ) and BCR mIgM, respectively. Therefore, TLR4, TCR (αβ) and BCR mIgM are all the immune receptors for BA on T and B cells.     

Role of TLR4 and TCR or BCR against baicalin-induced responses in T and B cells

Baicalin (BA), a flavonoid compound isolated from Scutellaria baicalensis, has been shown to possess a number of pharmacological effects including antiviral, anti-inflammatory, antioxidant and immune regulation. Here, we examined its effects on human T and B cells proliferation by MTT assay and found that BA stimulated T and B cells proliferation, independently and cooperatively with Con-A (T cells) or LPS (B cells). Then, we analyzed the effects of BA treatment on the mRNA expression of Toll-like receptors (TLRs), IL-2, IFN-γ and IL-12 in T and B cells by real-time RT-PCR and attempted to observe whether blocking TLR4 had influence on mRNA expression. We found that BA treatment significantly up-regulated TLR3, 7, 8 and 9 mRNA expressions in T and B cells, IL-2 and IFN-γ in T cells and IL-12 in B cells. The increased mRNA expressions were suppressed after blocking TLR4. We further analyzed the effects of BA treatment on TCR vβ and CD79 mRNA expression levels in T and B cells and explored whether blocking TCR (αβ) or BCR mIgM F(ab′)₂ had an influence on mRNA expression. We found that BA treatment significantly improved TCR vβ and CD79 mRNA expression in T and B cells, respectively, and the improvements were all inhibited after blocking TCR (αβ) or BCR mIgM F(ab′)₂. Our results suggested that BA participates in innate and adaptive immune regulation by up-regulating the mRNA expression of TLRs (3, 7, 8 and 9), IL-2, IFN-γ and IL-12 in T and B cells, which is mediated by TLR4, and by improving the mRNA expression of TCR vβ and CD79, which is mediated by TCR (αβ) and BCR mIgM, respectively. Therefore, TLR4, TCR (αβ) and BCR mIgM are all the immune receptors for BA on T and B cells.     

Taurine chloramine inhibits NO and TNF-α production in zymosan plus interferon-γ activated RAW 264.7 cells

Taurine is present abundantly in various tissues, especially in leukocytes embattled to foreign invaders such as microorganisms or oxidants. Taurine-chloramine (Tau-Cl) is produced from taurine at the site of inflammation via the myeloperoxidase-halide pathway in leukocytes induced by oxidants and/or infectious materials. Previously, our data demonstrated that Tau-Cl inhibited nitric oxide (NO) production and TNF-α secretion induced by lipopolysaccharide (LPS), a Toll-like receptor 4 (TLR-4) ligand or lipoarabinomannan (LAM), a TLR-2 ligand plus interferon-γ (IFN-γ) in peritoneal macrophages or RAW 264.7 cells. Zymosan, a β-glucan of yeast cell wall, is a ligand for TLR-2 and dectin-1 and stimulates macrophages to produce proinflammatory mediators such as NO and TNF-α. Based on our previous data, we examined the effect of zymosan and IFN-γ induced production of NO and TNF-α in the absence or presence of Tau-Cl or taurine using RAW 264.7 cells. Production of NO and secretion of TNF-α is increased when zymosan is combined with IFN-γ. Tau-Cl inhibited production of NO and secretion of TNF-α in zymosan plus IFN-γ activated RAW 264.7 cells in a dose-dependent manner (99% vs. 48% using 0.8mM Tau-Cl). Taurine was without effect. Nitric oxide synthase protein (iNOS), induced by zymosan plus IFN-γ, was inhibited by Tau-Cl (0.8mM) as measured using western blot analysis. NOS mRNA was inhibited by Tau-Cl at four, eight and 16 hours post activation, but not at 24 hours. TNF-α mRNA was inhibited at four hours and eight hours, but not at 16 and 24 hours. These data suggest that expression of both iNOS and TNF-α mRNAs are inhibited by treatment with Tau-Cl within four and eight hours, but not at later time points. Transient suppression of activation of RAW 264.7 cells induced by zymosan may play a critical physiological role for taurine in protecting against tissue injury from initial overt inflammation. This study indicates that tropical treatment of taurine may ameliorate inflammatory dermatoses caused by an environmental yeast or abnormal immune function.     

低频超声对C6胶质瘤细胞TNF-α表达的影响

目的探讨低频超声对大鼠C6胶质瘤细胞内肿瘤坏死因子-α(TNF-α)表达水平的影响,为进一步研究低频超声开放血脑肿瘤屏障的机制提供实验依据。方法应用1MHz低频超声辐照体外培养C6胶质瘤细胞后,采用酶联免疫吸附试验(ELISA)和逆转录-聚合酶链反应(RT-PCR)法分别检测细胞培养液中TNF-α的含量及胶质瘤细胞中TNF-α mRNA的表达。结果ELISA结果显示C6胶质瘤细胞在低频超声辐照后1.5h～3h,其细胞培养液中TNF-α的含量达高峰。RT-PCR结果亦证明了低频超声辐照后1.5h～3h,TNF-α mRNA的表达水平与对照组相比达高峰。结论低频超声辐照可刺激大鼠C6胶质瘤细胞TNF-α分泌增加,TNF-α的表达上调可能在低频超声开放血肿瘤屏障的过程中发挥一定作用。