PD-1介导的免疫抑制在老年小鼠髋部骨折术后肺部感染中的作用及初步机制探索

Programmed cell death-1 is an inhibitory receptor that contributes to the immunosuppression induced by cancer, virus infection and sepsis. However, it is not know if PD-1 has a role in the development of postoperative immune dysfunction. In previous studies, we proved that hip fracture and surgery can induce immunosuppression in aged rats, as evidenced by increased bacterial susceptibility and IL-10 levels and decreased bacterial clearance and IFN-γlevels. We found in clinical later that the PD-1 expression in T cells were significant increased in aged hip fracture patients post-surgery, and the patients undergoing pulmonary infection had increased PD-1 expression compared to non-infections. These suggest that PD-1 may play an important role in the course of development of postoperative immunosuppression. In this study, hip fracture plus femoral intramedullary pinning model of aged mice will be constructed, and the expression levels of PD-1 in T cell subset , the immune response and bacterial susceptibility will be detected at different time point after model construction. From these studies, the role and mechanism of PD-1 pathway in immunosuppression following hip fracture surgery in aged mice will be explored.

程序性死亡受体1（Programmed death-1，PD-1）是一种重要的免疫抑制性受体，在癌症、病毒感染及脓毒血症等引起的免疫抑制过程中起着关键作用，但在创伤所致的免疫抑制过程中有何作用尚不明确。我们前期研究证实：髋部骨折及手术可导致老年大鼠出现免疫抑制，进而增加了术后肺部感染易感性。随后在临床中我们发现，老年髋部骨折患者术后T细胞PD-1表达明显增高，且出现肺部感染者T细胞PD-1表达明显高于未出现肺部感染者，提示PD-1可能在老年髋部骨折术后肺部感染发生过程中起着重要作用。本课题拟建立已发表的髋部骨折+髓内针内固定术动物模型，观察损伤后T细胞亚群PD-1表达变化；分析该变化与机体免疫功能及感染易感性的关系；明确PD-1阻断剂提高术后免疫功能、降低感染率及死亡率的有效性；试图从新的角度解释老年髋部骨折术后肺部感染高发的原因，为老年髋部骨折患者术后肺部感染的预防及治疗提供新的思路。

背景：髋部骨折是老年人最常见的骨质疏松性骨折之一，肺部感染是老年人髋部骨折术后最常见的并发症和死亡原因。创伤及手术打击导致的机体免疫功能障碍与肺部感染、脓毒血症及多器官功能衰竭等并发症的发生密切相关。程序性死亡受体1（Programmed death-1，PD-1）是机体一种重要的免疫抑制分子，主要表达于T细胞表面，对T细胞功能起负调控作用，PD-1在肿瘤、慢性病毒感染及脓毒血症所引起的免疫抑制过程中起着举足轻重的作用。.研究内容：1.建立老年股骨近端骨折+股骨髓内针内固定术动物模型，了解老年髋部骨折术后免疫炎症反应及细菌易感性的变化。2.明确临床中老年髋部骨折患者围手术期外周血T细胞PD-1表达变化，分析其与感染并发症的关系。3.明确PD-1阻断剂对提高老年髋部骨折术后免疫功能、恢复T细胞功能，降低感染率。.主要结果：1.老年大鼠股骨近端骨折+股骨髓内针内固定术模型操作简单、可控，成功率高，术后14天成活率可达90%，变异浮动较小。髋部骨折及髓内针内固定术可导致老年大鼠术后早期（1-3）天出现全身炎症反应和肺损伤，同时免疫功能受损、细菌易感性增加。2.老年髋部骨折患者髓内针内固定术后外周血T细胞PD-1表达明显增高，至术后第5天仍未降至术前水平；术后第3天与术后第1天T细胞PD-1表达的差值（PD-1D3-D1）预测术后28天内感染并发症发生的敏感性和特异性均较高，大于3.4%时具有良好的预警价值。3. PD-1阻断剂可有效提升老年小鼠髋部骨折术后免疫功能，部分恢复T细胞功能，降低细菌易感性及死亡率。.临床意义：本研究明确了PD-1在老年髋部骨折术后肺部感染中起着重要作用，外周血PD-1可作为术后肺部感染的预警指标，PD-1拮抗剂有望降低老年髋部骨折术后肺部感染的发病率。