Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital (BWH) and Harvard Medical School, Boston, Massachusetts, USA.
Research Laboratory of Electronics, Massachusetts Institute of Technology, Boston, Massachusetts, USA.
JCI Insight. 2021 Aug 9;6(15):e148866. doi: 10.1172/jci.insight.148866.
Sepsis is a critical illness characterized by dysregulated inflammatory responses lacking counter-regulation. Specialized proresolving mediators are agonists for antiinflammation and for promoting resolution, and they are protective in preclinical sepsis models. Here, in human sepsis, we mapped resolution circuits for the specialized proresolving mediators resolvin D1 and resolvin D2 in peripheral blood neutrophils and monocytes, their regulation of leukocyte activation and function ex vivo, and their relationships to measures of clinical severity. Neutrophils and monocytes were isolated from healthy subjects and patients with sepsis by inertial microfluidics and resolvin D1 and resolvin D2 receptor expression determined by flow cytometry. The impact of these resolvins on leukocyte activation was determined by isodielectric separation and leukocyte function by stimulated phagolysosome formation. Leukocyte proresolving receptor expression was significantly higher in sepsis. In nanomolar concentrations, resolvin D1 and resolvin D2 partially reversed sepsis-induced changes in leukocyte activation and function. Principal component analyses of leukocyte resolvin receptor expression and responses differentiated sepsis from health and were associated with measures of sepsis severity. These findings indicate that resolvin D1 and resolvin D2 signaling for antiinflammation and resolution are uncoupled from leukocyte activation in early sepsis and suggest that indicators of diminished resolution signaling correlate with clinical disease severity.
脓毒症是一种以炎症反应失调为特征的危急病症，缺乏反向调节。特异性促炎消退介质是抗炎和促进消退的激动剂，在临床前脓毒症模型中具有保护作用。在这里，在人类脓毒症中，我们绘制了外周血中性粒细胞和单核细胞中特异性促炎消退介质 1 型 resolvin D1 和 2 型 resolvin D2 的消退回路，它们对白细胞激活和功能的体外调节，以及它们与临床严重程度测量的关系。通过惯性微流控技术从健康受试者和脓毒症患者中分离中性粒细胞和单核细胞，并通过流式细胞术确定 resolvin D1 和 resolvin D2 受体的表达。通过等电分离和刺激吞噬溶酶体形成来确定这些 resolvin 对白细胞激活的影响。脓毒症患者的白细胞促消退受体表达显著升高。在纳摩尔浓度下，resolvin D1 和 resolvin D2 部分逆转了脓毒症诱导的白细胞激活和功能变化。白细胞 resolvin 受体表达和反应的主成分分析将脓毒症与健康区分开来，并与脓毒症严重程度的测量指标相关。这些发现表明，在早期脓毒症中，resolvin D1 和 resolvin D2 的抗炎和消退信号与白细胞激活脱耦联，并表明消退信号减弱的指标与临床疾病严重程度相关。
