Targeting a leukocyte disintegrin metalloprotease during bacterial pneumonia

描述(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。与其他生物相比，铜绿假单胞菌医院内肺炎的死亡率更高，呼吸机相关肺炎的死亡率高达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的耐药性增加及其局限性 可用于治疗铜绿假单胞菌的新抗生素的数量突显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。宿主对这种病原体急性肺部感染反应的一个关键组成部分是中性粒细胞的强劲募集，我们已经确定，在铜绿假单胞菌感染过程中，蛋白酶ADAM17是中性粒细胞从血液渗透到肺部的重要守门人。 ADAM17是一种由白细胞组成性表达的膜相关蛋白。它的活性是高度诱导的白细胞激活，并调节细胞表面黏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，白细胞中的ADAM17基因靶向显著减少了小鼠的急性铜绿假单胞菌肺部感染和菌血症。本研究的总体目标是确定ADAM17在急性铜绿假单胞菌肺部感染时对宿主反应的作用机制。我们推测，在严重感染期间，ADAM17的过度激活会促进中性粒细胞功能障碍和假单胞性肺炎。在R21(探索性/发展性)拨款申请的目标1中，我们将确定ADAM17在急性铜绿假单胞菌肺部感染中的免疫调节作用。为了确定条件性ADAM17基因敲除小鼠细菌清除增强的潜在机制，我们将根据初步发现，仔细评估中性粒细胞重新聚集到受感染的肺和空隙以及局部和全身炎症。在目标2中，我们将首次探索一种高选择性的小分子ADAM17抑制剂在小鼠急性假单胞菌肺炎期间的作用。我们将评估该抑制剂的治疗和预防使用，以及它对宿主反应的影响。这些研究的影响是，它们将极大地促进我们对ADAM17在肺部感染过程中的作用机制的理解，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.