IL-11对中子辐射小鼠肠道损伤保护作用的定量病理研究

目的定量研究IL-11对中子照射后小鼠肠道损伤的保护作用。方法4.0 Gy中子全身照射136只BALB/C二级小鼠,于照前和照后注射600μg/kg的rhIL-11(每日1次,连用3 d),并于照后6 h、1 d、2 d和5 d活杀取材,采用光镜和图像分析技术研究IL-11对中子照射后肠道病理形态、肠绒毛高度和隐窝细胞数的影响。结果4.0 Gy中子照射后,肠隐窝细胞核肿胀、浓缩及核碎片形成,再生微弱;照前和照后给予IL-11,肠绒毛高度增加、绒毛上皮和隐窝数量增多,有较多新生的肠隐窝,与单纯照射组比较,差异显著(p<0.05或0.01)。结论应用IL-11可减轻中子辐射肠道损伤的程度,增加存活隐窝细胞数量和绒毛高度,并促进其再生,有利于肠粘膜恢复。     

姜黄素对中子照射后小鼠空肠上皮NF-κB表达影响的定量病理研究

目的探讨姜黄素对中子照射后小鼠空肠上皮NF-κB表达的影响。方法选取二级雄性BALB/c小鼠120只,随机分为对照组、3 Gy中子照射组和姜黄素治疗组。照射组小鼠采用3 Gy中子全身均匀照射,姜黄素治疗组于照射后即日腹腔注射一次,剂量为200 mg/（kg.d）,每天1次,连续给药5 d。采用HE染色、免疫组织化学和图像分析等手段,检测小鼠空肠病理形态变化以及空肠上皮NF-κB表达的变化。结果3 Gy中子照射后3 d内,空肠黏膜大面积坏死脱落; 照后3 d偶见隐窝细胞再生,照后5 d见较多新生隐窝; 姜黄素治疗组在照后3 d隐窝再生较明显,照后5 d见大量新生绒毛,排列较为整齐。3 Gy中子照射后6 h-5 d,NF-κB由胞浆转入胞核内,在胞核内表达进行性增加,5 d呈强阳性; 姜黄素治疗组在照射后3 d和5 d,NF-κB在胞核内表达呈阳性,强度弱于照射组。结论3 Gy中子照射引起小鼠空肠严重损伤,姜黄素治疗可减轻损伤并促进肠道上皮再生修复,其保护作用可能与NF-κB信号通路抑制有关。     

中子及γ线照射小鼠肠道损伤的定量病理研究

目的 定量比较研究小鼠经中子及γ线照射后肠道损伤的病理特点。方法 350只二级雄性BALB/C小鼠,经不同剂量的中子和γ线照射,于照后6h、12h、1d、2d、3d、4d、5d、7d、10d、14d、21d及28d分批活杀,进行全肠长度及重量测量;全肠组织10%缓冲福尔马林固定,石蜡包埋制片, 潘氏细胞及HE染色,Leica图像分析仪检测隐窝细胞数密度和隐窝内潘氏细胞的面密度。结果 中子及γ线照射后全肠的长度缩短、重量减轻,且重量减轻先于长度缩短。2.5Gy中子照射后肠粘膜见明显损伤及损伤后恢复现象,4.0Gy以上照射未见明显恢复。g 射线5.5Gy照射未见粘膜剥脱,12Gy组隐窝再生能力介于中子4.0-5.5Gy之间。中子2.5Gy照后1d内,隐窝细胞数进行性减少,于照后3d增多,7d达高峰,而5.5Gy中子和12Gyγ线于照后3d内均明显进行性减少(p<0.01)。γ线5.5Gy隐窝细胞增加发生时间早,高峰提前。中子2.5Gy照后7d时潘氏细胞明显增加(p<0.05);而5.5Gy组于照后2d潘氏细胞相对增多(p<0.05)。5.5Gyγ线于照后5d增加(p<0.05)。结论 照射后肠隐窝细胞明显损伤,相同剂量照射后,中子对隐窝细胞损伤明显重于γ线;射线对潘氏细胞影响较小,相同剂量的中子及γ线照射后,潘氏细胞出现不同的变化规律。     

IL-3基因在γ线照后小鼠骨髓造血细胞中表达的形态定量研究

本文用图像分析和免疫组化等技术研究小鼠骨髓辐射损伤后造血细胞IL- 3 基因表达及意义。结果表明: 照后4 周内小鼠骨髓出现明显损伤及损伤后重建现象。免疫组化显示正常小鼠骨髓中仅少部分造血细胞浆内IL- 3 呈弱阳性; 5-5Gy 照后6h ～6d, 造血细胞浆内IL- 3 进行性减少, 尤其照射1d 后, 基本不见造血细胞表达IL- 3 ; 照射后10d , 少部分造血细胞中始见IL- 3 表达, 呈弱阳性; 照射后15 ～21d, 造血细胞中IL- 3 逐渐增加, 达最高峰, 表现为IL-3 表达的造血细胞增多, 阳性强度增强。然后4 周, 造血细胞内IL- 3 呈减少趋势, 但仍高于正常小鼠骨髓。定量分析表明IL- 3 于照后15 ～28d , 其单位面积的积分光密度及数密度明显增加( P< 0-01 或P< 0-05) , 尤以照后21d 为显著( P< 0-01) 。据此作者认为, 内源性IL- 3 基因表达在骨髓辐射损伤后造血功能重建中可能起明显的促进作用     

TNF-α和IL-1α在鼠肺组织照射后不同时间的表达

目的探讨BALB/C小鼠肺组织照射后,TNF-α和IL-1α细胞因子在肺和肝脏的释放特点。方法 雄性BALB/C小鼠30只随机分配到照射组(R)和对照组(C)。R组:24只/组,C组:6只/组,照射组用6MV-X射线单次25Gy胸部照射;两组小鼠在照射后1个月、2个月、3个月被处死,采用免疫组化方法检测照射小鼠肺和肝脏组织中TNF-α和IL-1α表达水平。结果 R组的TNF-α和IL-1α在肺和肝脏的表达水平在照射后1个月、2个月、3个月明显高于C组(P＜0.01),在2个月后表达最高。结论 肺组织照射后TNF-α和IL-1α在肺和肝脏的表达水平明显增高,在照射后2个月的小鼠中TNF-α和IL-1α表达尤为显著。     

ERK通路在中子和γ线致IEC-6细胞损伤中的变化及IL-11的调控作用

目的复制中子和γ线致肠道损伤的体外模型,探讨ERK通路的变化规律及IL-11对其调控作用,为阐明中子和1线致伤差异的分子机制并寻找有效的防治措施提供依据。方法采用4Gy中子和10Gy1射线照射IEC-6大鼠肠上皮细胞,并于照射前12h或照射后即刻给予100ng／ml的rhIL-11,采用流式细胞术、Westernblot和图像分析技术,分别检测IEC-6细胞凋亡和坏死率以及Raf-1、MEK1／2、ERK1／2表达及活化的变化。结果中子和叫线均可造成IEC-6细胞损伤,且前者损伤更重;应用IL-11后,二组凋亡率和坏死率均出现下降。1射线照射后6～24h,IEC．6细胞Raf-1表达和活化及MEK1／2活化升高,ERK1／2活化减弱,IL-11处理组于照射后5～15min可增加Raf-1和MEK1／2活性,照射后6h抑制ERK1／2活化。中子照后6～24h,Raf-1表达和活化及MEK1／2活化无明显变化,ERK1／2表达和活化升高,与照射组比较,IL-11处理后6h,Raf-1表达变化不明显,照射后6～24h,MEK1／2活化升高,IL-11在照射后6h抑制ERKl／2活化,照后24h增加ERK1／2表达及活化。结论中子照射造成IEC-6细胞ERK1／2活化,而γ射线照射则表现为抑制作用;IL-11通过调控ERK通路对二者造成的肠损伤具有防护作用。     

超高剂量率FLASH照射降低小鼠肠道正常组织损伤

目的研究与常规剂量率照射相比, 超高剂量率(FLASH)照射是否可降低小鼠肠道的辐射损伤。方法 FLASH照射和常规剂量率照射均使用电子线, 剂量率分别为750 Gy/s和0.5 Gy/s。105只小鼠采用简单随机化法随机分组。取21只进行体重观察比较, 每组7只, 用9 Gy FLASH和常规剂量率照射小鼠全腹后, 隔日测小鼠体重, 与对照组进行三组间比较。取24只进行病理检查, 对照组小鼠5只, 用12 Gy FLASH(10只)和常规剂量率(9只)照射小鼠全腹后3.5 d, 取小鼠肠道做病理切片, HE染色后比较两组小鼠每毫米小肠的再生隐窝数与再生隐窝百分比。另取20只, 每组10只, 分别用FLASH和常规剂量率照射小鼠全腹后, 观察记录小鼠生存情况。各组10只小鼠, 进行分次照射观察体重, 其中FLASH照射为4.5 Gy×2次, 常规剂量率照射为9 Gy×1次。再各取10只小鼠, 进行进行分次照射观察生存情况, 其中FLASH照射为6 Gy×2次, 常规剂量率照射为12 Gy×1次。两次照射间隔1 min。使用EBT3胶片监测FLASH和常规剂量率照射小鼠实际受照射剂量。符...     

姜黄素对中子照射后小鼠空肠上皮细胞增殖活力的影响

目的探讨姜黄素对中子照射后小鼠空肠上皮细胞增殖活力的影响。方法选取二级雄性BALB/c小鼠120只,随机分为对照组、3Gy中子照射组和3Gy中子照射+姜黄素治疗组。照射组和姜黄素治疗组小鼠采用3Gy中子全身均匀照射,姜黄素治疗组于照射后即日腹腔注射200mg.kg-1.d-1的姜黄素,每天1次,连续给药5 d。于照射后6 h、1 d、3 d和5 d活杀取材,留取小鼠空肠组织,采用AgNOR、Feulgen染色和图像分析等手段,定量检测小鼠空肠上皮细胞核内嗜银蛋白数密度和DNA含量积分光密度的变化。结果照射组和姜黄素组于照后6 h～5 d,空肠上皮细胞核内AgNOR和DNA含量明显下降(P<0.01);照后3～5 d姜黄素组小鼠空肠上皮细胞AgNOR和DNA含量较照射组有所增加(P<0.05或0.01),但相比对照组仍较低。结论 3Gy中子照射引起小鼠空肠上皮细胞增殖活力明显降低;应用姜黄素治疗可增加空肠上皮细胞的增殖活力,对中子辐射肠上皮损伤具有保护作用。     

中子照射小鼠脾脏损伤特点及rhIL-11的治疗作用

目的探讨中子照射小鼠脾脏的损伤特点及重组人白介素-11（recombinant human inter-leukin-11,rhIL-11）对小鼠中子照射脾脏损伤的治疗作用。方法选取二级雄性BALB/c小鼠90只,随机分为对照组、3Gy中子照射组和rhIL-11治疗组。照射组小鼠采用3 Gy中子全身照射,rhIL-11给药剂量为600μg/kg/d,每天1次,连续给药7 d。采用HE染色、电镜、核仁组成区嗜银相关蛋白（argyrophylic nucleolar organizer regions,AgNORs）染色和图像分析等手段,观察小鼠脾脏病理形态变化以及脾脏淋巴细胞增殖活力的改变。结果3 Gy中子照射后小鼠脾小体内淋巴细胞数量显著减少,以坏死为主,淋巴细胞内AgNORs面积与核面积比显著减少; rhIL-11治疗后3 d小鼠脾小体内见大量淋巴细胞增生,淋巴细胞内AgNOR面积与核面积比高于照射组。结论3 Gy中子照射可致小鼠脾脏损伤,rhIL-11可减轻其损伤,促进淋巴细胞增生。     

低氧对小鼠小肠的放射防护作用

为探讨放射治疗中氧效应,在低氧状态下对小鼠一次性照射,计数小肠纵断面隐窝数,观察低氧对小鼠的防护作用。结果为:未受照射的低氧组与空气组的组织学表现或隐窝计数无显著差异,表明短时间单纯吸入低氧(11％)72小时后不会对小肠产生明显影响。5Gy照射后72小时后78％隐窝明显再生,与对照组无明显差异。8Gy,10Gy,12Gy,15Gy,18Gy组与空气对照组都有显著性统计差异。     

Expression of interleukin-11 (IL-11) and IL-11 receptor alpha in human gastric carcinoma and IL-11 upregulates the invasive activity of human gastric carcinoma cells

Previous investigations have shown that interleukin-11 (IL-11) and the IL-11 receptor (IL-11R) have been correlated with the regulation of tumor progression, cellular growth and differentiation in several malignant tumors. The objectives of this study were to clarify the role of IL-11 and IL-11Ralpha in human gastric carcinoma. IL-11 and IL-11Ralpha were studied in 73 cases of surgically resected human gastric adenocarcinomas by immunohistochemistry. The invasive activity and cell signaling pathway of gastric carcinoma cell lines were also examined. Among the 73 cases of adenocarcinoma, 53 (72.6%) and 47 cases (64.4%) showed positive staining in carcinoma cells for the IL-11 and IL-11Ralpha proteins, respectively. Histologically, IL-11 expression correlated only with Lauren's classification (p<0.05). The expression of IL-11Ralpha correlated with the grade of tumor invasion (p<0.05) and vessel infiltration (p<0.01). All of the four gastric carcinoma cell lines expressed both IL-11 and IL-11Ralpha proteins in western blot analysis. Recombinant human IL-11 (rhIL-11) promoted the migration of SCH cells by the activation of the phosphatidylinositol-3 kinase pathway. Wortmannin diminished the promotion of chemotactic motility and invasive activity by rhIL-11. These findings suggest that the IL-11/IL-11R pathway plays an important role in the progression and the differentiation of human gastric carcinomas.     

白细胞介素-11的临床应用

白细胞介素-11是一种多效性细胞因子,能促进巨核细胞的分化和成熟,升高外周血小板数,保护胃肠道粘膜,调节机体的免疫功能,具有良好的临床应用前景.现综述有关白细胞介素-11临床应用的研究进展.     

白细胞介素-11的临床应用

白细胞介素-11是一种多效性细胞因子,能促进巨核细胞的分化和成熟,升高外周血小板数,保护胃肠道粘膜,调节机体的免疫功能,具有良好的临床应用前景.现综述有关白细胞介素-11临床应用的研究进展.     

Interleukin-11 (IL-11) enhances clonal proliferation of acute myelogenous leukemia cells with strong expression of the IL-11 receptor alpha chain and signal transducing gp130.

We examined the effect of recombinant human interleukin (IL)-11 alone or in combination with various colony-stimulating factors (CSFs), including IL-3, granulocyte/macrophage (GM)-CSF, granulocyte (G)-CSF, stem cell factor (SCF), flt3 ligand (FL), and thrombopoietin (TPO), on colony formation by leukemic progenitor cells (L-CFU) obtained from 33 patients with acute myelogenous leukemia (AML). Leukemic colony formation was found in approximately 70 to 80% of the patients in the presence of at least one of the above CSFs. Although IL-11 alone did not support L-CFU, the growth of these progenitors in the presence of other cytokines was enhanced by IL-11 in 16 out of 33 patients and it showed a synergistic action with G-CSF in 12 of them. This synergistic action occurred in seven out of nine M5 patients (French-American-British (FAB) classification). A single cell clone-sorting experiment clearly demonstrated that this synergistic effect was operative at the single progenitor cell level. The number of leukemic cells proliferating in the presence of G-CSF+IL-11 was significantly higher than in the presence of G-CSF alone, suggesting that IL-11 recruited dormant leukemic progenitors into the cell cycle. Flow cytometric analysis revealed that all types of AML blast cells (M0 approximately M6) ubiquitously expressed gp130, although the level of expression was significantly higher in M5 cells. In contrast, expression of the IL-11 receptor alpha chain (IL-11Ralpha) varied between FAB types. Blast cells obtained from M1, M3 and M5 patients showed higher levels of expression, with M5 cells showing the strongest expression. Interestingly, the leukemic progenitor cells for which proliferation was synergistically enhanced by IL-11 had significantly higher expression of both IL-11Ralpha and gp130. These results suggest that administration of IL-11 in vivo may stimulate the proliferation of leukemic progenitor cells, particularly M5 cells, in the presence of G-CSF, and that the responsiveness of L-CFU to IL-11 may be predicted by a simple receptor assay.     

Expression of interleukin (IL)-11 and IL-11 receptor in human colorectal adenocarcinoma: IL-11 up-regulation of the invasive and proliferative activity of human colorectal carcinoma cells

Previous investigations have shown that interleukin (IL)-11/IL-11 receptor alpha-chain (IL-11Ralpha), a member of the PI3K, MAPK and JAK-STAT activating family of cytokines/receptors, correlates with the regulation of tumor progression. In this study, we established the IL-11/IL-11Ralpha expression profile in human colorectal adenocarcinoma (CRC) and clarified its signaling pathway and role in the invasion activity of CRC cell lines. To elucidate the role of IL-11/IL-11Ralpha, we examined 103 cases of CRC and 24 cases of colorectal adenoma by immunohistochemistry. In addition, we investigated the invasive activity of cell signaling pathway of CRC cell lines. The IL-11Ralpha expression was correlated with tumor invasion and lymphatic infiltration (p<0.01, respectively). Recombinant human IL-11 (rhIL-11) promoted the migration and proliferation of HT-29 cells and activated the PI3K and p44/p42 MAPK pathways. Wortmannin, a PI3K inhibitor, and PD98059, a p44/p42 MAPK inhibitor, significantly reduced the promotion of invasion and proliferation activity by rhIL-11, respectively. In summary, the IL-11Ralpha expression was correlated with clinicopathological features and IL-11 promoted the invasion via the PI3K and up-regulated the proliferation via the p44/p42 MAPK in CRC cells. These findings suggested that the IL-11/IL-11R pathway plays an important role in the progression of CRC.     

基因重组人白细胞介素-11治疗恶性肿瘤化疗所致血小板减少症的临床探讨

目的观察基因重组人白细胞介素-11(rhIL-11)治疗恶性肿瘤化疗所致血小板减少症的临床疗效及不良反应。方法本组51例患者随机分为治疗组(27例)和对照组(24例)。治疗组病例化疗后外周血血小板计数≤50×109/L时,给予rhIL-11 1.5 mg皮下注射,1/d,连续用药5~14 d,平均9.2 d;当外周血血小板升至≥100×109/L时停用rhIL-11观察血像。对照组病例仅以输注血小板及对症治疗为主。结果治疗组患者应用rhIL-11前后自身比较血小板计数最低值显著升高,差异有显著性(P<0.01);治疗组患者化疗后应用rhIL-11血小板计数最低值较对照组化疗后的最低值显著升高,差异也有显著性(P<0.01);治疗组应用白介素-11后血小板计数低于5.0×109/L的天数比对照组明显缩短,两者比较差异也有显著性(P<0.01)。共治疗27例恶性肿瘤化疗所致的血小板减少症,显效9例(33.3%),有效18例(66.7%)。结论在恶性肿瘤化疗所致的血小板减少症的治疗中,rhIL-11的升血小板作用显著、安全、经济实用。     

急性白血病患者血清IL-11及sgp130水平的测定

 目的 探讨IL-11及sgp130在初诊急性白血病（AL）诱导缓解过程中的变化及临床意义。方法 采用ELISA检测方法分别对47例初诊AL患者治疗前及获完全缓解(CR)后的血清IL-11及sgp130含量进行动态观测，同时观察患者外周血白细胞和血小板数量的变化。结果 AL患者的血清IL-11水平明显低于正常人（p<0.05），经过诱导化疗获CR后又明显升高并接近正常水平，且与外周血血小板数呈正相关；而sgp130水平明显高于正常人（p<0.05）,获CR后又明显下降且与外周血白细胞数呈正相关。结论 检测AL患者血清IL-11及sgp130水平可作为了解AL患者病情判断疗效和预后的有意义的指标。