Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY; Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY.
Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY.
Surgery. 2023 Oct;174(4):1071-1077. doi: 10.1016/j.surg.2023.06.032. Epub 2023 Jul 29.
Sepsis is a dysregulated host response to infection syndrome leading to life-threatening organ dysfunction. Sepsis-induced intestinal dysfunction is a key element in the progression to multisystem organ failure. The stimulator of interferon genes is an intracellular protein implicated in intestinal injury in sepsis. H151, a small molecule inhibitor of stimulator of interferon genes, has not yet been studied as a potential therapeutic in sepsis. We hypothesize that H151 therapeutically reduces sepsis-induced acute intestinal injury.
Male mice underwent cecal ligation and puncture and were treated with intraperitoneal H151 (10 mg/kg body weight) or vehicle. Intestines and serum were collected for analysis 20 hours after cecal ligation and puncture. Oral gavage of mice with FITC-dextran was performed 15 hours after cecal ligation and puncture. Five hours after gavage, serum was collected, and intestinal permeability was assessed. Mice were monitored for 10 days after cecal ligation and puncture to assess survival.
Zonula occludens 1 tight junctional protein expression was reduced after cecal ligation and puncture and recovered with H151 treatment. This was associated with a 62.3% reduction in intestinal permeability as assessed by fluorimetry. After cecal ligation and puncture, treatment with H151 was associated with a 58.7% reduction in intestinal histopathologic injury (P < .05) and a 56.6% reduction in intestinal apoptosis (P < .05). Intestinal myeloperoxidase activity was decreased by 70.8% after H151 treatment (P < .05). Finally, H151 improved 10-day survival from 33% to 80% after cecal ligation and puncture (P = .011).
H151, a novel stimulator of interferon genes inhibitor, reduces intestinal injury, inflammation, and permeability when administered as a treatment for cecal ligation and puncture-induced sepsis. Thus, targeting stimulator of interferon genes shows promise as a therapeutic strategy to ameliorate sepsis-induced acute intestinal injury.
败血症是一种宿主对感染的失调反应综合征，可导致危及生命的器官功能障碍。败血症引起的肠道功能障碍是多系统器官衰竭进展的关键因素。干扰素基因刺激物是一种细胞内蛋白，与败血症中的肠道损伤有关。干扰素基因刺激物小分子抑制剂 H151 尚未作为败血症的潜在治疗药物进行研究。我们假设 H151 治疗可减轻败血症引起的急性肠道损伤。
雄性小鼠接受盲肠结扎和穿刺，并接受腹腔内注射 H151（10mg/kg 体重）或载体。盲肠结扎和穿刺后 20 小时收集肠道和血清进行分析。盲肠结扎和穿刺后 15 小时对小鼠进行 FITC-葡聚糖灌胃。灌胃后 5 小时收集血清，并评估肠道通透性。盲肠结扎和穿刺后 10 天监测小鼠以评估存活率。
盲肠结扎和穿刺后紧密连接蛋白 Zonula occludens 1 的表达减少，用 H151 治疗后恢复。这与通过荧光法评估的肠道通透性降低 62.3%相关。盲肠结扎和穿刺后，用 H151 治疗与肠道组织病理损伤减少 58.7%（P<0.05）和肠道细胞凋亡减少 56.6%（P<0.05）相关。用 H151 治疗后肠道髓过氧化物酶活性降低 70.8%（P<0.05）。最后，H151 将盲肠结扎和穿刺后的 10 天存活率从 33%提高到 80%（P=0.011）。
新型干扰素基因刺激物抑制剂 H151 在作为盲肠结扎和穿刺诱导的败血症的治疗药物时可减轻肠道损伤、炎症和通透性。因此，靶向干扰素基因刺激物作为一种改善败血症引起的急性肠道损伤的治疗策略具有潜力。
