Therapeutic assessment of N-formyl-methionyl-leucyl-phenylalanine (fMLP) in reducing periprosthetic joint infection.
Therapeutic assessment of N-formyl-methionyl-leucyl-phenylalanine (fMLP) in reducing periprosthetic joint infection.
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DOI：
10.22203/ecm.v042a09
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发表时间：
2021-08-26
影响因子：
3.1
通讯作者：
Shafikhani SH
中科院分区：
文献类型：
--
作者：
Hamilton JL;Mohamed MF;Witt BR;Wimmer MA;Shafikhani SH
尽管采取了许多预防措施，包括预防性抗生素，但假体周围关节感染（PJI）仍然是关节成形术后的破坏性并发症，导致疼痛、痛苦、发病率和巨大的经济负担。人类拥有强大的先天免疫系统，如果能迅速得到警告，就能有效地控制感染。不幸的是，病原体使用许多机制来抑制先天免疫应答。研究假设是，即使在没有抗生素的情况下，能够在植入物植入的手术部位启动和指导先天性免疫应答（尤其是中性粒细胞）的免疫调节剂也会增强免疫应答并减少PJI。为了检验这一假设，将N-甲酰-甲硫氨酰-亮氨酰-苯丙氨酸（fMLP）（吞噬白细胞包括嗜中性粒细胞的有效化学引诱剂）用于具有金黄色葡萄球菌（S. aureus)具有良好的抗菌活性。将接受髓内股骨植入物的小鼠分为三组：i）单独植入物; ii）植入物+ S。金黄色葡萄球菌; iii）植入物+ fMLP + S.金黄色。fMLP处理降低了S.第3天金黄色葡萄球菌感染水平约为2-Log。此外，在第10天，fMLP治疗减少了感染诱导的植入物周围骨膜反应、局灶性皮质丢失和小鼠股骨远端的炎性浸润面积。最后，fMLP治疗在第10天降低了感染小鼠的疼痛行为，并增加了植入腿的承重。数据表明，如果在手术部位局部给药，fMLP治疗是一种有希望的减少PJI的新方法。未来的工作将是通过与抗生素和/或用fMLP包被的植入物组合来进一步增强和优化基于fMLP的治疗方法。
Despite many preventive measures, including prophylactic antibiotics, periprosthetic joint infection (PJI) remains a devastating complication following arthroplasty, leading to pain, suffering, morbidity and substantial economic burden. Humans have a powerful innate immune system that can effectively control infections, if alerted quickly. Unfortunately, pathogens use many mechanisms to dampen innate immune responses. The study hypothesis was that immunomodulators that can jumpstart and direct innate immune responses (particularly neutrophils) at the surgical site of implant placement would boost immune responses and reduce PJI, even in the absence of antibiotics. To test this hypothesis, N-formyl-methionyl-leucyl-phenylalanine (fMLP) (a potent chemoattractant for phagocytic leukocytes including neutrophils) was used in a mouse model of PJI with Staphylococcus aureus (S. aureus). Mice receiving intramedullary femoral implants were divided into three groups: i) implant alone; ii) implant + S. aureus; iii) implant + fMLP + S. aureus. fMLP treatment reduced S. aureus infection levels by ~ 2-Log orders at day 3. Moreover, fMLP therapy reduced infection-induced peri-implant periosteal reaction, focal cortical loss and areas of inflammatory infiltrate in mice distal femora at day 10. Finally, fMLP treatment reduced pain behaviour and increased weight-bearing at the implant leg in infected mice at day 10. Data indicated that fMLP therapy is a promising novel approach for reducing PJI, if administered locally at surgical sites. Future work will be toward further enhancement and optimisation of an fMLP-based therapeutic approach through combination with antibiotics and/or implant coating with fMLP.