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）：空气传播的病原体驱动肺部炎症，并在人与人之间传播。此外，免疫介导的组织损伤导致发病、器官衰竭和死亡。基质金属蛋白酶（MMPs）由于其降解肺细胞外基质结构成分的独特能力，在这种免疫病理学中起着重要作用。最近，我们已经证明MMP是人结核病（TB）中组织损伤的关键驱动因素（Elkington J Clin Invest 2011）。几种MMP抑制剂已被开发用于其他炎症性疾病，并在人体中具有已证实的安全性记录。MMP抑制可能代表一种新的预防性治疗，以缩短感染持续时间，并降低人类空气传播呼吸道感染的死亡率。假设：MMP活性驱动基质破坏，病原体传播和呼吸衰竭在人类空气感染。目的：通过研究两种具有不同病理学的全球重要病原体来研究MMP抑制作为空气传播传染病的宿主靶向疗法：（i）导致肺基质慢性破坏的结核分枝杆菌，和（ii）驱动快速基质重塑和传播的流感。 我们将通过研究体外人细胞模型和体内MMP人源化小鼠来确定MMP在TB中的作用，并研究MMP抑制对改善患者预后的治疗效果。将使用生物电喷雾技术开发人TB肉芽肿的体外模型，以产生三维TB浸渍的球状体来研究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学，以确定MMP活性和体内抑制的影响。 我们将研究甲型流感在上皮细胞、单核细胞和巨噬细胞中MMP的上调。将使用流感感染的雪貂模型来研究体内MMP抑制活性及其减少免疫介导的组织损伤的能力。总结：这项研究确定了MMP抑制剂，限制空气传播感染的病理，以减少发病率，传播和死亡率。这些结果不仅与结核病和大流行性流感有关，而且与其他迅速致命的空气传播感染有关（例如，SARS冠状病毒）。我们将建立一个新的治疗模式，针对过度的主机MMP活性，以改善肺部感染的结果。 公共卫生相关性：空气传播感染是对世界人口的主要健康威胁，大流行性流感和多重耐药病原体都有可能迅速传播。病原体驱动细胞外基质的破坏以促进它们的传播并引起发病率和死亡率。基质金属蛋白酶在免疫介导的组织损伤中具有关键作用。本项目研究基质金属蛋白酶抑制作为一种新的治疗方法，以减少发病率和死亡率从空气传播感染。