Accelerating Inflammation Resolution to CounterACT Chemical Injury

加速炎症消退以对抗化学损伤

基本信息

批准号：
8547809
负责人：
SVEN-ERIC JORDT
金额：
$ 16.09万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-19 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8547809
关键词：
Acrolein Ammonia Animal Disease Models Anti-Inflammatory Agents Anti-inflammatory Area Arthritis Asthma Attenuated Blood Vessels Bulla CD59 Antigen Cardiopulmonary Cells Chemical Injury Chemical Warfare Agents Chemicals Chlorine Colitis Corrosives Cutaneous Data Dietary Fatty Acid Dose Ear Edema Exposure to Extravasation Fatty Acids Gases Generations Healed Health Hour Hydrochloric Acid Inflammation Inflammation Process Inflammatory Inflammatory Response Inhalation Exposure Injury Iodoacetamide Lipoxins Lung Lung Compliance Maintenance Mediator of activation protein Mental Depression Modeling Morbidity - disease rate Mus Mustard Gas Neutrophil Infiltration Omega-3 Fatty Acids Oxygen Pathology Pathway interactions Pharmaceutical Preparations Phase Phosgene Play Proteins Recovery Regimen Reporting Research Research Design Resistance Resolution Riots Role Route Sepsis Serum Signal Pathway Skin Stimulus Stress Sulfonic Acids Therapeutic Effect Time Tissues Treatment Protocols Trinitrobenzenes Vesicants cytokine efficacy testing healing improved lipid mediator lung injury mouse model prevent response tissue repair wound

项目摘要

DESCRIPTION (provided by applicant): Exposures to chemical threat agents oftentimes induce strong inflammatory tissue responses that contribute to morbidity and prevent tissue repair and recovery. Pulmonary exposures to chlorine trigger a potent inflammatory response resulting in vascular leakage, cardiopulmonary depression, neutrophil infiltration and a pulmonary and systemic hypercytokinemia comparable to the cytokine storm observed in sepsis. Similar inflammatory responses are observed after inhalation exposures to phosgene and acidic (HCl) or alkaline gases (ammonia) and reactive industrial chemicals such as acrolein, and to riot control agents (CS, CN or CR), and following cutaneous exposures to vesicants. Classical anti-inflammatory treatments against chemical injury have focused on interference with target pathways involved in the initiation and maintenance of inflammation. These strategies have only been partially successful, due to the large variety of pathways and pathologies involved. The inflammatory response is divided into three temporal phases, initiation, amplification and maintenance, and resolution. A new area of inflammation research has focused on the process of inflammation resolution, an active mechanism involving the activation of signaling pathways during inflammation initiation, and the later generation of omega 3 fatty-acid derived inflammation-resolving mediators that activate resolution mechanisms. In our preliminary studies we observe that post exposure treatment with Resolvin D1, an inflammation-resolving agent, strongly inhibited skin edema formation and inflammation in mice exposed to the vesicant, CEES, and the electrophilic riot control agent, CS. Our proposed studies are designed to 1: Examine the effects of inflammation-resolving agents in mouse models of cutaneous exposures to vesicants and electrophilic chemical threats and, 2: Study the effects of inflammation-resolving agents on pulmonary injury progression in mice exposed to chlorine and HCl.

描述（由申请人提供）：暴露于化学威胁剂通常会引起强烈的炎症组织反应，从而导致发病并阻止组织修复和恢复。肺部接触氯会引发强烈的炎症反应，导致血管渗漏、心肺抑制、中性粒细胞浸润以及肺部和全身高细胞因子血症，与脓毒症中观察到的细胞因子风暴相当。吸入暴露于光气和酸性（HCl）或碱性气体（氨）和反应性工业化学品（例如丙烯醛）和防暴剂（CS、CN或CR）以及皮肤暴露于起疱剂后，观察到类似的炎症反应。针对化学损伤的经典抗炎治疗集中于干扰参与炎症引发和维持的靶途径。由于涉及的途径和病理多种多样，这些策略仅取得了部分成功。炎症反应分为三个时间阶段：启动、放大和维持以及消退。炎症研究的一个新领域集中于炎症消退过程，这是一种涉及炎症起始过程中信号通路激活的主动机制，以及新一代 omega 3 脂肪酸衍生的炎症消解介质，可激活消退机制。在我们的初步研究中，我们观察到，在暴露于起泡剂 CEES 和亲电防暴剂 CS 的小鼠中，使用消炎剂 Resolvin D1 进行暴露后处理，可强烈抑制皮肤水肿形成和炎症。我们提出的研究旨在 1：检查炎症消解剂对皮肤暴露于起泡剂和亲电化学威胁的小鼠模型的影响，2：研究炎症消解剂对暴露于氯和亲电化学威胁的小鼠肺损伤进展的影响。盐酸。