中性粒细胞在骨折愈合中的作用方式及干预后的促愈合效应

Role of neutrophils in fracture healing and the promoting effect on healing after intervention

背景:巨噬细胞存在特殊的促炎/抗炎表型,通过组织工程技术调节表型转变,使得其成为了在骨损伤修复中研究最多的免疫细胞。最近的研究发现中性粒细胞在骨损伤修复过程中同样发挥重要作用,但目前尚无此类综述。目的:总结目前中性粒细胞在骨折愈合中的作用方式,以及干预中性粒细胞促进骨折愈合的治疗措施。方法:检索2000年1月至2024年2月Web of Science、PubMed、中国知网及万方数据库,中文检索词为“中性粒细胞、骨折愈合、骨损伤、骨修复、骨重建”,英文检索词为“neutrophil,fracture healing,bone damage,bone repair,bone remodeling”。通过纳入排除标准筛选文献,最终纳入72篇进行综述。结果与结论:①发现中性粒细胞的历史漫长,早期由于缺乏染色技术忽视了其重要性,1900年Paul Ehrlich发明三酸染料区别出中性粒细胞,开启了研究的序幕;②正常状态下,中性粒细胞迁移到各器官辅助其发挥生理功能;病理状态下,中性粒细胞依赖吞噬作用、脱颗粒及中性粒细胞胞外陷阱发挥抗菌作用;③中性粒细胞主要参与骨折愈合早期血肿炎症阶段,通过释放细胞因子募集其他免疫细胞及间充质干细胞,同时产生纤连蛋白促进血肿形成构建局部微环境;④中性粒细胞在骨折愈合的不同阶段转化为N1/N2两种不同亚型,两者相互协调促进骨修复;⑤骨折断端募集的中性粒细胞通过分泌肿瘤坏死因子α、白细胞介素6、白细胞介素10、成纤维细胞生长因子2、单核细胞趋化蛋白1、血小板源性生长因子等细胞因子参与骨折愈合的过程;⑥中性粒细胞通过与骨折愈合不同阶段主要细胞成分的相互作用,调节成骨/破骨平衡;⑦类似于组织工程技术调节巨噬细胞极化在骨折愈合中的广泛研究与应用,未来针对干预中性粒细胞促进骨折愈合的疗法具有广阔前景。

BACKGROUND:Macrophages exhibit distinct pro-inflammatory and anti-inflammatory phenotypes.Through tissue engineering techniques,their phenotype transition has made them one of the most studied immune cells in bone injury repair.Recent studies have found that neutrophils also play a significant role in bone injury repair processes,but there is currently no such review available.OBJECTIVE:To summarize the current role of neutrophils in fracture healing and interventions targeting neutrophils to promote fracture healing.METHODS:We searched the Web of Science,PubMed,WanFang Data,and CNKI databases from January 2000 to February 2024 with the key words of“neutrophil,fracture healing,bone damage,bone repair,bone remodeling”in Chinese and English.Literature screening was conducted based on inclusion and exclusion criteria,resulting in a final selection of 72 articles for review.RESULTS AND CONCLUSION:(1)The history of neutrophils has been long,with their importance initially overlooked due to a lack of staining techniques.In 1900,Paul Ehrlich’s invention of triacid staining distinguished neutrophils,marking the beginning of research in this field.(2)Under normal conditions,neutrophils migrate to various organs to assist in their physiological functions.In pathological states,neutrophils exert their antimicrobial effects through phagocytosis,degranulation,and the formation of neutrophil extracellular traps.(3)Neutrophils primarily participate in the early hematoma inflammation stage of fracture healing by releasing cytokines to recruit other immune cells and mesenchymal stem cells.They also produce fibrinogen to promote hematoma formation and establish a local microenvironment.(4)Neutrophils transform into two distinct subtypes,N1 and N2,at different stages of fracture healing,coordinating with each other to promote bone repair.(5)Neutrophils recruited to the fracture site participate in the healing process by secreting cytokines such as tumor necrosis factor-alpha,interleukin-6,interleukin-10,fibroblast growth factor-2,monocyte chemoattractant protein-1,and platelet-derived growth factor.(6)Neutrophils regulate osteogenesis/osteolysis balance through interactions with the main cellular components involved in different stages of fracture healing.(7)Similar to the widespread research and application of tissue engineering techniques in modulating macrophage polarization in fracture healing,interventions targeting neutrophils to promote fracture healing hold promising prospects for the future.