Targeting matrix metalloproteinases to limit immunopathology in airborne infectio

描述（由申请人提供）：空气传播的病原体引起肺部炎症，并在人与人之间传播。此外，免疫介导的组织损伤会导致发病、器官衰竭和死亡。基质金属蛋白酶（MMPs）由于其独特的降解肺细胞外基质结构成分的能力，在这种免疫病理中起着核心作用。最近，我们已经证明MMPs是人类结核病（TB）组织损伤的关键驱动因素（Elkington J clininvest 2011）。一些MMP抑制剂已经开发用于其他炎症条件，并已证明在人的安全记录。抑制MMP可能是一种新的辅助治疗方法，可以缩短感染持续时间，降低人类空气传播呼吸道感染的死亡率。假设：在人类空气传播感染中，MMP活动驱动基质破坏、病原体传播和呼吸衰竭。目的：通过研究两种具有不同病理的全球重要病原体，研究MMP抑制作为空气传播传染病的宿主靶向治疗方法：(i)导致肺基质慢性破坏的结核分枝杆菌，以及（ii）导致基质快速重塑和传播的流感。我们将通过体外人细胞模型和体内MMP人源化小鼠的研究，确定MMPs在结核病中的作用，并研究抑制MMP的治疗效果，以改善患者的预后。将利用生物电喷雾技术开发人结核肉芽肿体外模型，以产生三维结核浸渍球体来研究MMP抑制剂。我们将研究MMP-1人源化小鼠的分枝杆菌感染病理，以确定体内MMP活性和抑制的影响。我们将研究甲型流感在上皮细胞、单核细胞和巨噬细胞中的MMP上调。一个雪貂流感感染模型将用于研究MMP在体内的抑制活性及其减少免疫介导的组织损伤的能力。摘要：本研究确定了MMP抑制剂可以限制空气传播的病理，从而降低发病率、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（如SARS冠状病毒）有关。我们将建立一种针对宿主MMP活性过高的新治疗模式，以改善肺部感染的预后。

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.