Department of Critical Care Medicine, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150000, Heilongjiang, China.
The State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510000, Guangdong, China.
Respir Res. 2018 Sep 29;19(1):190. doi: 10.1186/s12931-018-0869-x.
Pneumonia is a major cause of high morbidity and mortality in critically illness, and frequently requires support with mechanical ventilation. The latter can lead to ventilator-induced lung injury characterized by neutrophil infiltration. The cationic human neutrophil peptides (HNP) stored in neutrophils can kill microorganisms, but excessive amount of HNP released during phagocytosis may contribute to inflammatory responses and worsen lung injury. Based on our previous work, we hypothesized that blocking the cell surface purinergic receptor P2Y will attenuate the HNP-induced inflammatory responses while maintaining their antimicrobial activity in pneumonia followed by mechanical ventilation.
Plasma HNP levels were measured in patients with pneumonia who received mechanical ventilation and in healthy volunteers. FVB littermate control and HNP transgenic (HNP) mice were randomized to receive P. aeruginosa intranasally. The P2Y antagonist (MRS2578) or vehicle control was given after P. aeruginosa instillation. Additional mice underwent mechanical ventilation at either low pressure (LP) or high pressure (HP) ventilation 48 h after pneumonia, and were observed for 24 h.
Plasma HNP concentration increased in patients with pneumonia as compared to healthy subjects. The bacterial counts in the bronchoalveolar lavage fluid (BALF) were lower in HNP mice than in FVB mice 72 h after P. aeruginosa instillation. However, upon receiving HP ventilation, HNP mice had higher levels of cytokines and chemokines in BALF than FVB mice. These inflammatory responses were attenuated by the treatment with MRS2578 that did not affect the microbial effects of HNP.
HNP exerted dual effects by exhibiting antimicrobial activity in pneumonia alone condition while enhancing inflammatory responses in pneumonia followed by HP mechanical ventilation. Blocking P2Y can attenuate the inflammation without affecting the antibacterial property of HNP. The P2Y receptor may be a novel therapeutic target in attenuation of the leukocyte-mediated excessive host responses in inflammatory lung diseases.
肺炎是危重病患者高发病率和高死亡率的主要原因，常需要机械通气支持。后者可导致以中性粒细胞浸润为特征的呼吸机诱导性肺损伤。储存于中性粒细胞中的阳离子人中性粒细胞肽（HNP）可杀死微生物，但吞噬过程中释放的大量 HNP 可能导致炎症反应并加重肺损伤。基于我们之前的工作，我们假设阻断细胞表面嘌呤能受体 P2Y 将减轻 HNP 诱导的炎症反应，同时保持其在肺炎后机械通气中的抗菌活性。
测量接受机械通气的肺炎患者和健康志愿者的血浆 HNP 水平。FVB 同窝对照和 HNP 转基因（HNP）小鼠随机接受铜绿假单胞菌鼻腔内感染。在铜绿假单胞菌滴注后给予 P2Y 拮抗剂（MRS2578）或载体对照。另外的小鼠在肺炎后 48 小时接受低压力（LP）或高压力（HP）通气，并观察 24 小时。
与健康受试者相比，肺炎患者的血浆 HNP 浓度增加。与 FVB 小鼠相比，铜绿假单胞菌感染 72 小时后 HNP 小鼠的支气管肺泡灌洗液（BALF）中的细菌计数较低。然而，在接受 HP 通气后，HNP 小鼠的 BALF 中的细胞因子和趋化因子水平高于 FVB 小鼠。用 MRS2578 治疗可减轻这些炎症反应，而 MRS2578 不影响 HNP 的抗菌作用。
HNP 在单独肺炎条件下表现出抗菌活性，而在肺炎后 HP 机械通气中增强炎症反应，从而发挥双重作用。阻断 P2Y 可以减轻炎症而不影响 HNP 的抗菌特性。P2Y 受体可能是炎症性肺疾病中减轻白细胞介导的过度宿主反应的新的治疗靶点。
