PDF(Pubmed)
Abstract：
Trauma and its associated complications, including dysregulated inflammatory responses, severe infection, and disseminated intravascular coagulation (DIC), continue to pose lethal threats worldwide. Following injury, cell-free nucleic acids (cfNAs), categorized as damage-associated molecular patterns (DAMPs), are released from dying or dead cells, triggering local and systemic inflammatory responses and coagulation abnormalities that worsen disease progression. Harnessing cfNA scavenging strategies with biomaterials has emerged as a promising approach for treating posttrauma systemic inflammation. In this study, the effectiveness of cationic hyperbranched polyaminoglycosides derived from tobramycin (HPT) and disulfide-included HPT (ss-HPT) in scavenging cfNAs to mitigate posttrauma inflammation and hypercoagulation is investigated. Both cationic polymers demonstrate the ability to suppress DAMP-induced toll-like receptor (TLR) activation, inflammatory cytokine secretion, and hypercoagulation by efficiently scavenging cfNAs. Additionally, HPT and ss-HPT exhibit potent antibacterial efficacy attributed to the presence of tobramycin in their chemical composition. Furthermore, HPT and ss-HPT exhibit favorable modulatory effects on inflammation and therapeutic outcomes in a cecal ligation puncture (CLP) mouse abdominal trauma model. Notably, in vivo studies reveal that ss-HPT displayed high accumulation and retention in injured organs of traumatized mice while maintaining a higher biodegradation rate in healthy mice, contrasting with findings for HPT. Thus, functionalized ss-HPT, a bioreducible polyaminoglycoside, holds promise as an effective option to enhance therapeutic outcomes for trauma patients by alleviating posttrauma inflammation and coagulation complications.
摘要：
创伤及其相关并发症，包括炎症反应失调,严重感染,和弥散性血管内凝血（DIC），继续在全球范围内构成致命威胁。受伤后,无细胞核酸（cfNA），分类为损伤相关分子模式(DAMP)，从死亡或死亡细胞中释放出来，引发局部和全身炎症反应和凝血异常，使疾病进展恶化。利用生物材料的cfNA清除策略已成为治疗创伤后全身性炎症的有希望的方法。在这项研究中,研究了妥布霉素（HPT）和包含二硫化物的HPT（ss-HPT）衍生的阳离子超支化聚氨基糖苷类在清除cfNA以减轻创伤后炎症和高凝状态中的有效性。两种阳离子聚合物均显示出抑制DAMP诱导的toll样受体（TLR）活化的能力，炎性细胞因子分泌，通过有效清除cfNA和高凝。此外,HPT和ss-HPT表现出有效的抗菌功效,这归因于在其化学组成中存在妥布霉素。此外，在盲肠结扎穿刺（CLP）小鼠腹部创伤模型中，HPT和ss-HPT对炎症和治疗结果表现出有利的调节作用。值得注意的是,体内研究表明，ss-HPT在受创伤小鼠的受损器官中表现出高度的积累和保留，同时在健康小鼠中保持较高的生物降解率，与HPT的发现形成对比。因此，功能化的ss-HPT，一种生物可还原的聚氨基糖苷，有望通过减轻创伤后炎症和凝血并发症来提高创伤患者的治疗效果。
