Emergency Department, Shanghai Baoshan Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, China (mainland).
Med Sci Monit. 2020 May 25;26:e921319. doi: 10.12659/MSM.921319.
BACKGROUND Sepsis causes acute kidney injury (AKI) in critically ill patients. Roflumilast, a phosphodiesterases-4 (PDE4) inhibitor, has been shown to be therapeutically effective in sepsis-induced organ injury. However, the function of roflumilast in sepsis-induced AKI is not clearly understood. The present study aimed to explore the protective effect of roflumilast on sepsis-induced AKI in mice. MATERIAL AND METHODS A sepsis model was established by cecal ligation and puncture surgery. Roflumilast (1 mg/kg and 3 mg/kg) was used once daily for 7 consecutive days for treatment. Kidney tissues were pathologically examined by hematoxylin and eosin (H&E) and periodic acid-Schiff (PAS) staining. The levels of kidney injury markers including blood urea nitrogen (BUN), creatinine (Cre), kidney injury molecule-1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL), and inflammatory cytokines including interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, and IL-1ß were detected by their corresponding test kits. The protein expression was measured using western blot and cell apoptosis of kidney tissue was determined by TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) assay. RESULTS Roflumilast was demonstrated to alleviate sepsis-induced AKI by reducing histopathological changes and decreasing the levels of kidney injury markers in a concentration-dependent way. The production of TNF-alpha, IL-6, and IL-1ß was significantly suppressed by roflumilast. Besides, roflumilast inhibited the activation of NLRP3 (nucleotide-binding domain (NOD)-like receptor protein 3) and NF-kappaB (nuclear factor kappa-light-chain-enhancer of activated B cells). Additionally, roflumilast inhibited cell apoptosis and changes in expression of apoptosis related proteins induced by sepsis. Finally, high concentration of roflumilast (3 mg/kg) did not have an adverse effect on liver, heart, lung, or spleen. CONCLUSIONS Our study indicated that roflumilast could ameliorate AKI induced by sepsis through restraining inflammatory response and apoptosis of the kidney, providing a molecular basis for a novel medical treatment of septic AKI.
脓毒症会导致危重症患者发生急性肾损伤（AKI）。磷酸二酯酶-4（PDE4）抑制剂罗氟司特已被证明在脓毒症诱导的器官损伤中具有治疗作用。然而，罗氟司特在脓毒症诱导的 AKI 中的作用尚不清楚。本研究旨在探讨罗氟司特对脓毒症诱导的小鼠 AKI 的保护作用。
通过盲肠结扎穿孔术建立脓毒症模型。罗氟司特（1mg/kg 和 3mg/kg）每天治疗 1 次，连续 7 天。用苏木精和伊红（H&E）及过碘酸-Schiff（PAS）染色法对肾组织进行病理检查。通过相应的试剂盒检测肾损伤标志物（血尿素氮（BUN）、肌酐（Cre）、肾损伤分子-1（KIM-1）和中性粒细胞明胶酶相关脂质运载蛋白（NGAL））和炎症细胞因子（白细胞介素（IL）-6、肿瘤坏死因子（TNF）-α和 IL-1β）的水平。采用 Western blot 法测定蛋白表达，采用 TUNEL（末端脱氧核苷酸转移酶 dUTP 缺口末端标记）法测定肾组织细胞凋亡。
罗氟司特通过减轻脓毒症诱导的 AKI 的组织病理学变化和降低肾损伤标志物的水平，呈浓度依赖性减轻脓毒症诱导的 AKI。罗氟司特显著抑制 TNF-α、IL-6 和 IL-1β的产生。此外，罗氟司特抑制 NLRP3（核苷酸结合寡聚化结构域（NOD）样受体蛋白 3）和 NF-κB（核因子 kappa 轻链增强子的 B 细胞）的激活。此外，罗氟司特抑制脓毒症诱导的细胞凋亡和凋亡相关蛋白表达的变化。最后，高浓度的罗氟司特（3mg/kg）对肝、心、肺或脾没有不良影响。
本研究表明，罗氟司特通过抑制肾脏的炎症反应和凋亡，可改善脓毒症引起的 AKI，为脓毒症性 AKI 的新的治疗方法提供了分子基础。
