Targeting matrix metalloproteinases to limit immunopathology in airborne infectio

靶向基质金属蛋白酶以限制空气传播感染的免疫病理学

• 批准号: 8391388
• 负责人: Jeanine M D'Armiento
• 金额: $ 14.93万
• 依托单位: UNIVERSITY OF SOUTHAMPTON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-18 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8391388
• 关键词: 3-Dimensional; Animal Model; Animals; Automobile Driving; Biological Models; Biology; Cell Culture System; Cell model; Cells; Cessation of life; Chronic; Clinical Trials; Collagen; Communicable Diseases; Disease; Elastin; Epithelial Cells; Extracellular Matrix; Ferrets; Growth; Health; Human; Immune; Immune response; In Vitro; Infection; Inflammatory; Influenza; Inhibition of Matrix Metalloproteinases Pathway; Interstitial Collagenase; Lung; Lung Inflammation; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Mediating; Mediator of activation protein; Metalloproteinase Gene; Methodology; Modeling; Morbidity - disease rate; Multi-Drug Resistance; Mus; Mycobacterium Infections; Mycobacterium tuberculosis; Necrosis; Organ failure; Outcome; Outcome Study; Pathology; Patients; Peptide Hydrolases; Peripheral Blood Mononuclear Cell; Persons; Population; Pulmonary Tuberculosis; Regulation; Research; Respiratory Failure; Respiratory Tract Infections; Role; SARS coronavirus; Safety; Signal Pathway; Signal Transduction; System; Technology; Therapeutic Effect; Tissues; Transgenic Organisms; Tuberculosis; Up-Regulation; Virus Shedding; human disease; human mortality; immunopathology; improved; in vitro Model; in vivo; inhibitor/antagonist; macrophage; man; monocyte; mortality; mouse model; mycobacterial; novel; novel therapeutic intervention; novel therapeutics; pandemic influenza; pathogen; prevent; transmission process; tuberculosis granuloma

DESCRIPTION (provided by applicant): Airborne pathogens drive lung inflammation and are transmitted from person to person. Furthermore, immune-mediated tissue damage causes morbidity, organ failure and death. Matrix metalloproteinases (MMPs) have a central role in this immunopathology due to their unique ability to degrade the structural components of the lung extracellular matrix. Recently, we have demonstrated that MMPs are critical drivers of tissue damage in human tuberculosis (TB) (Elkington J Clin Invest 2011). Several MMP inhibitors have been developed for other inflammatory conditions and have a proven safety record in man. MMP inhibition may represent a novel adjunctive therapy to shorten the duration of infectivity, and reduce mortality from human airborne respiratory infections. Hypothesis: MMP activity drives matrix destruction, pathogen dissemination and respiratory failure in human airborne infection. Aims: to investigate MMP inhibition as host-targeted therapy for airborne infectious disease by studying two globally important pathogens with contrasting pathologies: (i) Mycobacterium tuberculosis which causes chronic destruction of the lung matrix, and (ii) Influenza which drives rapid matrix remodeling and transmission. We will define the role of MMPs in TB and investigate the therapeutic effects of MMP inhibition to improve patient outcomes by studying in vitro human cellular models and in vivo MMP humanized mice. In vitro models of human TB granulomas will be developed using a bio-electrospray technology to produce 3-dimensional TB-impregnated spheroids to study MMP inhibitors. We will investigate the pathology of mycobacterial infection in MMP-1 humanized mice to define the effects of MMP activity and inhibition in vivo. We will study MMP upregulation by influenza A in epithelial cells monocytes and macrophages. A ferret model of influenza infection will be used to study MMP inhibitory activity in vivo and its ability to reduce immune-mediated tissue damage. Summary: This research identifies MMP inhibitors that limit pathology of airborne infection to reduce morbidity, transmission and mortality. The results are relevant not only to TB and pandemic influenza, but also to other rapidly fatal airborne infections (e.g., SARS coronavirus). We will establish a new therapeutic paradigm targeting excessive host MMP activity to improve outcomes in pulmonary infection. PUBLIC HEALTH RELEVANCE: Airborne infection is a primary health threat to the world population, and there is a potential for rapid spread of both pandemic influenza and multidrug resistant agents. Pathogens drive destruction of the extracellular matrix to facilitate their sprea and cause morbidity and mortality. Matrix metalloproteinases have a critical role in immune-mediated tissue damage. This project investigates matrix metalloproteinase inhibition as a new therapeutic approach to reduce morbidity and mortality from airborne infection.

描述（由申请人提供）：空中病原体驱动肺部炎症，并从人到人传播。此外，免疫介导的组织损伤会导致发病率，器官衰竭和死亡。基质金属蛋白酶（MMP）在这种免疫病理学中具有核心作用，因为它们具有降解肺细胞外基质的结构成分的独特能力。最近，我们证明了MMP是人类结核病（TB）组织损伤的关键驱动因素（Elkington J Clin Invest 2011）。已经为其他炎症状况开发了几种MMP抑制剂，并具有人为良好的安全记录。 MMP抑制作用可能代表一种新型的辅助疗法，可缩短感染的持续时间，并降低人类空气呼吸道感染的死亡率。假设：MMP活性驱动了人类空降感染中的基质破坏，病原体传播和呼吸衰竭。目的：通过研究两种具有对比的病理学的全球重要病原体，研究MMP抑制作用，作为宿主靶向传染病的宿主疗法：（i）结核分枝杆菌肺结核，导致肺部基质的慢性破坏，以及（ii）造成了造成快速矩阵的流感型流感。 我们将定义MMP在结核病中的作用，并研究MMP抑制作用，通过研究体外人类细胞模型和体内MMP人源化小鼠的治疗作用，以改善患者的结局。将使用生物电喷雾技术开发人类结核肉芽肿的体外模型，以生产3维TB浸渍的球体来研究MMP抑制剂。 我们将研究MMP-1人源化小鼠中分枝杆菌感染的病理，以定义MMP活性和体内抑制作用的作用。 我们将研究上皮细胞单核细胞和巨噬细胞中流感的MMP上调。流感感染的雪貂模型将用于研究体内MMP抑制活性及其减少免疫介导的组织损伤的能力。摘要：这项研究确定了限制空气传播感染病理的MMP抑制剂，以降低发病率，传播和死亡率。结果不仅与结核病和大流行性流感有关，而且与其他快速致命的空气传播感染（例如SARS冠状病毒）有关。我们将建立一个针对过度宿主MMP活性的新的治疗范式，以改善肺部感染的预后。 公共卫生相关性：空中感染是对世界人口的主要健康威胁，并且有可能同时迅速传播大流行性流感和抗多药物。病原体驱动细胞外基质的破坏，以促进其Sprea并导致发病率和死亡率。基质金属蛋白酶在免疫介导的组织损伤中具有关键作用。该项目研究了基质金属蛋白酶抑制作用，作为一种新的治疗方法，可降低空气传播感染的发病率和死亡率。