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：
8290066
负责人：
Haichao Wang
金额：
$ 32.87万
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 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8290066
关键词：
Achievement Affect Alkanesulfonates Animal Model Animals Antibiotic Therapy Attenuated Autophagocytosis Bacterial exotoxin CSF3 gene Camellia sinensis Cause of Death Cells Cessation of life China Chinese Herbs Chinese People Complementary and alternative medicine DNA Data Development Disease Endotoxemia Endotoxins Epigallocatechin Gallate Exotoxins Functional disorder Goals Greater sac of peritoneum Green tea Growth Factor HMGB1 gene Hour Human Immune In Vitro Infiltration Inflammation Inflammation Mediators Inflammatory Inflammatory Response Injury Intensive Care Intensive Care Units Interferon Type II Intravenous Investigation Leukocytes Ligation Light Macrophage Inflammatory Protein-1 Mediator of activation protein Medicinal Herbs Microbe Modeling Multiple Organ Failure Mus Nitric Oxide Onset of illness Oral Oral Administration Organ Outcome Pathogenesis Peritoneal Phagocytosis Inhibition Phytotherapy Property Puncture procedure RANTES Recycling Route Salvia miltiorrhiza Seminal Sepsis Septic Shock Sodium Steroids Stimulus TLR2 gene TNF gene Testing Therapeutic Therapeutic Agents Tissues cell motility chemokine cytokine extracellular improved in vivo intravenous administration macrophage monocyte novel protective effect public health relevance research study treatment strategy uptake

项目摘要

DESCRIPTION (provided by applicant): Despite recent advance 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. Its pathogenesis is partly attributable to dys-regulated inflammatory responses that are propagated by early proinflammatory cytokines (e.g., TNF and IFN-gamma) but sustained by late-acting proinflammatory mediators (e.g., HMGB1). Agents targeting early proinflammatory cytokines (e.g., TNF) could be protective if given prophylatically; whereas agents capable of inhibiting HMGB1 release or activities could rescue animals from lethal sepsis even if given after onset of disease. Our seminal discovery of HMGB1 as a late mediator of lethal sepsis has prompted further investigation for developing new experimental therapeutics. We have generated preliminary data indicating that major components of several commonly used Chinese herbs, Danshen (Salvia miltiorrhiza, steroid-like tanshinones) and Green tea (Camellia sinensis, epigallocatechin gallate, EGCG) effectively attenuated endotoxin-induced HMGB1 release, and improved animal survival in murine models of endotoxemia and sepsis when given intraperitoneally. However, it is not known whether and how herbal components, individually or in combination, affect HMGB1 release induced by other inflammatory stimuli (e.g., G+ bacterial exotoxin, CpG-DNA, TNF, or IFN-gamma), and consequently influence the outcome of lethal endotoxemia and sepsis if given via clinically feasible (intravenous or oral) route of administration. The experiments outlined in Aim 1 will test the hypothesis that herbal components affect HMGB1 release induced by other exogenous (e.g., G+ exotoxin or CpG-DNA) or endogenous (e.g., TNF or IFN-gamma) stimuli, and that herbal components divergently influence HMGB1-induced release of nitric oxide, chemokines, and growth factors. In Aim 2, we will test a novel hypothesis that herbal components inhibit HMGB1 release either by facilitating endocytic "re-uptake" (recycling) of extracellular HMGB1, or by stimulating autophagic HMGB1 degradation. The experiments outlined in Aim 3 will test the hypothesis that oral or intravenous administration of herbal components protects animals against lethal endotoxemia and sepsis by modulating peritoneal leukocyte infiltration, systemic and peritoneal inflammation, tissue injury, and organ dysfunction. Answers to these questions will significantly improve our understanding of immune modulatory mechanisms of two commonly used Chinese medicinal herbs, and shed light on the development of alternative strategies for treatment of sepsis and other inflammatory diseases. PUBLIC HEALTH RELEVANCE: Sepsis remains the most common cause of death in the intensive care units, claiming > 225,000 victims annually in the U.S. alone. It is a multi-factorial disorder that triggers an uncontrolled systemic inflammatory response, ultimately leading to multiple organ failure and death. Our recent discovery of HMGB1 as a late mediator of experimental sepsis has prompted investigation of Chinese medicinal herbs as potential HMGB1- targeting therapeutic agents. The long-term goal of this application is to elucidate novel mechanisms by which major components of two medicinal herbs [Danshen (Salvia miltiorrhiza) and Green tea (Camellia sinensis)] inhibit HMGB1 release, and consequently protect animals against lethal endotoxemia and sepsis.

描述（由申请人提供）：尽管最近抗生素治疗和重症监护取得了进展，但脓毒症仍然是重症监护室最常见的死亡原因，仅在美国每年就有超过 225,000 名受害者死亡。其发病机制部分归因于失调的炎症反应，这些炎症反应由早期促炎细胞因子（例如 TNF 和 IFN-gamma）传播，但由晚期促炎介质（例如 HMGB1）维持。如果预防性给予，针对早期促炎细胞因子（例如 TNF）的药物可能具有保护作用；而能够抑制 HMGB1 释放或活性的药物即使在疾病发作后给予，也可以使动物免于致命的败血症。我们对 HMGB1 作为致命性脓毒症晚期介质的开创性发现促使我们进一步研究开发新的实验疗法。我们已经生成的初步数据表明，几种常用中药丹参（丹参、类固醇类丹参酮）和绿茶（茶树、表没食子儿茶素没食子酸酯、EGCG）的主要成分可有效减弱内毒素诱导的 HMGB1 释放，并提高动物存活率腹腔内给药时在内毒素血症和败血症的小鼠模型中。然而，尚不清楚草药成分是否以及如何单独或组合影响其他炎症刺激（例如 G+ 细菌外毒素、CpG-DNA、TNF 或 IFN-gamma）诱导的 HMGB1 释放，从而影响治疗结果如果通过临床上可行的给药途径（静脉内或口服）给药，可能会导致致命的内毒素血症和败血症。目标 1 中概述的实验将检验以下假设：草药成分影响其他外源性（例如 G+ 外毒素或 CpG-DNA）或内源性（例如 TNF 或 IFN-gamma）刺激诱导的 HMGB1 释放，并且草药成分对 HMGB1 的影响不同-诱导释放一氧化氮、趋化因子和生长因子。在目标 2 中，我们将测试一个新的假设，即草药成分通过促进细胞外 HMGB1 的内吞“再摄取”（再循环）或通过刺激自噬性 HMGB1 降解来抑制 HMGB1 释放。目标 3 中概述的实验将检验以下假设：口服或静脉注射草药成分可通过调节腹膜白细胞浸润、全身和腹膜炎症、组织损伤和器官功能障碍，保护动物免受致命性内毒素血症和败血症。这些问题的答案将显着提高我们对两种常用中药免疫调节机制的理解，并有助于开发治疗脓毒症和其他炎症性疾病的替代策略。公共卫生相关性：败血症仍然是重症监护病房最常见的死亡原因，仅在美国每年就有超过 225,000 名受害者死亡。它是一种多因素疾病，会引发不受控制的全身炎症反应，最终导致多器官衰竭和死亡。我们最近发现 HMGB1 作为实验性脓毒症的晚期介质，促使人们对中草药作为潜在的 HMGB1 靶向治疗剂进行研究。该申请的长期目标是阐明两种草药[丹参（Salvia miltiorriza）和绿茶（Camellia sinensis）]的主要成分抑制HMGB1释放的新机制，从而保护动物免受致命性内毒素血症和败血症。