First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 Viale Benedetto XV, 16132, Genoa, Italy.
IRCCS Ospedale Policlinico San Martino Genoa-Italian Cardiovascular Network, Genoa, Italy.
Intern Emerg Med. 2024 Jun;19(4):901-917. doi: 10.1007/s11739-023-03515-1. Epub 2024 Jan 31.
Sepsis is among the most important causes of mortality, particularly within the elderly population. Sepsis prevalence is on the rise due to different factors, including increasing average population age and the concomitant rise in the prevalence of frailty and chronic morbidities. Recent investigations have unveiled a "trimodal" trajectory for sepsis-related mortality, with the ultimate zenith occurring from 60 to 90 days until several years after the original insult. This prolonged temporal course ostensibly emanates from the sustained perturbation of immune responses, persevering beyond the phase of clinical convalescence. This phenomenon is particularly associated with the aging immune system, characterized by a broad dysregulation commonly known as "inflammaging." Inflammaging associates with a chronic low-grade activation of the innate immune system preventing an appropriate response to infective agents. Notably, during the initial phases of sepsis, neutrophils-essential in combating pathogens-may exhibit compromised activity. Paradoxically, an overly zealous neutrophilic reaction has been observed to underlie multi-organ dysfunction during the later stages of sepsis. Given this scenario, discovering treatments that can enhance neutrophil activity during the early phases of sepsis while curbing their overactivity in the later phases could prove beneficial in fighting pathogens and reducing the detrimental effects caused by an overactive immune system. This narrative review delves into the potential key role of neutrophils in the pathological process of sepsis, focusing on how the aging process impacts their functions, and highlighting possible targets for developing immune-modulatory therapies. Additionally, the review includes tables that outline the principal potential targets for immunomodulating agents.
脓毒症是最重要的死亡原因之一,尤其是在老年人群中。由于人口平均年龄的增长以及衰弱和慢性疾病发病率的上升等多种因素,脓毒症的发病率呈上升趋势。最近的研究揭示了脓毒症相关死亡率的“三峰”轨迹,最终高峰出现在最初损伤后 60 至 90 天,甚至几年后。这种延长的时间过程显然源于免疫反应的持续失调,持续时间超过临床康复阶段。这种现象与衰老的免疫系统密切相关,其特征是广泛的失调,通常被称为“炎症老化”。炎症老化与固有免疫系统的慢性低度激活有关,阻止其对感染因子产生适当的反应。值得注意的是,在脓毒症的初始阶段,中性粒细胞——对抗病原体的关键——可能表现出活性受损。矛盾的是,在脓毒症的后期阶段,观察到过度活跃的中性粒细胞反应是多器官功能障碍的基础。鉴于这种情况,发现可以在脓毒症早期增强中性粒细胞活性,同时抑制其在后期过度活跃的治疗方法,可能有助于对抗病原体并减少过度活跃的免疫系统造成的有害影响。本综述深入探讨了中性粒细胞在脓毒症病理过程中的潜在关键作用,重点关注衰老过程如何影响其功能,并强调了开发免疫调节治疗的可能靶点。此外,该综述还包括了概述免疫调节剂主要潜在靶点的表格。