Department of Critical Care Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China; Department of Critical Care Medicine, East Hospital, Tongji University School of Medicine, Shanghai, China.
Department of Critical Care Medicine, East Hospital, Tongji University School of Medicine, Shanghai, China.
Life Sci. 2018 Jun 15;203:92-98. doi: 10.1016/j.lfs.2018.04.029. Epub 2018 Apr 18.
PMNs (polymorphonuclear neutrophil) play important roles in early stage of inflammation induced ARDS (Acute Respiratory Distress Syndrome). Both HBP (Heparin-Binding Protein) released from active PMNs and β2 integrins on the surface of PMNs are involved in vascular leakage. The role and relationship of HBP and β2 integrins on ARDS still requires study.
We established ARDS model using C57BL/6 mice with cecal ligation and puncture and eliminating HBP and β2 integrin with respective antibodies. The mice were also challenged with HBP endotracheal instillation. Histopathology score, lung wet/dry ratio, bronchoalveolar lavage fluid protein, plasma HBP and β2 integrin on PMNs from all groups were measured. β2 integrin and HBP were analyzed after incubated PMNs with streptococcal and pretreat with anti-CD18, anti-HBP, 1-phosphatidylinositol 3-kinase (PI3K) inhibitor and p38 mitogen-activated protein kinase (MAPK) inhibitor.
All lung injury indicatrix accompanied with HBP and β2 integrin elevated in CLP group, and HBP and β2 integrin were in correlation with each other and both were in correlation with the severity of lung injury. Endotracheal instillation HBP induced lung injury in CLP mice. Inhibiting both HBP and integrin ameliorated lung injury. HBP release was suppressed by inhibiting integrin and PI3K pathway, while integrin level did not decrease after eliminating HBP.
Both HBP and β2 integrin play important roles in ARDS. HBP released from PMNs is β2 integrin-PI3K signaling pathway dependent process revealing potential novel therapeutic targets for ARDS treatment.
PMN（多形核中性粒细胞）在诱导性 ARDS（急性呼吸窘迫综合征）的炎症早期发挥重要作用。从活性 PMN 释放的 HBP（肝素结合蛋白）和 PMN 表面的β2 整合素都参与血管渗漏。HBP 和β2 整合素在 ARDS 中的作用和关系仍需要研究。
我们使用 C57BL/6 小鼠通过盲肠结扎和穿刺建立 ARDS 模型，并使用相应的抗体消除 HBP 和β2 整合素。还通过气管内滴注 HBP 对小鼠进行了挑战。测量了所有组的组织病理学评分、肺湿/干比、支气管肺泡灌洗液蛋白、血浆 HBP 和 PMN 上的β2 整合素。孵育 PMN 后用链球菌分析β2 整合素和 HBP，并预处理用抗 CD18、抗 HBP、1-磷酸肌醇 3-激酶（PI3K）抑制剂和 p38 丝裂原活化蛋白激酶（MAPK）抑制剂。
CLP 组所有肺损伤指标均伴有 HBP 和β2 整合素升高，且 HBP 和β2 整合素相互关联，与肺损伤的严重程度相关。气管内滴注 HBP 可诱导 CLP 小鼠肺损伤。抑制 HBP 和整合素可改善肺损伤。抑制整合素和 PI3K 途径可抑制 HBP 释放，而消除 HBP 后整合素水平并未降低。
HBP 和β2 整合素在 ARDS 中均发挥重要作用。PMN 释放的 HBP 是β2 整合素-PI3K 信号通路依赖的过程，为 ARDS 的治疗提供了新的潜在治疗靶点。
