DISRUPTION OF MICROTUBULES IN-VIVO BY VINCRISTINE INDUCES LARGE MEMBRANE COMPLEXES AND OTHER CYTOPLASMIC ABNORMALITIES IN MEGAKARYOCYTES AND PLATELETS OF NORMAL RATS LIKE THOSE IN HUMAN AND WISTAR FURTH RAT HEREDITARY MACROTHROMBOCYTOPENIAS
DISRUPTION OF MICROTUBULES IN-VIVO BY VINCRISTINE INDUCES LARGE MEMBRANE COMPLEXES AND OTHER CYTOPLASMIC ABNORMALITIES IN MEGAKARYOCYTES AND PLATELETS OF NORMAL RATS LIKE THOSE IN HUMAN AND WISTAR FURTH RAT HEREDITARY MACROTHROMBOCYTOPENIAS
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DOI：
10.1002/jcp.1041620111
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发表时间：
1995-01-01
影响因子：
5.6
通讯作者：
JACKSON, CW
中科院分区：
文献类型：
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作者：
STENBERG, PE;MCDONALD, TP;JACKSON, CW
在遗传性大血小板减少症，如灰色血小板综合征、May-Hegglin畸形和Epstein‘s综合征以及Wistar Furth大鼠中，血小板微管结构异常与血小板形成异常有关，提示微管结构异常可能是这些临床实体中血小板形成缺陷的原因之一。在这里，我们使用微管解聚剂长春新碱(VCR)检测了微管破裂对巨核细胞胞浆细胞器组织的影响。Wistar大鼠在单独给药、5-氟尿嘧啶(5-FU)单独给药或5-FU+VCR 0.1~1.0 mg/kg静脉注射后，每隔30分钟~8小时固定骨髓作透射电子显微镜观察。给予5-FU以增加巨核细胞的频率，以便于超微结构的评估。VCR单独或与5-FU合用均可引起Wistar大鼠巨核细胞胞浆内形成大的膜复合体，与人遗传性巨核细胞减少症和Wistar Furth大鼠巨核细胞相同。在5-FU和VCR后，巨核细胞中含有这些大的膜复合体的比例随着时间的推移而增加，在VCR剂量为0.75-1.0 mg/kg时达到最大(与三分之二的巨核细胞相似)。大多数巨核细胞表现出其他异常，包括质膜起泡，致密隔室数量增加，扩张的分界膜(DMS)通道，其中含有免疫细胞化学鉴定为分泌a颗粒蛋白的致密物质，以及子宫内膜增生的发生率增加。单独使用5-FU的大鼠没有表现出这些异常，除了致密脑室的增加。单用长春新碱或5-氟尿嘧啶和长春新碱处理的大鼠的血小板也出现异常，包括膜复合体、圆形、微管蛋白准晶体的形成、膜泡的发育以及表面连接小管系统(SCCS)池内蛋白质物质的存在。5-FU、VCR处理的Wistar大鼠和未处理的Wistar Furth大鼠的血小板膜复合体由SCCS和致密管系统组成，5-FU、VCR处理的大鼠巨核细胞膜复合体由DMS和光滑内质网组成。我们得出结论，完整的微管在巨核细胞DMS的组织中起主要作用，并可能有助于巨核细胞α颗粒的稳定。(C)1995年Wiley-Liss公司
Abnormal organization of platelet microtubules is associated with abnormal platelet formation in hereditary macrothrombocytopenias such as the gray platelet syndrome, May-Hegglin anomaly, and Epstein's syndrome, and that of the Wistar Furth rat, suggesting that aberrant microtubule organization may contribute to defective platelet formation in these clinical entities. Here, we examined the consequence of microtubule disruption on the organization of megakaryocyte cytoplasmic organelles using the microtubule depolymerizing agent, vincristine (VCR). Wistar rat bone marrow was fixed and processed for transmission electron microscopy after VCR administration alone, after 5-fluorouracil (5-FU) administration alone, or after 5-FU followed by intravenous injection of 0.1-1.0 mg/kg VCR for intervals of 30 min to 8 hr. 5-FU was given to increase megakaryocyte frequency to facilitate ultrastructural evaluations. VCR alone or in combination with 5-FU caused formation of large membrane complexes in the cytoplasm of Wistar rat megakaryocytes at all dosages studied, identical to those found in megakaryocytes of human hereditary macrothrombocytopenias and the Wistar Furth rat. The proportion of megakaryocytes with these large membrane complexes increased with time after 5-FU and VCR, and was maximal (similar to two-thirds of megakaryocytes) at VCR dosages of 0.75-1.0 mg/kg. The majority of megakaryocytes displayed other abnormalities, including blebbing of plasma membranes, an increased number of dense compartments, dilated demarcation membrane (DMS) channels, which contained dense material immunocytochemically identified as secreted a-granule proteins, and an increased incidence of emperipolesis. Rats administered 5-FU alone did not demonstrate these abnormalities, with the exception of an increase in dense compartments. Platelets from rats treated with VCR alone or 5-FU and VCR also showed abnormalities including membrane complexes, rounded shape, formation of tubulin paracrystals, development of membrane blebs, and the presence of proteinaceous material within the cisternae of the surface-connected canalicular system (SCCS). The membrane complexes in platelets of 5-FU-, VCR-treated Wistar rats as well as untreated Wistar Furth rats were composed of elements of both the SCCS and dense tubular system; membrane complexes in megakaryocytes of 5-FU-, VCR-treated rats were composed of both DMS and smooth endoplasmic reticulum. We conclude that intact microtubules play a major role in the organization of the megakaryocyte DMS and may contribute to the stability of megakaryocyte alpha-granules. (C) 1995 Wiley-Liss, Inc.