Curcumin Therapy in an Infectious Model of Acute Respiratory Distress Syndrome

姜黄素治疗急性呼吸窘迫综合征感染模型

基本信息

批准号：
7587782
负责人：
Lucille London
金额：
$ 23.4万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-01-01 至 2010-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7587782
关键词：
Action Potentials Acute Adenoviruses Adult Respiratory Distress Syndrome Affect Alveolar Animal Model Anti-Inflammatory Agents Antioxidants Apoptosis Apoptotic Blood Vessels CCL2 gene Caring Caveolins Cellular Infiltration Characteristics Chronic Chronic Phase Clinical Clinical Trials Curcumin Data Development Diffuse Disease Edema Event Exhibits Extravasation Fibrosis Glucocorticoids Goals Hamman-Rich syndrome Hemorrhage Histologic Human Human Characteristics Infection Infectious Agent Infiltration Inflammation Inflammatory Infiltrate Influenza Influenza A Virus, H5N1 Subtype Ingestion Lead Lesion Lung Lung diseases MEKs Mediating Medical Membrane Mitogen-Activated Protein Kinases Modeling Molecular Morbidity - disease rate Mus Outcome Pathway interactions Patients Phosphorylation Play Process Protein Isoforms Protein Kinase C Proteins Reovirus Type 1 Resistance Role SARS coronavirus Signal Pathway Signal Transduction Pathway Spices Staging Supportive care Symptoms Syndrome Testing Therapeutic Therapeutic Agents Tissues Tumeric United States alveolar epithelium antimicrobial base caveolin 1 chemokine cytokine design improved lung injury macrophage mortality neutrophil outcome forecast prophylactic public health relevance research study therapy development

项目摘要

DESCRIPTION (provided by applicant): Acute Respiratory Distress Syndrome (ARDS) is an all-too-common form of severe lung injury that is triggered by a variety of factors including infectious, non-infectious and other damaging events. ARDS is a multi-factorial disorder in which inflammation and tissue fibrosis is the leading cause of morbidity and mortality. It is a plural symptom disorder that affects up to 200,000 patients annually in the US. Although supportive therapy has improved survival somewhat, there are no effective therapeutic agents for improving clinical outcome of patients with ARDS. In particular, glucocorticoids are not effective in treating this disorder. Therefore, there is an urgent need for the development of treatments to halt the progression of ARDS. ARDS in humans has several characteristic features, exemplified by diffuse alveolar damage (DAD), neutrophil and macrophage infiltration, fibrosing alveolitis, and lack of responsiveness to glucocorticoids. We have developed a small animal model of infectious-induced ARDS that displays many of the characteristics of human ARDS: (I) Histologically, our ARDS model exhibits DAD, hyaline membranes, hemorrhage due to vascular leakage, and disruption of alveolar epithelium; (II) Infiltrates composed primarily of neutrophils and macrophages; (III) The chronic phase demonstrates fibrosing alveolitis; (IV) Treatment with glucocorticoids does not lead to significant modulation of the disease process; (V) A role for apoptosis involving the Fas/FasL pathway has been suggested in our infectious model of ARDS. Thus, this model provides a very relevant model for infection-induced ARDS and for deciphering the mechanism of action of the potent anti-oxidant, anti-microbial, anti-inflammatory agent, curcumin. We hypothesize that the ingestion on a regular basis of curcumin the major component of the Indian spice turmeric, modulates cellular infiltration, proinflammatory cytokine expression, and signal transduction pathways in the lungs, leading to resistance against infectious-induced ARDS. Our preliminary data suggest that treatment with curcumin inhibits DAD and fibrotic lesion development in reovirus 1/L-induced ARDS. Our specific aims will elucidate the mechanisms of action of curcumin focusing on the inflammatory infiltrate, the release of cytokines, apoptosis, and the signal transduction pathways activated and modulated by curcumin. Elucidating the underlying mechanisms of action of potential CAM therapies such as curcumin will facilitate their integration into conventional medical care. 1. Aim #1 will test the hypothesis that curcumin significantly improves ARDS survival and inhibits development of DAD and fibrosis by modulating the inflammatory infiltrate and expression of key cytokines/chemokines including G- & G/M-CSF, IFN3, MCP-1, MIP-2, and MIP-11. 2. Aim #2 will test the hypothesis that curcumin modulates signaling pathways involved in ARDS, which includes pathways mediated by PKC, Caveolin-1, ERK/MEK, NFkB, TGF2, and apoptotic pathways. PUBLIC HEALTH RELEVANCE: The central goals of these experiments are to investigate the molecular mechanism through which curcumin, a potential CAM therapeutic, protects against infectious ARDS. Although supportive therapy has improved survival somewhat in human ARDS patients, there are no effective therapeutic agents for improving clinical outcome of patients with ARDS. Therefore, there is an urgent need for the development of treatments to halt the progression of ARDS. Elucidating the underlying mechanisms of action of potential CAM therapies will facilitate their integration into conventional medical care. In addition, mechanistic studies of CAM therapies will improve the identification of key study endpoints, and thus, strengthen the design of CAM clinical trials.

描述（由申请人提供）：急性呼吸窘迫综合征（ARDS）是一种非常常见的严重肺损伤形式，由多种因素引发，包括感染性、非感染性和其他破坏性事件。 ARDS 是一种多因素疾病，其中炎症和组织纤维化是发病和死亡的主要原因。它是一种多种症状的疾病，在美国每年影响多达 200,000 名患者。尽管支持治疗在一定程度上提高了生存率，但尚无有效的治疗药物可改善 ARDS 患者的临床结果。特别是，糖皮质激素对于治疗这种疾病无效。因此，迫切需要开发治疗方法来阻止 ARDS 的进展。人类 ARDS 有几个特征，例如弥漫性肺泡损伤 (DAD)、中性粒细胞和巨噬细胞浸润、纤维化肺泡炎以及对糖皮质激素缺乏反应。我们开发了一种感染性ARDS小动物模型，它显示了人类ARDS的许多特征：（I）在组织学上，我们的ARDS模型表现出DAD、透明膜、血管渗漏引起的出血以及肺泡上皮的破坏； (II) 主要由中性粒细胞和巨噬细胞组成的浸润细胞； (III)慢性期表现为纤维化肺泡炎； (IV) 糖皮质激素治疗不会显着调节疾病进程； (V) 在我们的 ARDS 感染模型中已表明涉及 Fas/FasL 途径的细胞凋亡的作用。因此，该模型为感染引起的 ARDS 以及破译强效抗氧化剂、抗微生物、抗炎剂姜黄素的作用机制提供了一个非常相关的模型。我们假设，定期摄入姜黄素（印度香料姜黄的主要成分）可调节细胞浸润、促炎细胞因子表达和肺部信号转导途径，从而对感染引起的 ARDS 产生抵抗力。我们的初步数据表明，姜黄素治疗可抑制呼肠孤病毒 1/L 诱导的 ARDS 中 DAD 和纤维化病变的发展。我们的具体目标是阐明姜黄素的作用机制，重点关注炎症浸润、细胞因子的释放、细胞凋亡以及姜黄素激活和调节的信号转导途径。阐明姜黄素等潜在 CAM 疗法的潜在作用机制将有助于它们融入传统医疗保健。 1. 目标 #1 将检验姜黄素通过调节关键细胞因子/趋化因子（包括 G- 和 G/M-CSF、IFN3、MCP-1）的炎症浸润和表达，显着改善 ARDS 生存并抑制 DAD 和纤维化发展的假设。 MIP-2 和 MIP-11。 2. 目标 #2 将检验姜黄素调节 ARDS 相关信号通路的假设，其中包括 PKC、Caveolin-1、ERK/MEK、NFkB、TGF2 介导的通路和细胞凋亡通路。公共健康相关性：这些实验的中心目标是研究姜黄素（一种潜在的 CAM 治疗剂）预防传染性 ARDS 的分子机制。尽管支持疗法在一定程度上改善了人类 ARDS 患者的生存率，但尚无有效的治疗药物可改善 ARDS 患者的临床结果。因此，迫切需要开发治疗方法来阻止 ARDS 的进展。阐明潜在 CAM 疗法的潜在作用机制将有助于它们融入传统医疗保健。此外，CAM 疗法的机制研究将提高关键研究终点的确定，从而加强 CAM 临床试验的设计。