CYTOKINES AND ENDOTOXIN-INDUCED ABORTION

细胞因子和内毒素引起的流产

基本信息

  • 批准号:
    3332037
  • 负责人:
  • 金额:
    $ 13.58万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    1993
  • 资助国家:
    美国
  • 起止时间:
    1993-08-01 至 1998-07-31
  • 项目状态:
    已结题

项目摘要

Understanding the basis for pregnancy failure is an important medical/biological goal. The present study is designed to determine the role of intrauterine cytokine production by macrophages in endotoxin- induced abortion in mice. The mouse uterus contains high numbers of macrophages that are under the regulatory control of estrogen and progesterone. Control is mediated through hormone-induced local production of macrophage colony stimulating factor (CSF-l) by uterine epithelial cells. Uterine macrophage function, assessed by production of the pro- inflammatory cytokines, interleukin l (IL-I), interleukin 6 (IL-6) and tumor necrosis factor alpha (TNFalpha) is increased relative to non- reproductive organs. This is important, because the products of stimulated macrophages are positively and negatively involved in many pathologic processes, including endotoxin-induced toxicity. Pathologic responses are greatest when macrophages are exposed to multiple stimuli. For example, stimulation of macrophages with interferon gamma (IFNgamma) does not result in significant pathology, but prestimulation of macrophages with IFNgamma greatly increases endotoxin-induced effects. Endotoxin produces abortions in mice at dose levels that are not clinically toxic for adults. We hypothesized that the abortifacient ability of endotoxin might be related to the heightened responsiveness of normal uterine macrophages that could occur as a results of their having been prestimulated with ovarian hormones and CSF-1. We further hypothesized that abortion might result from overproduction in the uterus of toxic products of macrophages such as TNFgamma. To test these hypotheses, we propose to quantitate IL- 1, IL-6 and TNFalpha mRNA, bioactivity and immunoreactivity (ELISA) in uterus, liver, spleen, placenta and fetus before and after exposure of mice to abortion-producing regimens of endotoxin. Statistical comparisons will be made between untreated pregnant mice and mice treated with endotoxin or non-toxic endotoxin to determine the relationship of cytokine levels to pregnancy success. To test the hypothesis that individual cytokines cause abortions, we will determine whether mice can be protected from endotoxin-induced abortion by treating them with TNFalpha antibody or IL-1r antagonist. Since the studies are based on the rationale that endotoxin induces macrophages to produce cytokines, studies will be performed to determine if endotoxin-induced cytokine production is macrophage-dependent. In vitro studies with cell lines and in vivo studies with ovariectomized mice will be performed to evaluate the hypothesis that uterine macrophages, preconditioned by exposure to the physiologic stimuli, estradiol- 17beta, progesterone and CSF-1, exhibit heightened responses to endotoxin . These studies will provide increased understanding of the basis for fetal failure.
了解妊娠失败的基础是一个重要的 医学/生物学目标。本研究旨在确定 巨噬细胞产生的子宫内细胞因子在内毒素- 小鼠人工流产。小鼠子宫中含有大量的 在雌激素的调节控制下的巨噬细胞, 孕酮控制是介导的通过烟草诱导的本地生产 巨噬细胞集落刺激因子(CSF-1)通过子宫上皮细胞 细胞子宫巨噬细胞功能,通过产生的前- 炎性细胞因子,白细胞介素1(IL-1),白细胞介素6(IL-6)和 肿瘤坏死因子α(TNF α)相对于非肿瘤细胞增加, 生殖器官这一点很重要,因为受刺激的产品 巨噬细胞积极和消极地参与了许多病理过程, 过程,包括内毒素诱导的毒性。病理反应是 当巨噬细胞暴露于多种刺激时最大。比如说, 用干扰素γ(IFN γ)刺激巨噬细胞不 导致显著的病理学,但巨噬细胞的预刺激 IFN γ大大增加内毒素诱导的作用。内毒素产生 在对成年小鼠无临床毒性的剂量水平下, 我们推测内毒素的流产能力可能是 与正常子宫巨噬细胞的反应性增强有关 这可能是由于他们被预先刺激, 卵巢激素和CSF-1。 我们进一步假设堕胎可能 由于子宫内巨噬细胞的有毒产物过度产生 例如TNF γ。 为了验证这些假设,我们建议定量IL-10。 1,IL-6和TNF α mRNA,生物活性和免疫反应性(ELISA), 子宫、肝脏、脾脏、胎盘和胎儿 小鼠流产产生方案的内毒素。 统计学比较 将在未处理的妊娠小鼠和用 内毒素或无毒内毒素,以确定细胞因子之间的关系 怀孕成功的水平。为了验证一个假设, 细胞因子导致流产,我们将确定小鼠是否可以保护 通过TNF α抗体治疗内毒素诱导的流产,或 IL-1 r拮抗剂。由于这些研究是基于以下基本原理, 内毒素诱导巨噬细胞产生细胞因子,研究将 以确定内毒素诱导的细胞因子产生是否 巨噬细胞依赖性细胞系体外研究和体内研究 将进行卵巢切除小鼠,以评估以下假设: 子宫巨噬细胞,通过暴露于生理 刺激物,雌二醇-17 β,孕酮和CSF-1,表现出升高 对内毒素的反应这些研究将提供更多 了解胎儿衰竭的原因。

项目成果

期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
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Gary W. Wood其他文献

Summary care record early adopter programme: an independent evaluation by University College London.
摘要护理记录早期采用者计划:伦敦大学学院的独立评估。
  • DOI:
  • 发表时间:
    2008
  • 期刊:
  • 影响因子:
    0
  • 作者:
    T. Greenhalgh;K. Stramer;T. Bratan;Emma Byrne;J. Russell;Y. Mohammad;Gary W. Wood;S. Hinder
  • 通讯作者:
    S. Hinder
Big is beautiful? A survey of body image perception and its relation to health in British Bangladeshis with diabetes
大就是美?
  • DOI:
    10.1080/13548500412331334163
  • 发表时间:
    2005
  • 期刊:
  • 影响因子:
    0
  • 作者:
    T. Greenhalgh;Mu'min Chowdhury;Gary W. Wood
  • 通讯作者:
    Gary W. Wood
Successful treatment of a malignant rat glioma with cytotoxic T lymphocytes.
用细胞毒性 T 淋巴细胞成功治疗恶性大鼠神经胶质瘤。
  • DOI:
  • 发表时间:
    1992
  • 期刊:
  • 影响因子:
    4.8
  • 作者:
    F. P. Holladay;Teresa Heitz;Yen;Masahiro Chiga;Gary W. Wood
  • 通讯作者:
    Gary W. Wood
Role of uterine cytokines in pregnancy: A review
  • DOI:
    10.1016/s0143-4004(05)80368-6
  • 发表时间:
    1994-01-01
  • 期刊:
  • 影响因子:
  • 作者:
    Gary W. Wood
  • 通讯作者:
    Gary W. Wood
Failure of in vitro-expanded hyperimmune cytotoxic T lymphocytes to affect survival of mouse embryos in vivo.
体外扩增的超免疫细胞毒性 T 淋巴细胞未能影响体内小鼠胚胎的存活。

Gary W. Wood的其他文献

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{{ truncateString('Gary W. Wood', 18)}}的其他基金

Neoantigen-specific Adoptive T Cell Therapy for Glioblastoma, IND-BB-13135, protocol submitted 04/25/2020
胶质母细胞瘤新抗原特异性过继 T 细胞疗法,IND-BB-13135,方案于 2020 年 4 月 25 日提交
  • 批准号:
    10505087
  • 财政年份:
    2022
  • 资助金额:
    $ 13.58万
  • 项目类别:
CYTOKINES AND ENDOTOXIN-INDUCED ABORTION
细胞因子和内毒素引起的流产
  • 批准号:
    2203145
  • 财政年份:
    1993
  • 资助金额:
    $ 13.58万
  • 项目类别:
CYTOKINES AND ENDOTOXIN-INDUCED ABORTION
细胞因子和内毒素引起的流产
  • 批准号:
    2403327
  • 财政年份:
    1993
  • 资助金额:
    $ 13.58万
  • 项目类别:
CYTOKINES AND ENDOTOXIN-INDUCED ABORTION
细胞因子和内毒素引起的流产
  • 批准号:
    2203146
  • 财政年份:
    1993
  • 资助金额:
    $ 13.58万
  • 项目类别:
CYTOKINES AND ENDOTOXIN-INDUCED ABORTION
细胞因子和内毒素引起的流产
  • 批准号:
    2203144
  • 财政年份:
    1993
  • 资助金额:
    $ 13.58万
  • 项目类别:
IMMUNOREGULATION IN PREGNANCY
怀孕期间的免疫调节
  • 批准号:
    3314683
  • 财政年份:
    1983
  • 资助金额:
    $ 13.58万
  • 项目类别:
IMMUNOREGULATION IN PREGNANCY
怀孕期间的免疫调节
  • 批准号:
    3314682
  • 财政年份:
    1983
  • 资助金额:
    $ 13.58万
  • 项目类别:
IMMUNOREGULATION IN PREGNANCY
怀孕期间的免疫调节
  • 批准号:
    3314684
  • 财政年份:
    1983
  • 资助金额:
    $ 13.58万
  • 项目类别:
IMMUNOREGULATION IN PREGNANCY
怀孕期间的免疫调节
  • 批准号:
    3314678
  • 财政年份:
    1983
  • 资助金额:
    $ 13.58万
  • 项目类别:
IMMUNOREGULATION IN PREGNANCY
怀孕期间的免疫调节
  • 批准号:
    3314686
  • 财政年份:
    1983
  • 资助金额:
    $ 13.58万
  • 项目类别:

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