Mechanisms Regulating Neutrophil Activation in Pregnancy

妊娠期中性粒细胞激活的调节机制

• 批准号: 6626031
• 负责人: HOWARD R PETTY
• 金额: $ 13.39万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6626031
• 关键词: NAD(H) phosphate; calcium flux; cell biology; cellular respiration; clinical research; contact inhibition; endopeptidases; enzyme activity; female; fluorimetry; gender difference; glucose 6 phosphate dehydrogenase; glycosidases; hexokinase; human subject; immunofluorescence technique; immunosuppression; lactate dehydrogenases; leukocyte activation /transformation; male; membrane lipids; neutrophil; nicotinamide adenine dinucleotide; pentose phosphate shunt; pregnancy immunology; pyruvate kinase; trophoblast

DESCRIPTION (provided by applicant): This application is submitted in response to an RFA that requested applications to identify and characterize differences in the innate and adaptive immune response between genders, with a specific call for interdisciplinary clinical and basic research studies that may be important in the understanding and treatment of autoimmune diseases. Neutrophils are key cells in the development of homeostatic as well as pathologic inflammatory responses. These cells play a central role in the generation of tissue damage in autoimmune diseases (i.e., rheumatoid arthritis) as well as in infectious diseases, including sepsis. The studies outlined in this application are designed to study the differences in neutrophil function in non-pregnant women, pregnant women, and men. Studies conducted in our laboratory have established that neutrophils of normal pregnant women have a unique immunological state, which has not been previously recognized. This state exhibits the simultaneous expression of activated and inhibited neutrophil properties as reflected in cell calcium signaling, metabolism, and oxidant production. We have demonstrated that these properties reverse shortly after delivery and, thus, may account for the increase in postpartum disease activity in some autoimmune disorders. Our preliminary studies have identified biochemical bases for the changes in neutrophil physiology observed in normal pregnancy and implicated the hexose monophosphate shunt (HMS) and lipid rafts in the regulation of calcium signaling, metabolism and oxidant production. Strikingly, we have identified that trophoblast cells (which are in direct contact with maternal neutrophils in the intervillous space) have the capacity to reverse neutrophil activation upon contact. Using ultra-fast microscopy, we have been able to demonstrate interference with normal calcium signaling and reactive oxygen metabolite (ROM) production upon cell-to-cell contact. More importantly, we have determined that this property of trophoblasts resides in the glycocalyx and can be released in soluble form. This factor may account for the clinical improvement of some autoimmune diseases during pregnancy and their worsening after delivery. Moreover, our findings and proposed strategy may offer a unique opportunity for the identification of endogenous mechanisms affecting women's health. We propose that studying neutrophil biology during pregnancy will result in a mechanistic understanding of factors responsible for clinical improvement in certain autoimmune diseases during pregnancy and will also lead to the development of novel therapeutic approaches to control inflammation and autoimmunity.

描述（由申请人提供）：本申请书提交于 对要求应用程序识别和表征的RFA的响应 性别之间先天性和适应性免疫反应的差异， 特别呼吁进行跨学科临床和基础研究， 可能对理解和治疗自身免疫性疾病很重要。 中性粒细胞是体内平衡发展的关键细胞， 病理性炎症反应。这些细胞在人类的免疫系统中起着核心作用。 自身免疫性疾病中组织损伤的产生（即，类风湿 关节炎）以及感染性疾病，包括败血症。研究 本申请中概述的目的是研究 中性粒细胞功能在非妊娠妇女，妊娠妇女和男性。研究 在我们实验室进行的研究已经确定，正常的中性粒细胞 孕妇具有独特的免疫状态， 以前认识的。这种状态同时表现出 激活和抑制中性粒细胞的特性，反映在细胞钙 信号传导、代谢和氧化剂产生。我们已经证明 这些性质在交付后不久就发生了逆转，因此，可能是 某些自身免疫性疾病中产后疾病活动性增加。我们 初步研究已经确定了生物化学基础的变化， 在正常妊娠中观察到的中性粒细胞生理学， 单磷酸盐分流（HMS）和脂筏在钙调节中的作用 信号传导、代谢和氧化剂产生。令人惊讶的是，我们发现 滋养层细胞（与母体中性粒细胞直接接触） 在绒毛间隙）具有逆转中性粒细胞活化的能力 一旦接触。利用超高速显微镜，我们已经能够证明 干扰正常钙信号和活性氧代谢产物 (ROM)在细胞与细胞接触时产生。更重要的是我们有 确定滋养细胞的这种特性存在于糖萼中， 可以以可溶形式释放。这一因素可以解释临床 妊娠期某些自身免疫性疾病的改善和恶化 分娩后。此外，我们的研究结果和拟议的战略可能会提供一个 独特的机会，以确定内源性机制， 妇女的健康。我们建议研究怀孕期间的中性粒细胞生物学 将导致对临床疾病的因素的机械理解， 改善某些自身免疫性疾病在怀孕期间，也将导致 开发新的治疗方法来控制炎症， 自身免疫