粒细胞集落刺激因子与感染

集落刺激因子是调节体内外造血干细胞及成熟白细胞功能的一组糖蛋白生长因子，而粒细胞集落刺激因子则是其中一种主要作用于中性粒细胞的集落刺激因子。本文阐述粒细胞集落刺激因子的产生与作用，对感染的反应性性即体内存在感染时其上升情况，以及对免疫缺隐患者的治疗等问题。     

粒细胞集落刺激因子与心血管疾病

近年来大量的研究表明骨髓干细胞能够促进心肌梗死后侧支循环的形成,加快血管损伤后内皮的修复.粒细胞集落刺激因子是一类血液生长因子,近来研究发现它可以动员骨髓干细胞,使它们归巢到梗死区域,复制、分化并促进心肌的修复.本文就粒细胞集落刺激因子在心血管疾病,包括心肌梗死、血管损伤后再狭窄和心力衰竭中的作用机制及应用进行综述.     

粒细胞集落刺激因子对阿尔茨海默病大鼠脑内炎症的影响

目的探讨粒细胞集落刺激因子(G-CSF)治疗阿尔茨海默病(AD)大鼠对脑内炎症反应的影响。方法 54只Wistar雄性大鼠(3~4个月龄),随机选取18只作为正常组、36只制作AD大鼠模型成功后采用随机数字表法各选取18只分别作为治疗组、模型组;模型组和正常组采用HE染色法对大脑皮层组织进行观察,治疗组给予G-GCS(0.3 ml·kg-1·d-1),模型组和正常组分别给予等量磷酸盐缓冲液(PBS)注射,又分别于第7、14、21天进行相关指标的检测并进行组间比较。结果正常组治疗第7、14、21天的大脑皮层细胞IL-1β染色光密度值均显著低于模型组、治疗组(P0.05),治疗组治疗14、21 d后大脑皮层细胞IL-1β染色光密度值低于模型组(P0.05)。正常组治疗第7、14、21天的大脑皮层细胞TNF-α染色光密度值均显著低于模型组、治疗组(P0.05),治疗组治疗14、21 d后大脑皮层细胞TNF-α染色光密度值低于模型组(P0.05)。结论 AD大鼠对脑内炎症反应作用显著增强,G-CSF可以有效降低AD大鼠的炎症反应作用,对大鼠大脑皮层细胞具有一定的保护作用。     

粒细胞集落刺激因子对心脏缺血—再灌注损伤大鼠心功能的影响

将32只Wistar大鼠在缺血—再灌注的复灌过程中分别灌入粒细胞集落刺激因子（G-CSF）0 ng/ml（I/R组）、10 ng/ml（G10组）、50 ng/ml（G50组）、300 ng/ml（G300组）,测定左心室收缩压（LVSP）、左心室舒张末压（LVEDP）、左心室内压上升最大速率（＋dp/dtmax）、左心室内压下降最大速率（-dp/dtmax）;用氯化三苯基四氮唑染色法检测心肌梗死面积。结果G10组的心功能指标（除LVEDP外）与I/R组相比无统计学差异（P〉0.05）;G50组LVSP高于I/R组,LVEDP低于I/R组（P〈0.05）;与I/R组相比,G300组LVSP、＋dp/dtmax和-dp/dtmax显著升高、LVEDP显著降低,G50组、G300组梗死面积百分比显著降低（P均〈0.01）。提示一定剂量的G-CSF可改善大鼠离体心脏的心功能,缩小心肌梗死面积。     

粒细胞集落刺激因子及其受体

粒细胞集落刺激因子（Ｇ－ＣＳＦ）是一种多肽链的细胞生长因子,可特异地调节粒系细胞的增殖与分化,并能增强成熟粒细胞的功能,对机体应激防御系统有重要意义。近年来发现Ｇ－ＣＳＦ与白血病细胞的凋亡有一定关系。Ｇ－ＣＳＦ功能的发挥有赖于与效应细胞表面的特异性受体的结合。随着基因克隆技术的发展,Ｇ－ＣＳＦ重组产品已广泛用于临床,为血液病及其他疾病的治疗提供了有力的手段。１　Ｇ－ＣＳＦ的生物学作用人类Ｇ－ＣＳＦ由单个基因编码,其基因位于１７号染色体的ｑ２１－２２区,长约２．５ｋｂ,有５个外显子和４个内含子;其…     

粒细胞集落刺激因子治疗心肌梗死

粒细胞集落刺激因子治疗心肌梗死,能动员骨髓干细胞迁移至梗死部位,并分化为心肌细胞、平滑肌细胞、血管内皮细胞,从而减少梗死面积,改善心脏功能,但动物实验结果仍存在着矛盾,临床应用的有效性和安全性还需进一步探讨.     

粒细胞集落刺激因子对大鼠肺动脉高压模型的影响

目的:探讨粒细胞集落刺激因子(G-CSF)对野百合碱(MCT)诱导的大鼠肺动脉高压(PAH)的治疗作用。方法:动物随机分为3组:正常对照组(CON组)、MCT组和MCT/G-CSF组,腹腔注射MCT诱导大鼠PAH模型,采用G-CSF腹腔注射动员自体骨髓干细胞(BMSC),动员结束后行肺组织CD34免疫组化染色,第5周分别对3组大鼠进行血流动力学检测,处死大鼠,取肺、右心组织行苏木素-伊红(HE)染色。结果:1.动员结束后第2天,CD34+细胞浸润至肺血管平滑肌层和血管内皮细胞周围,以及肺泡间隔内;2.实验第35天,MCT组大鼠肺小动脉管壁增厚、管腔明显狭窄,血流动力学指标明显高于CON组(P<0.01);3.MCT/G-CSF组肺血管病变明显改善、肺泡结构完整,血流动力学指标明显低于MCT组(P<0.05)。结论:G-CSF可以动员骨髓干细胞并归巢致受损肺组织内,部分逆转PAH的血流动力学和病理学改变、减缓PAH的进展,用于PAH的研究和治疗。     

粒细胞集落刺激因子治疗粒细胞缺乏症疗效观察

1999～2003年，我院应用重组粒细胞集落刺激因子(rhG-CSF)治疗粒细胞缺乏症，疗效较好。现报告如下。     

G-CSF对创伤性脑损伤大鼠神经再生作用的研究

目的探讨应用粒细胞集落刺激因子（G—CSF）治疗对44伤性脑损伤（TBI）大鼠模型神经功能恢复及神经细胞再生的作用。方法将60只健康雄性Wistar大鼠随机分成假手术对照组、脑创伤对照组、G—CSF治疗组。采用Feeney法制备中度脑创伤模型,O—CSF治疗组在大鼠脑创伤后立即给予G—CSF50μg／（kg·d）,两对照组给予等量的生理盐水,连续3d。通过BrdU标记新生增殖细胞,于术后1d、4d、7d、14d对各组大鼠进行神经功能缺失评分（mNSS）,并取大鼠脑组织行HE染色观察脑组织病理改变,免疫组织化学荧光法进行BrdU染色、BrdU／NeuN双染色检测新生增殖细胞及其分化方向。结果G—CSF治疗组4d、7d、14d时mNSS评分明显低于脑创伤对照组（P〈0．05）,高于假手术对照组（P〈0．05）。BrdU阳性细胞数在用药后4d、7d、14d时G—CSF治疗组明显高于40伤对照组、假手术对照组（P〈0．05）,并且于7d时达高峰;对比7d时创伤周围脑组织BrdU／NeuN双阳性细胞数,O—CSF治疗组明显高于脑创伤对照纽、假手术对照组（P〈0．05）,脑创伤对照纽、假手术对照组相比差异有统计学意义（P〈0．05）。结论应用G～CSF治疗TBI大鼠能明显促进大鼠神经功能恢复,增加创伤周围脑组织细胞增殖,并向神经元细胞方向分化。     

A case of anaplastic carcinoma of the pancreas producing granulocyte-colony stimulating factor

We report a case of anaplastic carcinoma of the pancreas with production of granulocyte-colony stimulating factor (G-CSF) in a 59-year-old male. He was referred to our hospital with a chief complaint of epigastralgia and suffered from leukocytosis. Differential diagnosis included pancreatic tumors and submucosal tumor of the stomach, but definite preoperative diagnosis could not be made. He underwent distal pancreactomy, total gastrectomy with Roux-en-Y reconstruction and splenectomy. He recovered uneventfully postoperatively and was discharged from hospital on the 14th postoperative day. Histological examination showed anaplastic carcinoma of the pancreas. Since the peripheral leukocyte count was sharply decreased after the operation, we suspected the tumor would be producing G-CSF. Then immunohistochemistry showed a positive stain in the tumor. Therefore, we diagnosed the tumor as anaplastic carcinoma of the pancreas producing G-CSF. Three months after the resection, local recurrence was detected by abdominal computed tomography. The patient died of hemorrhagic shock due to tumor invasion of the intestine 8 months after the operation.     

Effects of granulocyte-colony stimulating factor on peritoneal defense mechanisms and bacterial translocation after administration of systemic chemotherapy in rats

AIM: To investigate the effects of granulocyte-colony stimulating factor (G-CSF) on peritoneal defense mechanisms and bacterial translocation after systemic 5-Fluorouracil (5-FU) administration. METHODS: Thirty Wistar albino rats were divided into three groups; the control, 5-FU and 5-FU + G-CSF groups. We measured bactericidal activity of the peritoneal fluid, phagocytic activity of polymorphonuclear leucocytes in the peritoneal fluid, total peritoneal cell counts and cell types of peritoneal washing fluid. Bacterial translocation was quantified by mesenteric lymph node, liver and spleen tissue cultures. RESULTS: Systemic 5-FU reduced total peritoneal cell counts, neutrophils and macrophage numbers. It also altered bactericidal activity of the peritoneal fluid and phagocytic activity of polymorphonuclear leucocytes in the peritoneal fluid. 5-FU also caused significant increase in frequencies of bacterial translocation at the liver and mesenteric lymph nodes. G-CSF decreased bacterial translocation, it significantly enhanced bactericidal activity of the peritoneal fluid and phagocytic activity of polymorphonuclear leucocytes in the peritoneal fluid. It also increased total peritoneal cell counts, neutrophils and macrophage numbers. CONCLUSION: Systemic 5-FU administration caused bacterial translocation, decreased the bactericidalactivity of peritoneal fluid and phagocytic activity of polymorphonuclear leucocytes in the peritoneal fluid. G-CSF increased both bactericidal activity of the peritoneal fluid and phagocytic activity of polymorphonuclear leucocytes in the peritoneal fluid, and prevented the bacterial translocation. We conclude that intraperitoneal GCSF administration protects the effects of systemic 5-FU on peritoneal defense mechanisms.     

An erythropoietic stimulating factor similar to erythropoietin released by macrophages after treatment with silica

Summary An erythropoietic stimulating factor (ESF) can be detected in the supernatant from fetal liver and adult bone marrow and spleen cells when preincubated with the macrophage-specific cytotoxic agent, silica. Stimulation is observed in 12-day fetal liver CFU-E cultures in the absence of added erythropoietin (Ep). The concentration of ESF in the supernatant added to CFU-E cultures is dependent on the preincubated cell dose and the volume added. The stimulating activity is abolished when mice are hypertransfused and increased above normal values when mice are bled. A concentrated silicatreated spleen supernatant was able to stimulate erythropoiesis in the polycythemic mouse bioassay. It is concluded that the ESF is similar, if not identical, to Ep.This work was supported by the Deutsche Forschungsgemeinschaft (Sonderforschungsbereich 112/Project A2) and the Volkswagen Foundation.     

粒细胞集落刺激因子保护急性损伤人胎肝细胞的实验研究

目的建立D-半乳糖胺(D-galactosamine,D-GalN)对人胎肝细胞急性损伤的模型,观察粒细胞集落刺激因子(Granulocyte-colony stimulating factor,G-CSF)对人胎肝细胞损伤的保护作用。方法分别用梯度浓度的D-GalN和不同的作用时间孵育人胎肝细胞,用四唑盐比色法(MTT法)检测细胞活性,以确定最佳的人胎肝细胞急性损伤造模条件。将胎肝细胞分为4组进行不同处理:第1组为空白对照组,第2组(G组)用G-CSF处理正常细胞,第3组(ND组)和第4组(GD组)都用D-GalN进行损伤造模,但GD组加入G-CSF作为治疗,第3组加入等量的0.9%氯化钠溶液作为实验对照。最后用MTT法和乳酸脱氢酶(LDH)释放量检测各组细胞活性。结果当D-GalN浓度为10 mg/ml,作用时间为12 h时,可以杀伤90%以上的人胎肝细胞,并且可以保证有足够的药物反应时间。空白对照组和G组的细胞活性差异无统计学差异,但GD组细胞活性明显高于ND组(P0.05)。结论 D-GalN对人胎肝细胞急性损伤的造模条件为D-GalN 10 mg/ml作用12 h。G-CSF对D-GalN造成的人胎肝细胞急性损伤具有保护作用。     

Use of granulocyte-colony stimulating factor during acute myocardial infarction to enhance bone marrow stem cell mobilization in humans: clinical and angiographic safety profile.

AIMS: There is increasing evidence that stem cell (SC) mobilization to the heart and their differentiation into cardiac cells is a naturally occurring process. We sought to assess the safety and feasibility of granulocyte-colony stimulating factor (G-CSF) administration in humans to enhance SC mobilization and left ventricle (LV) injury repair during myocardial infarction (MI). METHODS AND RESULTS: Twenty patients with STEMI (mean age, 61+/-10 years), of whom 14 were submitted to primary percutaneous coronary intervention, were randomized to G-CSF (5 microg/kg/day s.c. for 4 consecutive days) or placebo. At entry and then at months 3 and 6, (99m)Tc-sestamibi gated-SPECT was performed to estimate extension of perfusion defect (PD) and LV function. The study drug was well tolerated and induced a significant increase of white blood count, CD34(+) cells, and CD34(+) cells coexpressing AC133 and VEGFR-2. At follow-up, treated and placebo groups did not differ for the angiographic coronary late loss and showed a similar pattern of PD recovery, whereas in the former at 6 months LVEF and especially LVEDV tended to be relatively higher (P=0.068) and lower (P=0.054), respectively. CONCLUSION: G-CSF administration in acute MI patients was feasible and did not lead to any clinical or angiographic adverse events and resulted in CD34(+) and CD34(+)AC133(+)VEGFR2(+) cell mobilization.     

粒细胞集落刺激因子促进肝脏再生的机制

肝脏的一个特性即是在受到损伤后会通过自身的再生能力来恢复原有肝脏体积和功能,目前越来越多的证据显示重组人粒细胞集落刺激因子(granulocyte-colony stimulating factor,G-CSF)在促进肝脏再生的过程中有多方面的作用。深入了解G-CSF促进肝脏再生的机制对于其应用于肝损伤患者,促进肝脏再生,提高生存率有着重要意义。本文就G-CSF促进肝脏再生的机制进行综述。     

Granulocyte-colony stimulating factor therapy improves survival in patients with hepatitis B virus-associated acuteon-chronic liver failure

AIM:To evaluate the safety and efficacy of granulocyte-colony stimulating factor(G-CSF) therapy in patients with hepatitis B virus(HBV)-associated acuteon-chronic liver failure(ACLF).METHODS:Fifty-five patients with HBV-associated ACLF were randomized into two groups:the treatment group and the control group.Twenty-seven patients in the treatment group received G-CSF(5 μg/kg per day,six doses) treatment plus standard therapy,and 28 patients in the control group received standard therapy only.The peripheral CD34 + cell count was measured consecutively by flow cytometry.Circulating white blood cell count,biochemical parameters,and other clinical data of these patients were recorded and analyzed.All patients were followed up for a period of 3 mo to evaluate the changes in liver function and survival rate.RESULTS:The peripheral neutrophil and CD34 + cell counts in the G-CSF group increased on day 3 from the onset of therapy,continued to rise on day 7,and remained elevated on day 15 compared to those of the control group.Child-Turcotte-Pugh score of patients in the treatment group was improved on day 30 from the onset of G-CSF therapy,compared to that in the controls(P = 0.041).Model for End-Stage of Liver Disease score of patients in the treatment group was improved on day 7(P = 0.004) and remained high on day 30 from the onset of G-CSF therapy(P < 0.001) compared to that in controls.After 3 mo of follow-up observation,the survival rate in the treatment group(48.1%) was significantly higher than that in the control group(21.4%)(P = 0.0181).CONCLUSION:G-CSF therapy promoted CD34 + cell mobilization in patients with HBV-associated ACLF,and improved the liver function and the survival rate of these patients.     

Multiple myeloma with infiltration into skeletal muscle after injections of granulocyte-colony stimulating factors

Multiple myelomas often occur in elderly people with age-related complications as they age further. A 54-year-old man was first admitted with cerebral infarction and multiple myeloma (IgG kappa, stage IIIA) in November 1989. There was partial remission following chemotherapy. The karyotype of the marrow cells was 46, XY, and no p53 gene mutations were detected by polymerase chain reaction and single-strand conformation polymorphism analysis. In February 1999, chemotherapy (melphalan, vindesine, ranimustine, prednisolone) was administered as a result of aggravation of the myeloma. Later, after daily subcutaneous injection of 50 µg of nartograstim for 6 days to treat febrile neutropenia, the soft tissues around the right eye swelled gradually, but without redness accompanied by an elevation of the serum creatine-kinase concentration. When nartograstim was discontinued, however, the swelling disappeared and the creatine-kinase level normalized. Then in July, on the sixth day of daily subcutaneous injections of 75 µg of filgrastim following the same chemotherapy regimen, similar swelling of the soft tissues occurred around the left eye, and was again reversed by withdrawal of the drug. In July 2000, infusion of dexamethasone was conducted, and following daily subcutaneous-injection of 75 µg of filgrastim for 5 days, the right subclavicular soft tissue became swollen. The patient later died of myocardial infarction and an autopsy revealed an infiltration of myeloma cells into the right subclavicular muscle and bone marrow that was packed with myeloma cells. This case suggests that exposure to granulocyte-colony stimulating factors enables myeloma cells to proliferate and infiltrate into soft tissues.     

大鼠中度液压颅脑损伤后氧化应激反应的实验研究

目的：通过建立大鼠中度颅脑液压损伤模型,检测损伤病灶生化指标脂质氧化终产物丙二醛及抗氧化剂谷胱甘肽含量的变化,探讨其与继发性脑损伤之间的关系,为后续研究提供实验基础。方法雄性Sprague-Dawley大鼠48只,随机分成中度颅脑损伤组（mTBI组）和假手术组（sham-TBI组）,各24只。以液压中度颅脑损伤指标致伤TBI组。并于伤后6h、24h处死大鼠,通过ELISA技术测定抗氧化剂谷胱甘肽和脂质氧化产物丙二醛在两组的不同表达,采用独立样本t检验评价大鼠颅脑创伤后的氧化应激损伤。结果mTBI组脑组织见损伤灶及蛛网膜下腔出血,HE染色后可见神经元损伤核固缩,细胞坏死呈空泡状,而sham-TBI组未见神经元损伤表现。TBI后mTBI组中丙二醛浓度较sham-TBI组显著升高,随伤后时间延长丙二醛浓度显著升高（t6h＝6.49,P＜0.01;t24h＝11.22,P＜0.01）;而TBI后mTBI组谷胱甘肽浓度显著低于sham-TBI组,随伤后时间延长谷胱甘肽浓度显著降低（t6h＝9.25,P＜0.01;t24h＝11.24,P＜0.01）。结论液压颅脑损伤模型致伤能量能够测量,稳定性及重复性良好,伤情可能分级。中度闭合性颅脑外伤可导致脑组织病理学改变和氧化应激损伤,且氧化应激损伤指标与脑损伤时间有关,外伤后早期阻断氧化应激过程可以起到脑保护作用。     

Carcinosarcoma of the esophagus producing granulocyte-colony stimulating factor: report of a case

A 51-year-old man was admitted to the hospital for dysphagia, pyrexia, and leukocytosis. The serum level of granulocyte-colony stimulating factor (G-CSF) was elevated. Barium esophagography and endoscopy revealed a polypoid tumor in the middle portion of the esophagus. After an esophagectomy, the leukocyte count and serum G-CSF level normalized. The pathological diagnosis was carcinosarcoma of the esophagus with two components: namely, squamous cell carcinoma and sarcoma. Moreover, cancer cells were positive for G-CSF antibody. These findings confirmed that the esophageal carcinosarcoma in this case was a G-CSF-producing tumor. Although a G-CSF-producing esophageal carcinosarcoma is very rare, this disease should be considered when a patient has symptoms such as leukocytosis and pyrexia without an associated infection.