Mechanisms of Novel Herbal Therapies for Sepsis.

脓毒症新型草药疗法的机制。

基本信息

批准号：
9282696
负责人：
Haichao Wang
金额：
$ 34.12万
依托单位：
FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9282696
关键词：
Affect Animals Antibiotic Therapy Carbenoxolone Cause of Death Cells Connexin 43 Data Development Disease Dose Double-Stranded RNA Endotoxemia Genes Glycyrrhizic Acid HMGB1 gene Hepatic Tissue Hepatitis Herbal Medicine Human Infiltration Inflammasome Inflammation Inflammation Mediators Inflammatory Inflammatory Response Injury Intensive Care Intensive Care Units Investigation Lead Leukocytes Licorice Ligation Light Mediating Mediator of activation protein Medicinal Herbs Molecular Mus Nature Necrosis Nuclear Outcome Pathogenesis Peptic Ulcer Pharmacology Phosphorylation Phytotherapy Proteins Puncture procedure Role STAT1 gene Science Seminal Sepsis Signal Transduction Stimulus Survival Rate Testing Up-Regulation eIF-2 Kinase immunoregulation improved inhibitor/antagonist liver injury macrophage monocyte neutralizing antibody novel peptidomimetics protein kinase R public health relevance targeted treatment

项目摘要

DESCRIPTION (provided by applicant): Despite recent advances in antibiotic therapy and intensive care, sepsis remains the most common cause of death in the intensive care units, claiming > 225,000 victims annually in the U.S. alone. The pathogenesis of sepsis remains obscure, but is partly attributable to dys-regulated inflammatory responses sustained by late pro-inflammatory mediators (e.g., HMGB1, CIRP, and NO). Our seminal discovery of HMGB1 as a late mediator of lethal systemic inflammation (LSI) (Science, 285: 248-51, 1999) has prompted an investigation of the intricate molecular mechanisms underlying the pharmacological modulation of HMGB1 secretion by traditional herbal medicine. Gancao (Radix glycyrrhizae, or licorice) has been traditionally used in the treatment of peptic ulcer, hepatic injury, and hepatitis, but its protective mechanisms remain elusive. Our preliminary data indicated that carbenoxolone (CBX), a derivative of the major Gancao component, glycyrrhizin (glycyrrhizic acid, GZA), dose-dependently abrogated LPS-induced PKR (double-stranded RNA-activated protein kinase R) phosphorylation and HMGB1 secretion, and rescued mice from lethal sepsis (induced by cecal ligation and puncture, CLP) even if given in a delayed fashion. Meanwhile, compelling evidence has emerged to support the critical roles of: i) STAT1 signaling in cytoplasmic HMGB1 translocation (PNAS, 111: 3068-73, 2014); and ii) PKR in inflammasome activation and HMGB1 secretion (Nature, 488: 670-4, 2012). In light of the possible role of Cx43 and Panx1 hemichannels in ATP efflux, as well as the requirement of ATP for ultrapure LPS-induced HMGB1 secretion, it is important to test a novel hypothesis that prolonged stimulation with crude LPS or other key HMGB1 secretion stimuli (such as SAA and CIRP) may lead to upregulation of Panx1 and/or Cx43 hemichannel proteins, which facilitate ATP-dependent PKR and STAT1 phosphorylation, thereby contributing to HMGB1 secretion and lethal systemic inflammation (LSI). Accordingly, we propose to test: 1) the novel hypothesis that crude LPS and other important inflammatory stimuli (e.g., SAA and CIRP) up-regulate Panx1 and Cx43 hemichannel expression, and trigger PKR phosphorylation and HMGB1 secretion (Aim 1); 2) the novel roles of Panx1 and Cx43 hemichannels in the pathogenesis of lethal systemic inflammation (LSI) (Aim 2); and 3) the novel mechanisms by which Panx1 or Cx43 hemichannel inhibitors (such as mimetic peptides antagonists, neutralizing antibodies, and herbal inhibitors such as GZA and CBX) affect the outcomes of LSI (Aim 3). Collectively, these proposed studies will improve our understanding of the mechanisms by which herbal medicine effectively inhibits exogenous PAMPs or endogenous proinflammatory mediators-induced HMGB1 secretion, and shed light on the development of novel hemichannel-targeting therapies for LSI.

描述（由申请人提供）：尽管最近在抗生素治疗和重症监护方面取得了进展，但脓毒症仍然是重症监护病房中最常见的死亡原因，仅在美国每年就有超过 225,000 名受害者死亡。脓毒症的发病机制仍然不清楚，但已得到证实。部分归因于晚期促炎介质（例如 HMGB1、CIRP 和 NO）维持的失调炎症反应。我们对 HMGB1 作为晚期促炎介质的开创性发现。致死性全身炎症 (LSI) 介质 (Science, 285: 248-51, 1999) 促使人们对传统草药（甘草）调节 HMGB1 分泌的复杂分子机制进行了研究。传统上用于治疗消化性溃疡、肝损伤和肝炎，但其保护机制仍不清楚。甘草主要成分甘草甜素（甘草酸，GZA）的衍生物甘草酸（CBX），剂量依赖性地消除 LPS 诱导的 PKR（双链 RNA 激活蛋白激酶 R）磷酸化和 HMGB1 分泌，并将小鼠从致命的危险中拯救出来。即使延迟给药，也可能导致败血症（由盲肠结扎和穿刺引起，CLP）。同时，有令人信服的证据表明。的出现支持了以下关键作用：i) STAT1 信号在细胞质 HMGB1 易位中（PNAS, 111: 3068-73, 2014）；和 ii) PKR 在炎性体激活和 HMGB1 分泌中的关键作用（Nature, 488: 670-4, 2012）。鉴于 Cx43 和 Panx1 半通道在 ATP 流出中的可能作用，以及超纯 LPS 诱导的 HMGB1 分泌需要 ATP，重要的是测试一个新的假设，即用粗 LPS 或其他关键 HMGB1 分泌刺激物（例如 SAA 和 CIRP）进行长时间刺激可能会导致 Panx1 和/或的上调或 Cx43 半通道蛋白，其促进 ATP 依赖性 PKR 和 STAT1 磷酸化，从而促进 HMGB1 分泌和致命的全身炎症 (LSI)。建议测试：1）新假设，即粗制 LPS 和其他重要的炎症刺激（例如 SAA 和 CIRP）上调 Panx1 和 Cx43 半通道表达，并触发 PKR 磷酸化和 HMGB1 分泌（目标 1）； Panx1 和 Cx43 半通道在致死性全身炎症 (LSI) 发病机制中的作用（目标 2）和 3) 新机制；其中 Panx1 或 Cx43 半通道抑制剂（例如模拟肽拮抗剂、中和抗体以及 GZA 和 CBX 等草药抑制剂）会影响 LSI 的结果（目标 3）。总的来说，这些拟议的研究将增进我们对草药机制的理解。该药物可有效抑制外源性 PAMP 或内源性促炎介质诱导的 HMGB1 分泌，并为开发新型半通道靶向疗法提供线索大规模集成电路。