Morphine Actions on the Immune System

吗啡对免疫系统的作用

基本信息

批准号：
7578869
负责人：
SULIE L. CHANG
金额：
$ 29.56万
依托单位：
SETON HALL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1992
资助国家：
美国
起止时间：
1992-03-15 至 2012-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7578869
关键词：
Acetates Acquired Immunodeficiency Syndrome Acute Promyelocytic Leukemia Adhesions Adrenal Glands Animal Model Anti-Inflammatory Agents Anti-inflammatory Bacterial Infections Binding Body Temperature Brain Cell Culture Techniques Cells Chronic Clinical Coagulation Process Control Animal Corticosterone Data Endotoxins Exposure to Figs - dietary Funding Gagging Genes Genetic Transcription Genome Glycoproteins Goals HIV HIV Envelope Protein gp120 HIV-1 HL-60 Cells HL60 Human Hypothalamic structure Immune Immune system In Vitro Infection Inflammation Inflammatory Inflammatory Response Injection of therapeutic agent Interleukin-6 Leukocytes Lipopolysaccharides Mediating Messenger RNA Modeling Molecular Morphine Opioid Opioid Receptor Pathway interactions Patients Peritoneal Macrophages Phorbol Phorbols Physiological Pituitary Gland Placebos Plasma Predisposition Production Proviruses Rattus Receptor Signaling Recombinants Research Personnel STAT3 gene Sepsis Septic Shock Serum Signal Pathway Testing Therapeutic Intervention Tissues Transcription Factor AP-1 Transgenic Organisms Translating Up-Regulation Viral Viral Proteins Virus Diseases antithrombin III-protease complex clinically significant cytokine desensitization in vivo intraperitoneal mRNA Expression macrophage morphine acetate mu opioid receptors novel opioid abuse pressure programs promoter receptor expression response treatment effect

项目摘要

DESCRIPTION (provided by applicant): The goal of this renewal application (2DA07058-17) entitled, "Morphine Actions on the Immune System" is to elucidate the effects of chronic exposure to opioids, such as morphine, on various immune parameters. We propose to examine the interactions between morphine and the bacterial endotoxin, lipopolysaccharide (IPS), during infection with HIV-1, using the HIV transgenic rat (HIV Tg rat) and human cell culture models. The HIV Tg rat carries a gag-pol-deleted HIV-1 genome under the control of the HIV-1 viral promoter, and expresses 7 of the 9 HIV genes. This model shows no viral replication; however, it does develop various manifestations of human HIV infection, indicating that the presence of viral proteins in the host causes HIV progression. The actions of morphine are mediated through the mu opioid receptor (MOR). We found that MOR mRNA in the peritoneal macrophages and brain of the HIV Tg rat was significantly higher than that in control animals, and was further increased following systemic LPS treatment. We also found that in TPA- differentiated HL-60 promyelocytic leukemia cells (TPA-HL-60 cells), treatment with recombinant HIV glycoprotein 120 (gp120) or LPS up-regulated MOR expression, which appeared to be mediated through the actions of the pro-inflammatory cytokine, TNF-a. In addition, inhibition the NFkB1 transcriptional factor decreased the up-regulation of MOR expression by LPS and gp120. We, thus, hypothesize that the MOR signaling pathway serves as a convergence point for the inflammatory response to opioids, bacterial endotoxin, and HIV gp120 viral protein. To test our hypothesis, in Aim 1, we will determine the effects of chronic morphine exposure on LPS-induced leukocyte-endothelial interaction, cytokine production, and intravascular coagulation in HIV Tg rats. In Aim 2, the effects of morphine and LPS, alone and in combination, on MOR expression will be examined in HIV Tg rats. In Aims 3 and 4, the cross-effects of morphine, LPS, and gp120 on MOR expression, cytokine secretion, and the involvement of the NF/fB, AP-1, and STATS transcriptional factors will be examined in TPA-HL-60 cells. Few studies have examined the interactive effects of opioids and bacterial endotoxins in the course of HIV infection using either animal models or human cell cultures. Therefore, the data from the proposed studies can have substantial clinical significance in the understanding and treatment of HIV infection and AIDS.

描述（由申请人提供）：这个题为“吗啡对免疫系统的作用”的续展申请（2DA07058-17）的目的是阐明长期暴露于阿片类药物（例如吗啡）对各种免疫参数的影响。我们建议使用 HIV 转基因大鼠（HIV Tg 大鼠）和人类细胞培养模型来研究 HIV-1 感染期间吗啡与细菌内毒素、脂多糖 (IPS) 之间的相互作用。 HIV Tg 大鼠携带在 HIV-1 病毒启动子控制下的 gag-pol 缺失的 HIV-1 基因组，并表达 9 个 HIV 基因中的 7 个。该模型显示没有病毒复制；然而，它确实会出现人类艾滋病毒感染的各种表现，表明宿主体内病毒蛋白的存在会导致艾滋病毒的进展。吗啡的作用是通过 mu 阿片受体 (MOR) 介导的。我们发现HIV Tg大鼠腹膜巨噬细胞和大脑中的MOR mRNA显着高于对照动物，并且在全身LPS治疗后进一步增加。我们还发现，在 TPA 分化的 HL-60 早幼粒细胞白血病细胞（TPA-HL-60 细胞）中，用重组 HIV 糖蛋白 120 (gp120) 或 LPS 处理可上调 MOR 表达，这似乎是通过促炎细胞因子，TNF-a。此外，抑制 NFkB1 转录因子可降低 LPS 和 gp120 对 MOR 表达的上调。因此，我们假设 MOR 信号通路是阿片类药物、细菌内毒素和 HIV gp120 病毒蛋白炎症反应的汇聚点。为了检验我们的假设，在目标 1 中，我们将确定长期吗啡暴露对 LPS 诱导的白细胞-内皮相互作用、细胞因子产生和 HIV Tg 大鼠血管内凝血的影响。在目标 2 中，将在 HIV Tg 大鼠中检查吗啡和 LPS 单独或联合使用对 MOR 表达的影响。在目标 3 和 4 中，将在 TPA-HL-60 中检查吗啡、LPS 和 gp120 对 MOR 表达、细胞因子分泌以及 NF/fB、AP-1 和 STATS 转录因子参与的交叉影响细胞。很少有研究使用动物模型或人类细胞培养物来研究阿片类药物和细菌内毒素在艾滋病毒感染过程中的相互作用。因此，拟议研究的数据对于理解和治疗艾滋病毒感染和艾滋病具有重要的临床意义。