Clinical Pharmacology Department, Faculty of Medicine, Suez Canal University, 41522 Ismailia, Egypt.
Advanced Research Promotion Center, Health Sciences University of Hokkaido, Tobetsu, Japan; Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan.
Life Sci. 2023 Oct 1;330:122008. doi: 10.1016/j.lfs.2023.122008. Epub 2023 Aug 5.
Sepsis-induced cardiac dysfunction is the leading cause of higher morbidity and mortality with poor prognosis in septic patients. Our recent previous investigation provides evidence of the hallmarks of signal transducer and activator of transcription3 (STAT3) activation in sepsis and targeting of STAT3 with Stattic, a small-molecule inhibitor of STAT3, has beneficial effects in various septic tissues. We investigated the possible cardioprotective effects of Stattic on cardiac inflammation and dysfunction in mice with cecal ligation and puncture (CLP)-induced sepsis.
A polymicrobial sepsis model was induced by CLP in mice and Stattic (25 mg/kg) was intraperitoneally given at one and twelve hours after CLP operation. The cecum was exposed in sham-control mice without CLP. After 18 h of surgery, electrocardiogram (ECG) for anaesthized mice was registered followed by collecting of samples of blood and tissues for bimolecular and histopathological assessments. Myeloperoxidase, a marker of neutrophil infiltration, was assessed immunohistochemically.
CLP profoundly impaired cardiac functions as evidenced by ECG changes in septic mice as well as elevation of cardiac enzymes, and inflammatory markers with myocardial histopathological and immunohistochemical alterations. While, Stattic markedly reversed the CLP-induced cardiac abnormalities and restored the cardiac function by its anti-inflammatory activities.
Stattic treatment had potential beneficial effects against sepsis-induced cardiac inflammation, dysfunction and damage. Its cardioprotective effects were possibly attributed to its anti-inflammatory activities by targeting STAT3 and downregulation of IL-6 and gp130. Our investigations suggest that Stattic could be a promising target for management of cardiac sepsis and inflammation-related cardiac damage.
脓毒症引起的心脏功能障碍是导致脓毒症患者发病率和死亡率更高、预后不良的主要原因。我们最近的研究结果提供了证据，表明信号转导子和转录激活子 3（STAT3）在脓毒症中被激活，并且使用小分子 STAT3 抑制剂 Stattic 靶向 STAT3 在各种脓毒症组织中具有有益作用。我们研究了 Stattic 对盲肠结扎和穿刺（CLP）诱导的脓毒症小鼠心脏炎症和功能障碍的可能保护作用。
通过 CLP 在小鼠中诱导多微生物脓毒症模型，并在 CLP 手术后 1 小时和 12 小时腹腔内给予 Stattic（25mg/kg）。在没有 CLP 的假对照小鼠中暴露盲肠。手术后 18 小时，对麻醉小鼠进行心电图（ECG）记录，然后收集血液和组织样本进行双分子和组织病理学评估。髓过氧化物酶，一种中性粒细胞浸润的标志物，通过免疫组织化学进行评估。
CLP 严重损害了心脏功能，表现为脓毒症小鼠的心电图变化，以及心脏酶和炎症标志物的升高，同时伴有心肌组织病理学和免疫组织化学改变。而 Stattic 通过其抗炎活性显著逆转了 CLP 诱导的心脏异常，并恢复了心脏功能。
Stattic 治疗对脓毒症引起的心脏炎症、功能障碍和损伤具有潜在的有益作用。其心脏保护作用可能归因于其通过靶向 STAT3 和下调 IL-6 和 gp130 发挥抗炎作用。我们的研究表明，Stattic 可能是治疗心脏脓毒症和炎症相关心脏损伤的有前途的靶点。
