The emergence of severe sepsis is contingent upon the occurrence of a cytokine storm (CS), a multifaceted process intricately entwined with the temporal dimension, thereby rendering the infection response remarkably intricate. Consequently, it becomes imperative to discern and accurately identify the optimal timing for interventions, predicated upon the dynamic timeline of inflammatory changes. Moreover, the administration of exogenous low-dose pro-inflammatory agents has exhibited the potential to impede the relentless progression of the inflammatory cascade. Hence, the present study aims to scrutinize the impact of exogenous Local Inflammatory Response (eLIR) on the body surface in the context of the inflammatory cascade during sepsis, within a temporal framework, with a particular emphasis on the point of exacerbation of inflammation. Rats were induced sterile sepsis by intraperitoneal injection of zymosan (ZY) at an appropriate dosage. The temporal progression of inflammatory changes and eLIR effects were described based on the trend of serum crucial inflammatory cytokines, tring to quest time-point of inflammatory aggravation in sepsis. Then, the varying degrees of surface inflammation caused by eLIR on this time point leading to the final effects on the inflammatory cascade response were explored. In addition, given the authentic pathological progression of sepsis, further observation was conducted on the impact of another intervention timing of eLIR on the inflammatory cascade. The survival rate was measured. Serum and organ related inflammatory cytokines were detected, and organ histopathology was investigated. In present study, a dosage of 600 mg/kg ZY was found to be optimal for the sterile sepsis model. Initiating eLIR 6 h prior to ZY injection, the maximum effect point of eLIR could be precisely align with the inflammatory aggravation point of sterile sepsis. Initiating eLIR at this time, 3 sessions of eLIR were found to be more effective than 1 or 2 sessions in mitigating inflammatory responses during the initial stage of inflammation and the peak of inflammation. Notably, the findings also suggested that this intervention improve survival rate. In addition, the anti-inflammatory efficacy has been substantially diminished by the prompt initiation of 3 sessions of eLIR immediately after ZY injection at the onset of sepsis. Similarly, the current findings did not demonstrate a statistically significant enhancement in survival rates with eLIR at this time point. Compared with the initial stage of inflammation, low-scale inflammation caused by a certain intensity of eLIR (3 sessions) on the body surface can more effectively pry the inflammation aggravation time-point, thereby shifting the pro-inflammatory to anti-inflammatory milieu, impeding the disproportionate cytokines release in inflammatory diseases, slowing down the inflammatory cascade, and improving the survival rate of sepsis.

中文翻译：

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调节炎症级联的新治疗方法：及时的外源性局部炎症反应可减弱脓毒症引起的细胞因子风暴

严重败血症的出现取决于细胞因子风暴（CS）的发生，这是一个与时间维度错综复杂地交织在一起的多方面过程，从而使感染反应变得非常复杂。因此，必须根据炎症变化的动态时间线来辨别和准确确定干预的最佳时机。此外，外源性低剂量促炎剂的施用已显示出阻止炎症级联反应持续进展的潜力。因此，本研究旨在在脓毒症期间炎症级联的背景下，在时间框架内仔细检查外源性局部炎症反应（eLIR）对体表的影响，特别强调炎症恶化点。腹腔注射适当剂量的酵母聚糖（ZY）诱导大鼠无菌脓毒症。根据血清关键炎症细胞因子的变化趋势描述炎症变化的时间进展和eLIR效应，试图探寻脓毒症炎症加重的时间点。然后，探讨了该时间点eLIR引起的不同程度的表面炎症对炎症级联反应的最终影响。此外，考虑到脓毒症的真实病理进展，进一步观察eLIR的另一干预时机对炎症级联反应的影响。测量存活率。检测血清和器官相关炎症细胞因子，并研究器官组织病理学。在本研究中，发现 600 mg/kg ZY 的剂量对于无菌脓毒症模型是最佳的。在ZY注射前6小时启动eLIR，eLIR的最大作用点可以精确对准无菌脓毒症的炎症加重点。此时启动eLIR，发现3次eLIR比1或2次eLIR更有效地减轻炎症初期和炎症高峰期的炎症反应。值得注意的是，研究结果还表明这种干预措施可以提高生存率。此外，脓毒症发作时注射 ZY 后立即立即启动 3 个疗程的 eLIR 大大降低了抗炎功效。同样，目前的研究结果并未表明 eLIR 在该时间点对生存率有统计学上的显着提高。与炎症初期相比，一定强度的eLIR（3次）作用于体表引起的低度炎症，可以更有效地撬动炎症加重时间点，从而将促炎环境转变为抗炎环境，阻止炎症性疾病中不成比例的细胞因子释放，减缓炎症级联反应，提高脓毒症的生存率。