抗癌药所致血小板减少的对策

骨髓抑制是决定抗癌药剂量的因素之一。一般抗癌药剂量以给药后白细胞和血小板在2～4周内恢复正常为限。对于抗癌药所致的白细胞减少伴血小板一时减少,必须采取防止出血的对策。像用于白细胞减少的细胞因子G-CSF一样,对血小板有预防作用和对血小板的恢复有促进作用的促血小板生成素(TPO)目前正进行临床试验,但目前血小板输血是防止出血的唯一方法。动物实验已证明,TPO可刺激骨髓巨核细胞的增殖分化和血小板的生成,人体实验也有同样效果,因此TPO有希望用于抗癌药所致血小板减少的预防和促进血小板恢复。防止血小板减少的血小板输血　由…     

血小板生成素及其模拟物的研究进展

血小板生成素(TPO)是巨核细胞增殖、成熟和血小板产生的主要调节因子,并且在成熟血小板生成中,TPO的作用强于目前已知的几种相关造血因子。TPO模拟肽(TPOmimeticpeptide,TMP)或TPO非肽类模拟物(TPOnonpeptidemimics)是与TPO具有相似功能但不具有同源结构的小分子物质,能与TPO受体结合,产生类似TPO的生物学作用,且不具有免疫原性,因而越来越受到青睐。本文对TPO及其模拟物的研究进展进行综述。     

血小板生成素研究进展

血小板生成素(TPO)是一种能刺激巨核系祖细胞增殖、分化和成熟的重要造血调节因 子,能够促进血小板生成,控制循环血中血小板数量,具有广阔的临床应用潜力。本文简述了TPO 的分子生物学特征、分离纯化、检测、生物学作用和临床应用前景的研究进展。     

黄芪和当归的主要活性成分配伍对骨髓抑制小鼠造血功能的影响

目的探讨黄芪和当归的主要活性成分配伍对骨髓抑制小鼠模型的促造血作用。方法对芪归1∶1配伍提取物测定5种主要活性成分阿魏酸、芒柄花素、黄芪甲苷、毛蕊异黄酮、毛蕊异黄酮苷含量,以确定配伍剂量。小鼠随机分为空白对照组、模型组和各给药组。空白对照组给予溶剂灌胃7 d;模型组同上灌胃,于d 3腹腔注射环磷酰胺,连续3 d;各药物组灌胃给药,同上造模。检测外周血象、血清造血生长因子(HGF)含量、造血祖细胞集落数。结果芪归配伍提取物和活性成分配伍均可明显增加外周血白细胞(WBC)、红细胞(RBC)、血小板数(Pt)、血红蛋白(HGB)含量和骨髓造血组织面积,明显增加血清粒-巨噬细胞集落刺激因子(GM-CSF)、促血小板生成素(TPO)、促红细胞生成素(EPO)含量和骨髓粒-单核细胞集落形成单位(CFU-GM)、巨核细胞集落形成单位(CFU-MK)、红系集落形成单位(CFU-E)和爆式红系集落形成单位(BFU-E)数,两者作用相近。各成分中,阿魏酸可促进WBC和骨髓造血组织面积的恢复;5种成分均可促进RBC和HGB的恢复;阿魏酸和黄芪甲苷可促进Pt的恢复。5个成分均可升高TPO含量;阿魏酸和毛蕊异黄酮可升高GM-CSF含量;阿魏酸、毛蕊异黄酮和毛蕊异黄酮苷可升高EPO含量。除黄芪甲苷外,其它4种成分均可使CFU-GM增加;5种活性成分均可增加CFU-MK、CFU-E;仅阿魏酸可增加BFU-E。结论黄芪当归配伍发挥补血作用的主要药效物质是以上5种活性成分,这些活性成分配伍对促进造血可发挥增效作用。     

特发性血小板减少性紫癜再生障碍性贫血患者血小板生成素水平测定

血小板生成素(thrombopoietin,TPO)为调控巨核细胞造血和血小板生成的细胞因子,经研究发现其调节机制发生在转录后.为了探讨TPO在不同发病情况下的调节机制并为rh-TPO的临床应用提供理论依据,我们测定了特发性血小板减少性紫癜(ITP)、慢性再生障碍性贫血(CAA)患者血小板生成素水平,测定报告如下.     

血小板生成素对巨核细胞及血小板生成影响的研究

巨核细胞血小板系统的生长发育是一个复杂的过程 ,与其他系统的造血细胞相比 ,巨核细胞血小板是一类比较特殊的细胞 ,在骨髓中所占比例很小 ,故对该系统的研究一直落后于其他造血细胞。随着分子生物学技术的发展 ,特别是1994年 ,一种特异作用于巨核细胞系的造血生长因子——血小板生成素 (throm bopoietin,TPO)的成功克隆才使得该领域的研究有了飞速发展。本文就巨核细胞和血小板生长过程及 TPO的调节作用概述如下。1　巨核细胞血小板系统的生长发育像所有的造血细胞一样 ,巨核细胞也来源于骨髓的多能造血干细胞 (pluripotential hem ato…     

当归补血微丸对环磷酰胺所致小鼠贫血的影响

目的：探讨当归补血微丸对血虚模型小鼠造血功能的影响及机制.方法：选用环磷酰胺（CY）造小鼠血虚模型,同时灌服不同剂量的药物,测定小鼠的外周血象、血清红细胞生成素（EPO）含量及脾脏中EPO样造血生长因子的水平.结果：当归补血微丸各剂量均能增加血虚小鼠的红细胞、白细胞、血小板和血红蛋白数,对CY致贫血诱发的EPO增殖有拮抗作用,并能显著促进脾脏中EPO样生长因子的水平.结论：当归补血微丸能有效抑制CY所诱发的贫血.     

特发性血小板减小性紫癜再生障碍性贫血患者血小板生成素水平测定

血小板生成素 ( thrombopoietin,TPO)为调控巨核细胞造血和血小板生成的细胞因子 ,经研究发现其调节机制发生在转录后。为了探讨 TPO在不同发病情况下的调节机制并为 rh- TPO的临床应用提供理论依据 ,我们测定了特发性血小板减少性紫癜 ( ITP)、慢性再生障碍性贫血 ( CAA )患者血小板生成素水平 ,测定报告如下。1　资料和方法1.1　研究对象1.1.1　血小板减少疾病组 :CAA13例 ,平均年龄 40岁 ( 18～ 71岁 ) ,男 9例 ,女 4例。 ITP患者 2 6例 ,平均年龄 3 8岁( 12～ 76岁 ) ,男 11例 ,女 15例 ,诊断均符合文献 [1]标准。1.1.2　正常…     

类风湿关节炎的血小板计数与血清血小板生成素的相关性研究

目的:探讨血小板生成素(TPO)在类风湿关节炎(RA)患者血小板增多发生机制中的作用.方法:选取伴血小板增多RA患者29例、血小板正常RA患者28例及正常对照28例,采用酶联免疫吸附法(ELISA)检测血清TPO及白细胞介素-6(IL-6)水平,并与实验室参数进行相关性分析.结果:(1)伴血小板增多RA组血清TPO、IL-6水平均明显高于正常对照组(P ＜ 0.05或P ＜ 0.01);伴血小板增多RA组的TPO水平高于血小板正常RA组(P ＜ 0.05),而2组间IL-6水平差异无统计学意义(P ＞ 0.05).(2)伴血小板增多RA组血小板计数与血清TPO水平之间无相关性,而与血清IL-6、CRP呈正相关(r分别为0.566, 0.401,P ＜ 0.05或P ＜ 0.01).(3)伴血小板增多RA组血清TPO水平与IL-6水平无相关关系(r ＝ -0.069,P ＞ 0.05).结论:(1)伴血小板增多RA组血清TPO水平显著升高,提示TPO参与了RA患者血小板增多的发生机制.(2)RA患者血小板增多与体内炎症反应有关.     

刺梨汁对骨髓抑制小鼠造血功能的调控作用

目的探讨刺梨汁对环磷酰胺合并60Co致骨髓抑制小鼠造血功能的影响,研究其促进血细胞上调的作用机制。方法双抗体夹心法检测外周血常规、骨髓基质中红细胞生成素（EPO）、血小板生成素（TPO）、粒细胞生长因子（GCSF）的量。结果刺梨汁能明显改善骨髓抑制小鼠外周血常规,能有效平衡微环境中TPO的量,改善EPO的表达,对骨髓抑制小鼠骨髓细胞上清中GCSF有明显的正调控作用。结论刺梨汁能提高骨髓抑制小鼠外周血血细胞和骨髓有核细胞计数,可促进骨髓抑制小鼠骨髓细胞从G0/G1期进入增殖周期,并能有效调节骨髓微环境中TPO、EPO、GCSF的表达,从而促进骨髓抑制小鼠的造血功能,可作为一种治疗贫血的辅助保健药物。     

Evidence for a role of the 5-HT2C receptor in central lipopolysaccharide-, interleukin-1 beta-, and leptin-induced anorexia

We examined the role of serotonin (5-HT) and the 5-HT(1A) and 5-HT(2C) receptors in the anorectic effects of centrally administered lipopolysaccharide (LPS), interleukin-1 beta (IL-1 beta), and leptin. Food intake was measured in rats after intracerebroventricular (ICV) injections of LPS (20 ng), IL-1 beta (10 ng), or leptin (1 microg) at lights out, followed by intraperitoneal (IP) injections of either the 5-HT(1A) autoreceptor agonist 8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT) (125 microg/kg) or the 5-HT(2C) receptor antagonist SB 242084 (0.3 mg/kg) at the onset of anorexia. SB 242084 significantly attenuated the food intake reduction caused by all compounds (all P<.01). IP 8-OH-DPAT attenuated ICV IL-1 beta-induced anorexia (P<.01). We also tested the involvement of the median raphe 5-HT(1A) receptors in peripheral LPS- and IL-1 beta-induced anorexia. Rats were injected intraperitoneally with either LPS (100 microg/kg) or IL-1 beta (2 microg/kg) at lights out, and 8-OH-DPAT (4 nmol) was administered directly into the median raphe nucleus at the onset of anorexia. Median raphe injections of 8-OH-DPAT significantly attenuated both IL-1 beta- and LPS-induced anorexia (both P<.01). These results implicate the 5-HT(2C) receptors in the mediation of central LPS-, IL-1 beta-, and leptin-induced anorexia. Our results also suggest that the midbrain raphe nuclei play a role in mediating the anorectic response to peripheral LPS and IL-1 beta.     

Lack of evidence for a role of serotonin in interleukin-1-induced hypophagia

Interleukin-1 (IL-1) administration depresses food intake in rodents. IL-1 is known to increase the metabolism of serotonin, which is known to affect feeding behavior. Thus, serotonin is an obvious candidate for a mediator of the hypophagic response to IL-1. Therefore, we tested the ability of serotonergic agonists and antagonists to alter the hypophagic responses to IL-1 and bacterial lipopolysaccharide (LPS). Hypophagia was assessed in ad lib-fed mice by recording the intake of sweetened milk in a 30-min period. Acute intraperitoneal administration of mouse IL-1beta reliably decreased milk intake. This hypophagic response was not affected by any of the serotonin antagonists tested, including 5-HT(1A) (WAY100135 and propranolol), 5-HT(1B) (GR127935), 5-HT(2) (ritanserin, ketanserin, SB206553, and RS102221), mixed 5-HT(1/2) (methysergide and metergoline), and 5-HT(3) (tropisetron) receptor antagonists. The 5-HT(1A) agonists (8-OH-DPAT and ipsapirone) and a 5-HT(1B) agonist (CGS12066B) known to decrease the activity of serotonergic neurons, also had no effect. Mice pretreated with 5,7-dihydroxytryptamine to deplete brain serotonin ate less, but, nevertheless, displayed similar hypophagic responses to mIL-1beta or LPS. The results suggest that serotonin is not involved in the decrease in short-term milk intake induced by mIL-1beta or LPS in mice that have been fed ad lib.     

The proinflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha activate serotonin transporters.

Proinflammatory cytokines and serotonergic homeostasis have both been implicated in the pathophysiology of major psychiatric disorders. We have demonstrated that activation of p38 mitogen-activated protein kinase (MAPK) induces a catalytic activation of the serotonin transporter (SERT) arising from a reduction in the SERT Km for 5-hydroxytryptamine (5-HT). As inflammatory cytokines can activate p38 MAPK, we hypothesized that they might also activate neuronal SERT. Indeed, Interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha) stimulated serotonin uptake in both the rat embryonic raphe cell line, RN46A, and in mouse midbrain and striatal synaptosomes. In RN46A cells, IL-1beta stimulated 5-HT uptake in a dose- and time-dependent manner, peaking in 20 min at 100 ng/ml. This was abolished by IL-1ra (20 ng/ml), an antagonist of the IL-1 receptor, and by SB203580 (5 microM), a p38 MAPK inhibitor. TNF-alpha also dose- and time-dependently stimulated 5-HT uptake that was only partially blocked by SB203580. Western blots showed that IL-1beta and TNF-alpha activated p38 MAPK, in an SB203580-sensitive manner. IL-1beta induced an SB203580-sensitive decrease in 5-HT Km with no significant change in Vmax. In contrast, TNF-alpha stimulation decreased 5-HT Km and increased SERT Vmax. SB203580 selectively blocked the TNF-alpha-induced change in SERT Km. In mouse midbrain and striatal synaptosomes, maximal stimulatory effects on 5-HT uptake occurred at lower concentrations (IL-1beta, 10 ng/ml; TNF-alpha, 20 ng/ml), and over shorter incubation times (10 min). As with RN46A cells, the effects of IL-1beta and TNF-alpha were completely (IL-1beta) or partially (TNF-alpha) blocked by SB203580. These results provide the first evidence that proinflammatory cytokines can acutely regulate neuronal SERT activity via p38 MAPK-linked pathways.     

Effects of serotonin and serotonergic agonists and antagonists on the production of interferon-gamma and interleukin-10.

Serotonin (5-HT) is a neurotransmitter and an immune modulator. In vitro, antidepressants with a serotonergic mode of action have, at concentrations within the therapeutical range, negative immunoregulatory effects, i.e., they increase the production rate of interleukin-10 (IL-10), a negative immunoregulatory cytokine. We have hypothesized that part of these effects may be explained by the serotonergic activities of antidepressants on immunocytes. This study was carried out to examine the effects of 5-HT, p-chlorophenylalanine (PCPA), a 5-HT depleting agent, flesinoxan (a 5-HT1A agonist), m-chlorophenylpiperazine (mCPP; a 5-HT2A/2C agonist), and ritanserin (a 5-HT2A/2C antagonist) on the production rate of interferon-gamma (IFNgamma), a proinflammatory cytokine, and IL-10 by whole blood stimulated with polyclonal activators. The IFNgamma/IL-10 production ratio was computed, since this ratio reflects the pro- versus anti-inflammatory capacity of cultured whole blood. We found that: 1) 5-HT, 150 ng/mL, 1.5 microg/mL, and 15 microg/mL significantly decreased the IFNgamma/IL-10 ratio; 2) PCPA (5 microM) significantly suppressed the production of IFNgamma and IL-10; 3) flesinoxan (15 ng/mL; 1.5 microg/mL) had no significant effects on the production of the above cytokines; and 4) mCPP (2.7 microg/mL) and ritanserin (5.0 microg/mL) suppressed the IFNgamma/IL-10 ratio. It is concluded that intracellular 5-HT may be necessary for an optimal synthesis of IFNgamma and IL-10, and that extracellular 5-HT concentrations at or above serum values may suppress the production of the proinflammatory cytokine IFNgamma. The negative immunoregulatory effects of antidepressive drugs are probably not related to their serotonergic activities.     

Role of tumor necrosis factor-alpha in endotoxin-induced lung parenchymal hyporesponsiveness in mice

Although changes in airway responsiveness in pulmonary inflammation are commonly related to the action of infiltrated leukocytes, our previous report suggested a direct role of inflammatory cytokines in LPS-induced lung hyporesponsiveness. The aim of this study was to define if cytokines detected in the BALF (bronchoalveolar lavage fluid) of intratracheal LPS-treated mice could be, at least in part, responsible for 5-HT (5-hydroxytryptamine) lung hyporeactivity. Our results show that intratracheal instillation of LPS induced a time-dependent increase in IL-(interleukin-)1beta, IL-6, and TNF (tumor necrosis factor)alpha in the BALF. Cytokine production was paralleled by 5-HT lung hyporesponsiveness, and intratracheal administration of TNFalpha proved to be very efficient in inhibiting 5-HT responsiveness. In addition, systemic treatment with rolipram, an inhibitor of TNFalpha production, was paralleled by a significant recovery of lung responsiveness. On the contrary, IL-1beta and IL-6 were not demonstrated to play a relevant role in 5-HT hyporesponsiveness. It is concluded that TNFalpha could be a crucial mediator of LPS-induced lung hyporesponsiveness.     

Influence of continuous infusion of interleukin-1beta on depression-related processes in mice: corticosterone, circulating cytokines, brain monoamines, and cytokine mRNA expression

RATIONALE: Activation of the immune system typically occurs on a subchronic or chronic basis (e.g., in response to bacterial or viral insults). However, analyses of the effects of cytokine treatments have typically involved acute treatments, and limited data are available concerning the behavioral and central neurochemical impact of subchronic interleukin-1beta (IL-1beta) administration. OBJECTIVES: Several peripheral and central effects of IL-1beta treatment were assessed following single or repeated bolus injections or after infusion of the cytokine (through Alzet minipumps) over several days. RESULTS: The impact of an acute bolus injection of IL-1beta (1.0 microg) on plasma corticosterone and on circulating IL-1beta, IL-6, and TNF-alpha were diminished following 5-day IL-1beta treatment, although high levels of sickness were still apparent. When IL-1beta (1.0 or 2.0 mug/day) was continuously infused over 3 days, plasma corticosterone and sickness were elevated, but these effects were attenuated after 7 days (subchronic) of treatment. As well, the effects of IL-1beta treatment on diurnal variations of motor activity diminished over days. Despite the diminution of the behavioral and neuroendocrine effects of the cytokine after treatment 7 days, subchronic IL-1beta infusion altered prefrontal cortical and hippocampal serotonin and norepinephrine utilization, and within these regions, the messenger RNA (mRNA) expression of IL-1beta, IL-6, TNF-alpha, and their receptors, as well as that of 5-HT(2C), 5-HT(1B) receptors, and p11, was increased. DISCUSSION: The findings indicate that peripheral cytokine infusion markedly influences central cytokine mRNA expression and also influences 5-HT turnover, which might contribute to behavioral changes elicited by IL-1beta.     

Regulation of antigen-specific CTL and Th1 cell activation through 5-Hydroxytryptamine 2A receptor

Serotonin (5-Hydroxytryptamine, 5-HT) is one of the most extensively studied neurotransmitters in the central nervous system. Also expressed in peripheral tissues, 5-HT participates in vasoconstriction and in aggregation of platelets through 5-HT(2A) receptor (5-HT2AR). However, there have been few studies regarding the interaction between 5-HT and 5-HT2AR in the immune system. In the current study, we analyzed the role of 5-HT and its 5-HT2AR in the activation of antigen-specific Th1 and cytotoxic T lymphocytes (CTL) in mice. RT-PCR and western blotting analyses confirmed the expression of 5-HT2AR in both CD4 and CD8 T cells. Both antigen-specific and anti-CD3 stimulation of IL-2 and IFN-γ production from these cells were inhibited by a selective 5-HT2AR inhibitor, sarpogrelate hydrochloride. Concanavalin A (ConA) activation of CD4(+) and CD8(+) T cells, which were purified from mouse spleen following depletion of endogenous 5-HT, was enhanced by a selective 5-HT2AR agonist, (R)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). Such DOI-induced T cell activation was nullified by sarpogrelate. Moreover, an ELISPOT study showed that sarpogrelate also reduced antigen-specific induction of both CTL and Th1 cells in vivo following immunization of mice with cognate antigens. These data suggest that antigen-specific Th1 and CTL cells might be regulated by 5-HT signaling through 5-HT2AR on their surfaces and that 5-HT2AR inhibitor might have an immunosuppressive effect in vivo.     

The effect of lipopolysaccharide, interleukin-1 and tumour necrosis factor on the hepatic accumulation of 5-hydroxytryptamine and platelets in the mouse.

1. Injection of lipopolysaccharide (LPS; 0.5-500 microgram kg-1) into mice induced a dose-dependent, slowly developing increase in hepatic content of 5-hydroxytryptamine (5-HT). This sustained increase could not be attributed to an LPS-induced alteration of the pharmacokinetic handling of 5-HT by stimulation of its uptake or inhibition of its degradation. 2. Regional differences were apparent in the tissue content of histamine and 5-HT between mast cell-deficient (W/Wv) and normal (+/+) mice. LPS administration (0.5 mg kg-1) gave comparable increases in the hepatic level of 5-HT in mast cell-deficient and normal mice. 3. Reserpine pretreatment (1 mg kg-1) selectively reduced 5-HT levels in the blood, spleen, liver, brain and lung of normal mice. Prior treatment with this agent also abolished the LPS (0.5 mg kg-1)-induced hepatic accumulation of 5-HT. 4. Accumulation of 5-HT in the liver by LPS (0.1 mg kg-1) was temporally associated with both a fall in the levels of circulating platelets, and a reduction in the concentration of 5-HT in the blood. The LPS dose-dependent (0.5-500 micrograms kg-1) increase in hepatic 5-HT content was associated with a similar dose-dependent reduction in the circulating levels of 5-HT. 5. Interleukin-1, alpha and beta (10 micrograms kg-1) and tumour necrosis factor alpha (TNF alpha) (1 mg kg-1) significantly enhanced the accumulation of 5-HT within the liver. Administration of TNF alpha (10 micrograms kg-1) potentiated the increase in hepatic 5-HT content seen with IL-1 beta (10 micrograms kg-1).(ABSTRACT TRUNCATED AT 250 WORDS)     

The psychoneuroimmuno-pathophysiology of cytokine-induced depression in humans

Administration of the cytokines interferon-alpha and interleukin-2 is used for the treatment of various disorders, such as hepatitis C and various forms of cancer. The most serious side-effects are symptoms associated with depression, including fatigue, increased sleepiness, irritability, loss of appetite as well as cognitive changes. However, great differences exist in the prevalence of the development of depressive symptoms across studies. Differences in doses and duration of therapy may be sources of variation as well as individual differences of patients, such as a history of psychiatric illness. In addition, sensitization effects may contribute to differential responses of patients to the administration of cytokines. In animals administration of pro-inflammatory cytokines induces a pattern of behavioural alterations called 'sickness behaviour' which resembles the vegetative symptoms of depression in humans. Changes in serotonin (5-HT) receptors and in levels of 5-HT and its precursor tryptophan in depressed people support a role for 5-HT in the development of depression. In addition, evidence exists for a dysregulation of the noradrenergic system and a hyperactive hypothalamic-pituitary-adrenal (HPA) axis in depression. Some mechanisms exist which make it possible for cytokines to cross the blood-brain barrier. Pro-inflammatory cytokines such as IL-1beta, IFN-alpha, IFN-gamma and TNF-alpha affect the 5-HT metabolism directly and/or indirectly by stimulating the enzyme indoleamine 2,3-dioxygenase which leads to a peripheral depletion of tryptophan. IL-1, IL-2 and TNF-alpha influence noradrenergic activity and IL-1, IL-6 and TNF-alpha are found to be potent stimulators of the HPA axis. Altogether, administration of cytokines may induce alterations in the brain resembling those found in depressed patients, which leads to the hypothesis that cytokines induce depression by their influence on the 5-HT, noradrenergic and HPA system.