MICA: To evaluate the role of the histamine four receptor (H4R) in the clearance of lung pathogens using the H4R antagonist UCB1344778

囊性纤维化（CF）的一个标志是肺部严重和持续的细菌感染，尽管有大量的多形核白细胞（中性粒细胞）涌入。中性粒细胞是抵御感染微生物的第一道防线；然而，CF肺中性粒细胞吞噬病原体的能力降低。中性粒细胞功能在CF患者中受损的原因尚不清楚。我们的项目旨在了解是什么阻碍了肺中的中性粒细胞，以及如何克服这种抑制。我们认为，CF患者肺部的细菌会产生一种叫做组胺的物质，组胺通过与这些细胞膜表面表达的特定受体组胺-4受体（H4R）结合来阻止中性粒细胞的杀伤能力。我们假设，定植CF肺的革兰氏阴性菌产生的组胺通过影响中性粒细胞捕获病原体并在吞噬后杀死病原体的能力来损害中性粒细胞的吞噬作用。我们还认为，组胺的抑制作用是由于H4R对人类中性粒细胞的参与。我们证明H4R在人PMN中表达，它是PMN脱颗粒的有效抑制剂。此外，我们发现H4R也负调控细菌的吞噬，而用H4R拮抗剂治疗可以克服这种依赖组胺的吞噬抑制。在这个项目中，我们将通过使用H4R拮抗剂UCB1344778来探索H4R在中性粒细胞吞噬中的作用。我们将利用CF小鼠模型，通过体外和体内实验研究UCB1344778是否可以阻止组胺阻断病原体的捕获和抑制细胞内杀伤。本项目产生的临床前数据将用于CF和其他慢性肺部炎症疾病（如慢性阻塞性肺疾病）患者的未来临床研究。

A hallmark of cystic fibrosis (CF) is severe and persistent bacterial infections in the lungs despite massive influx of polymorphonuclear leukocytes (neutrophils). Neutrophils are the first line of defence against infecting microbes; however, CF pulmonary neutrophils have a reduced capacity to engulf pathogens. It remains unclear why the function of neutrophils is compromised in CF patients. Our project is aimed at understanding what blocks neutrophils in the lungs and how to overcome this inhibition. We believe that bacteria colonizing the lungs of CF patients produce a substance called histamine and that histamine blocks the killing capacity of neutrophils by binding to a specific receptor, the histamine-4 receptor (H4R), expressed on the membrane surface of these cells. We hypothesize that histamine produced by Gram-negative bacteria colonizing CF lungs impairs phagocytosis by neutrophils by affecting their ability to capture pathogens and killing them after engulfment. We also believe that the inhibitory effect of histamine is due to engagement of the H4R on human neutrophils. We demonstrated that the H4R is expressed in human PMNs and it is a potent inhibitor of PMN degranulation. Further, we showed that the H4R also negatively regulates engulfment of bacteria, while treatment with a H4R antagonist overcomes this histamine-dependent inhibition of engulfment. In this project, we will explore the role of the H4R in neutrophil engulfment by using the H4R antagonist UCB1344778. We will investigate whether UCB1344778 can prevent histamine from blocking capture of pathogens and inhibition of intracellular killing using model CF pathogens both in vitro and in vivo experiments suing a CF mouse model. The pre-clinical data generated in this project will be exploited for future clinical studies in patients with CF and other chronic lung inflammatory diseases (e.g. chronic obstructive pulmonary disease).