Centre for Translational Medicine and Therapeutics, William Harvey Research Institute, Barts & The London School of Medicine & Dentistry, Queen Mary University of London, London, United Kingdom.
Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany.
Front Immunol. 2024 Nov 4;15:1447901. doi: 10.3389/fimmu.2024.1447901. eCollection 2024.
Sepsis is a systemic condition caused by a dysregulated host response to infection and often associated with excessive release of proinflammatory cytokines resulting in multi-organ failure (MOF), including cardiac dysfunction. Despite a number of effective supportive treatments (e.g. ventilation, dialysis), there are no specific interventions that prevent or reduce MOF in patients with sepsis. To identify possible intervention targets, we re-analyzed the publicly accessible Gene Expression Omnibus accession GSE131761 dataset, which revealed an increased expression of spleen tyrosine kinase () in the whole blood of septic patients compared to healthy volunteers. This result suggests a potential involvement of SYK in the pathophysiology of sepsis. Thus, we investigated the effects of the highly selective SYK inhibitor PRT062607 (15mg/kg; i.p.) on sepsis-induced cardiac dysfunction and MOF in a clinically-relevant, murine model of sepsis. PRT062607 or vehicle (saline) was administered to 10-weeks-old C57BL/6 mice at 1h after the onset of sepsis induced by cecal ligation and puncture (CLP). Antibiotics (imipenem/cilastatin; 2mg/kg; s.c.) and analgesic (buprenorphine; 0.05mg/kg; i.p.) were administered at 6h and 18h post-CLP. After 24h, cardiac function was assessed by echocardiography and, after termination of the experiments, serum and cardiac samples were collected to evaluate the effects of SYK inhibition on the systemic release of inflammatory mediators and the degree of organ injury and dysfunction. Our results show that treatment of CLP-mice with PRT062607 significantly reduces systolic and diastolic cardiac dysfunction, renal dysfunction and liver injury compared to CLP-mice treated with vehicle. In addition, the sepsis-induced systemic inflammation (measured as an increase in inflammatory cytokines and chemokines in the serum) and the cardiac activation of NF-kB (IKK) and the NLRP3 inflammasome were significantly reduced in CLP-mice treated with PRT062607. These results demonstrate, for the first time, that SYK inhibition 1h after the onset of sepsis reduces the systemic inflammation, cardiac dysfunction and MOF, suggesting a potential role of the activation of SYK in the pathophysiology of sepsis. Novel therapeutic strategies that inhibit SYK activity may be of benefit in patients with diseases associated with local or systemic inflammation including sepsis.
脓毒症是一种全身性疾病，由宿主对感染的反应失调引起，常伴有促炎细胞因子的过度释放，导致多器官衰竭（MOF），包括心功能障碍。尽管有许多有效的支持治疗方法（例如通气、透析），但没有预防或减少脓毒症患者 MOF 的具体干预措施。为了确定可能的干预靶点，我们重新分析了公开可访问的基因表达综合数据集 GSE131761，该数据集显示与健康志愿者相比，脓毒症患者全血中脾酪氨酸激酶（）的表达增加。这一结果表明 SYK 可能参与了脓毒症的病理生理学过程。因此，我们研究了高度选择性 SYK 抑制剂 PRT062607（15mg/kg；腹腔注射）对临床相关的脓毒症小鼠模型中脓毒症诱导的心功能障碍和 MOF 的影响。在盲肠结扎和穿刺（CLP）诱导的脓毒症发作后 1 小时，用 PRT062607 或载体（生理盐水）处理 10 周龄 C57BL/6 小鼠。在 CLP 后 6 小时和 18 小时给予抗生素（亚胺培南/西司他丁；2mg/kg；皮下注射）和镇痛药（丁丙诺啡；0.05mg/kg；腹腔注射）。24 小时后，通过超声心动图评估心功能，实验结束后收集血清和心脏样本，以评估 SYK 抑制对全身炎症介质释放和器官损伤和功能障碍程度的影响。我们的结果表明，与用载体处理的 CLP 小鼠相比，用 PRT062607 治疗 CLP 小鼠可显著减轻收缩和舒张性心功能障碍、肾功能障碍和肝损伤。此外，PRT062607 处理的 CLP 小鼠中，脓毒症诱导的全身炎症（以血清中炎症细胞因子和趋化因子的增加来衡量）和 NF-kB（IKK）和 NLRP3 炎性小体的心脏激活显著降低。这些结果首次表明，脓毒症发作后 1 小时抑制 SYK 可减少全身炎症、心功能障碍和 MOF，提示 SYK 激活在脓毒症的病理生理学中可能发挥作用。抑制 SYK 活性的新型治疗策略可能对与局部或全身炎症相关的疾病（包括脓毒症）患者有益。
