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：
7744673
负责人：
Lucille London
金额：
$ 17.55万
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 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7744673
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）是一种非常普通的严重肺损伤形式，由多种因素触发，包括传染性，非感染和其他破坏性事件。 ARDS是一种多因素疾病，其中炎症和组织纤维化是发病率和死亡率的主要原因。这是一种多元症状障碍，在美国每年最多影响20万名患者。尽管支持疗法有所提高，但没有有效的治疗剂来改善ARDS患者的临床结局。特别是，糖皮质激素在治疗这种疾病方面无效。因此，迫切需要开发治疗，以阻止ARDS的发展。人类中的ARD具有多种特征，以弥漫性肺泡损伤（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的反应性不足。我们已经开发了一种传染性诱导的ARD的小动物模型，该模型表现出人类ARD的许多特征：（i）在组织学上，我们的ARDS模型表现出爸爸，透明膜，由于血管泄漏引起的出血和肺泡上皮的破坏；（ii）主要由中性粒细胞和巨噬细胞组成的浸润；（iii）慢性期表现出纤维化肺泡炎；（iv）用糖皮质激素治疗不会导致对疾病过程的显着调节；（v）在我们的ARDS的感染模型中提出了涉及FAS/FASL途径的凋亡的作用。因此，该模型为感染引起的ARDS提供了一个非常相关的模型，并解解了有效抗氧化剂，抗微生物，抗炎剂姜黄素的作用机理。我们假设在姜黄素定期摄入印度香料姜黄的主要成分，调节肺部的细胞浸润，促炎细胞因子表达和信号转导途径，从而导致对感染性诱导的ARD的抗性。我们的初步数据表明，用姜黄素治疗抑制了依杜氏病毒1/L诱导的ARD的纤维化病变的发育。我们的具体目的将阐明姜黄素的作用机理，姜黄素的作用机理，专注于炎症性浸润，细胞因子的释放，凋亡以及姜黄素激活和调节的信号转导途径。阐明潜在的CAM疗法（例如姜黄素）的基本作用机制将有助于其整合到常规医疗服务中。 1. AIM＃1将通过调节炎症性浸润和关键细胞因子/趋化因子的表达来显着提高姜黄素的假说，并抑制ARDS的存活，并抑制纤维化的发展和纤维化的发展，包括G-＆G/M-CSF，包括G-和G/M-CSF，IFN3，MCP-1，MCP-1，MIP-2，MIP-2和MIP-11。 2. AIM＃2将检验以下假设：姜黄素调节ARDS中涉及的信号通路，其中包括由PKC，Caveolin-1，ERK/MEK/MEK，NFKB，TGF2和凋亡途径介导的途径。公共卫生相关性：这些实验的核心目标是研究姜黄素（一种潜在的CAM治疗方法）可以防止感染性ARDS的分子机制。尽管支持疗法在人类ARDS患者中有所提高，但没有有效的治疗剂来改善ARDS患者的临床结局。因此，迫切需要开发治疗，以阻止ARDS的发展。阐明潜在CAM疗法的基本作用机制将有助于将其整合到常规医疗服务中。此外，CAM疗法的机理研究将改善关键研究终点的识别，从而加强CAM临床试验的设计。