Department of Critical Care Medicine, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
The State Key Laboratory of Respiratory Disease and the 1st Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Crit Care Med. 2018 Sep;46(9):e921-e927. doi: 10.1097/CCM.0000000000003265.
To examine the effects and mechanisms of human neutrophil peptides in systemic infection and noninfectious inflammatory lung injury.
Prospective experimental study.
University hospital-based research laboratory.
In vitro human cells and in vivo mouse models.
Wild-type (Friend virus B-type) and conditional leukocyte human neutrophil peptides transgenic mice were subjected to either sepsis induced by cecal ligation and puncture or acute lung injury by intratracheal instillation of hydrochloric acid followed by mechanical ventilation. Using human neutrophil peptides as bait, the basal cell adhesion molecule (CD239) and the purinergic P2Y purinoceptor 6 receptor were identified as the putative human neutrophil peptides receptor complex in human lung epithelial cells.
In the cecal ligation and puncture sepsis model, Friend virus B-type mice exhibited higher systemic bacterial load, cytokine production, and lung injury than human neutrophil peptides transgenic mice. Conversely, an increased lung cytokine production was seen in Friend virus B-type mice, which was further enhanced in human neutrophil peptides transgenic mice in response to two-hit lung injury induced by hydrochloric acid and mechanical ventilation. The human neutrophil peptides-mediated inflammatory response was mediated through the basal cell adhesion molecule-P2Y purinoceptor 6 receptor signal pathway in human lung epithelial cells.
Human neutrophil peptides are critical in host defense against infectious sepsis by their cationic antimicrobial properties but may exacerbate tissue injury when neutrophil-mediated inflammatory responses are excessive in noninfectious lung injury. Targeting the basal cell adhesion molecule/P2Y purinoceptor 6 signaling pathway may serve as a novel approach to attenuate the neutrophil-mediated inflammatory responses and injury while maintaining the antimicrobial function of human neutrophil peptides in critical illness.
研究人类中性粒细胞肽在全身感染和非感染性炎症性肺损伤中的作用和机制。
前瞻性实验研究。
以大学医院为基础的研究实验室。
体外人细胞和体内小鼠模型。
野生型（Friend 病毒 B 型）和条件性白细胞人类中性粒细胞肽转基因小鼠分别接受盲肠结扎和穿刺诱导的脓毒症或经气管内滴注盐酸后机械通气引起的急性肺损伤。使用人类中性粒细胞肽作为诱饵，鉴定出基底细胞黏附分子（CD239）和嘌呤能 P2Y 嘌呤受体 6 受体为人肺上皮细胞中人类中性粒细胞肽受体复合物的假定受体。
在盲肠结扎和穿刺脓毒症模型中，Friend 病毒 B 型小鼠表现出更高的全身细菌负荷、细胞因子产生和肺损伤，而非人类中性粒细胞肽转基因小鼠。相反，在 Friend 病毒 B 型小鼠中观察到肺细胞因子产生增加，而在盐酸和机械通气引起的双重打击肺损伤后，这种增加在人类中性粒细胞肽转基因小鼠中进一步增强。人类中性粒细胞肽介导的炎症反应是通过人肺上皮细胞中的基底细胞黏附分子-P2Y 嘌呤受体 6 受体信号通路介导的。
人类中性粒细胞肽通过其阳离子抗菌特性在宿主防御感染性脓毒症中起关键作用，但在非感染性肺损伤中中性粒细胞介导的炎症反应过度时，可能会加重组织损伤。靶向基底细胞黏附分子/P2Y 嘌呤受体 6 信号通路可能成为一种新的方法，以减轻中性粒细胞介导的炎症反应和损伤，同时保持人类中性粒细胞肽在危重病中的抗菌功能。
