Targeting a leukocyte disintegrin metalloprotease during bacterial pneumonia

描述（由申请人提供）：铜绿假单胞菌是全世界医院感染的主要原因之一。铜绿假单胞菌医院内肺炎与比其他生物体更高的死亡率相关，呼吸机相关性肺炎的死亡率高达30%。铜绿假单胞菌感染也是囊性纤维化患者死亡的主要原因。铜绿假单胞菌对抗生素耐药性的增加和对抗生素耐药性的限制 许多新的抗生素可用于其治疗强调了了解如何增强宿主对铜绿假单胞菌的反应的重要性，这是我们的长期目标。宿主对该病原体引起的急性肺部感染的反应的一个关键组成部分是嗜中性粒细胞的大量募集，我们已经确定蛋白酶ADAM 17是铜绿假单胞菌感染期间嗜中性粒细胞从血液浸润到肺部的重要守门人。 ADAM 17是一种由白细胞组成型表达的膜相关蛋白酶。其活性在白细胞活化时是高度可诱导的，并且蛋白酶调节细胞表面粘附分子的密度和可溶性促炎因子的释放。在我们的初步研究中，靶向白细胞中的ADAM 17基因显著减弱了小鼠急性铜绿假单胞菌肺部感染和菌血症。我们研究的总体目标是确定急性铜绿假单胞菌肺部感染期间ADAM 17对宿主反应发挥作用的机制。我们推测，在严重感染过程中，ADAM 17的过度激活促进了中性粒细胞功能障碍和假单胞菌肺炎。在这项R21（探索性/开发性）资助申请的目标1中，我们将确定ADAM 17在急性铜绿假单胞菌肺部感染期间的免疫调节作用。为了确定条件性ADAM 17基因敲除小鼠中增强细菌清除的潜在机制，我们将仔细评估中性粒细胞募集到感染的肺和空域以及局部和全身炎症，正如我们的初步研究结果所表明的那样。在目标2中，我们将首次探索高度选择性的小分子ADAM 17抑制剂在小鼠急性假单胞菌肺炎中的作用。我们将评估该抑制剂的治疗性和预防性使用及其对宿主反应的影响。这些研究的影响是，它们将极大地促进我们对肺部感染期间ADAM 17作用机制的理解，并表明这种免疫调节剂的治疗潜力。

DESCRIPTION (provided by applicant): Pseudomonas aeruginosa is one of the leading causes of nosocomial infections throughout the world. P. aeruginosa nosocomial pneumonias are associated with higher mortality than other organisms, and ventilator- associated pneumonia has a mortality rate as high as 30%. P. aeruginosa infection is also the leading cause of death in cystic fibrosis patients. The increasing resistance of P. aeruginosa to antibiotics and the limited number of new antibiotics available for its treatment underscores the importance of understanding how to enhance the host response to P. aeruginosa, which is our long-term goal. A key component of the host response to acute lung infection by this pathogen is a robust recruitment of neutrophils, and we have determined that the protease ADAM17 is an important gatekeeper of neutrophil infiltration from the blood into the lungs during P. aeruginosa infection. ADAM17 is a membrane-associated protease constitutively expressed by leukocytes. Its activity is highly inducible upon leukocyte activation, and the protease regulates the density of cell surface adhesion molecules and the release of soluble pro-inflammatory factors. In our preliminary studies, gene-targeting ADAM17 in leukocytes markedly attenuated acute P. aeruginosa lung infection and bacteremia in mice. The overall objective of our study is to determine the mechanism by which ADAM17 exerts itself on the host response during acute P. aeruginosa lung infection. We hypothesize that overactivation of ADAM17 during severe infection promotes neutrophil dysfunction and pseudomonal pneumonia. In Aim 1 of this R21 (exploratory/developmental) grant application, we will determine the immunomodulatory role of ADAM17 during acute P. aeruginosa lung infection. To determine the underlying mechanism of enhanced bacterial clearance in conditional ADAM17 knockout mice, we will carefully evaluate neutrophil recruitment into the infected lung and airspace as well as local and systemic inflammation, as suggested by our preliminary findings. In Aim 2, we will explore for the first time the effects of a highly selective, small-molecule ADAM17 inhibitor in mice during acute pseudomonal pneumonia. We will evaluate therapeutic and prophylactic use of the inhibitor, and its effects on the host response. The impact of these studies is that they will critically advance our understanding of the mechanisms of action of ADAM17 during lung infection, as well as indicate the therapeutic potential of this immune regulator.