Prekallikrein (PKK, also known as Fletcher factor and encoded by the gene KLKB1 in humans) is a component of the contact system. Activation of the contact system has been implicated in lethality in fulminant sepsis models. Pneumonia is the most frequent cause of sepsis. We sought to determine the role of PKK in host defense during pneumosepsis. To this end, mice were infected with the common human pathogen Klebsiella pneumoniae via the airways, causing an initially localized infection of the lungs with subsequent bacterial dissemination and sepsis. Mice were treated with a selective PKK-directed antisense oligonucleotide (ASO) or a scrambled control ASO for 3 weeks prior to infection. Host response readouts were determined at 12 or 36 h post-infection, including genome-wide messenger RNA profiling of lungs, or mice were followed for survival. PKK ASO treatment inhibited constitutive hepatic Klkb1 mRNA expression by >80% and almost completely abolished plasma PKK activity. Klkb1 mRNA could not be detected in lungs. Pneumonia was associated with a progressive decline in PKK expression in mice treated with control ASO. PKK ASO administration was associated with a delayed mortality, reduced bacterial burdens, and diminished distant organ injury. While PKK depletion did not influence lung pathology or neutrophil recruitment, it was associated with an upregulation of multiple innate immune signaling pathways in the lungs already prior to infection. Activation of the contact system could not be detected, either during infection in vivo or at the surface of Klebsiella in vitro. These data suggest that circulating PKK confines pro-inflammatory signaling in the lung by a mechanism that does not involve contact system activation, which in the case of respiratory tract infection may impede early protective innate immunity. © 2019 Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

中文翻译：

---

早孕激肽释放酶抑制小鼠肺炎期间的先天免疫信号传导并削弱宿主防御能力。

前激肽释放酶（PKK，也称为弗莱彻因子，在人类中由基因KLKB1编码）是接触系统的组成部分。在暴发性脓毒症模型中，接触系统的激活与致死率有关。肺炎是败血症的最常见原因。我们试图确定PKK在肺吸虫病期间在宿主防御中的作用。为此，小鼠经呼吸道感染了常见的人类病原体肺炎克雷伯菌，导致最初的肺部局部感染，随后细菌传播和败血症。在感染之前，将小鼠用选择性的PKK定向的反义寡核苷酸（ASO）或加扰的对照ASO处理3周。在感染后12或36 h确定宿主反应的读数，包括肺的全基因组信使RNA分析，或追踪小鼠的存活率。PKK ASO处理可抑制组成型肝Klkb1 mRNA表达> 80％，并且几乎完全消除了血浆PKK活性。在肺中未检测到Klkb1 mRNA。肺炎与用对照ASO治疗的小鼠中PKK表达的逐步下降有关。PKK ASO给药与延迟的死亡率，减少的细菌负担和减少的远处器官损伤有关。虽然PKK耗竭不影响肺部病理或嗜中性白细胞募集，但它与感染前已经存在的肺部多种先天免疫信号通路的上调有关。无论是在体内感染期间还是在体外克雷伯菌表面，都无法检测到接触系统的激活。这些数据表明循环中的PKK通过不涉及接触系统激活的机制限制了肺中的促炎信号传导，在呼吸道感染的情况下，这可能会阻碍早期的保护性先天免疫。©2019作者。John Wiley＆Sons Ltd代表大不列颠及爱尔兰病理学会出版的《病理学杂志》。