MECHANISMS BY WHICH NEUTROPHILS MODULATE THE SYSTEMIC INFLAMMATORY RESPONSE

中性粒细胞调节全身炎症反应的机制

• 批准号: 6289399
• 负责人: ROBERT L DANNER
• 金额: --
• 依托单位: CLINICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6289399
• 关键词: blood toxicology; cell cell interaction; chronic granulomatous disease; clinical research; colony stimulating factor; cytokine; endotoxins; host organism interaction; human subject; inflammation; leukocyte activation /transformation; macrophage; monocyte; neutrophil; protein biosynthesis; tumor necrosis factor alpha

Neutrophils have been considered to be end-differentiated cells that have little or no ability to modulate the inflammatory responses of other cells. More recently, it has become clear that neutrophils release certain cytokines and that altering neutrophil function or number has profound effects on the systemic inflammatory response induced by endotoxin or sepsis. The mechanisms by which neutrophils modulate inflammatory responses are not well defined but appear to be mediated by more than simple antibac-terial or antitoxin effects. Our work is focused on exploring the mechanisms by which neutrophils effect monocyte/macrophage and endothelial cell function. Further, we are collaborating with Dr. Malech (NIAID) to examine these effects in patients with chronic granulomatous disease and in volunteers given granulocyte colony stimulating factor (GCSF). We have found that produc-tion of pro-inflammatory cytokines is downregulated and production of anti-inflammatory cytokines is upregulated in monocytes cocultured with human neutrophils via a mechanism that requires direct cell-to-cell contact (Abstract, Invest Med, 1996). Ex vivo studies using a whole blood tumor necrosis factor assay in GCSF-stimulated normal volunteers show that neutrophil number and state of activation have profound effects on cytokine production (Abstract, American Thoracic Society, 1996). Recent work has defined the effects of neutrophils on monocyte production of anti-inflammatory cytokines such as interleukin (IL)-10 and IL-1ra. Current experiments are focusing on the cell surface molecules involved in these responses and have led to the identification of monoclonal antibodies that interfere with monocyte/neutrophil interactions. Regulation of the inflammatory response by neutro-phils may be an important mechanism that represents a potential new therapeutic target for treating sepsis.

中性粒细胞被认为是终末分化细胞，其很少或没有能力调节其他细胞的炎症反应。最近，人们已经清楚中性粒细胞释放某些细胞因子，并且改变中性粒细胞功能或数量对内毒素或脓毒症引起的全身炎症反应具有深远影响。中性粒细胞调节炎症反应的机制尚未明确，但似乎不仅仅是由简单的抗菌或抗毒素作用介导。我们的工作重点是探索中性粒细胞影响单核细胞/巨噬细胞和内皮细胞功能的机制。此外，我们正在与 Malech 博士 (NIAID) 合作，研究这些对慢性肉芽肿性疾病患者和服用粒细胞集落刺激因子 (GCSF) 的志愿者的影响。我们发现，通过一种需要直接细胞间接触的机制，在与人中性粒细胞共培养的单核细胞中，促炎细胞因子的产生被下调，而抗炎细胞因子的产生被上调（摘要，Invest Med，1996）。在 GCSF 刺激的正常志愿者中使用全血肿瘤坏死因子测定进行的离体研究表明，中性粒细胞数量和激活状态对细胞因子的产生具有深远的影响（摘要，美国胸科学会，1996）。最近的工作明确了中性粒细胞对单核细胞产生抗炎细胞因子（例如白细胞介素 (IL)-10 和 IL-1ra）的影响。目前的实验集中于参与这些反应的细胞表面分子，并鉴定出干扰单核细胞/中性粒细胞相互作用的单克隆抗体。中性粒细胞对炎症反应的调节可能是一种重要机制，代表着治疗脓毒症的潜在新治疗靶点。