Spasov Alexander, Kosolapov Vadim, Babkov Denis, Klochkov Vladlen, Sokolova Elena, Miroshnikov Mikhail, Borisov Alexander, Velikorodnaya Yulia, Smirnov Alexey, Savateev Konstantin, Fedotov Victor, Kotovskaya Svetlana, Rusinov Vladimir
Department of Pharmacology & Bioinformatics, Scientific Center for Innovative Drugs, Volgograd State Medical University, Volgograd 400131, Russia.
Department of Organic and Biomolecular Chemistry, Ural Federal University Named after the First President of Russia B.N. Yeltsin, Mira Street, 19, Yekaterinburg 620002, Russia.
Pharmaceuticals (Basel). 2022 Apr 27;15(5):537. doi: 10.3390/ph15050537.
Acute lung injury remains a challenging clinical condition, necessitating the development of novel, safe and efficient treatments. The prevention of macrophage M1-polarization is a viable venue to tackle excessive inflammation. We performed a phenotypic screening campaign to identify azolopyrimidine compounds that effectively inhibit LPS-induced NO synthesis and interleukin 6 (IL-6) secretion. We identified lead compound that inhibits IL-6 secretion with IC of 3.72 µM without apparent cytotoxicity and with minimal suppression of macrophage phagocytosis in contrast to dexamethasone. In a mouse model of LPS-induced acute lung injury, 30 mg/kg i.p. ameliorated anxiety-like behavior, inhibited IL-6 release, and limited neutrophil infiltration and pulmonary edema. A histological study confirmed the protective activity of . Treatment with compound prevented the migration of CD68 macrophages and the incidence of hemorrhage. Hence, we have identified a promising pharmacological approach for the treatment of acute lung injury that may hold promise for the development of novel drugs against cytokine-mediated complications of bacterial and viral infections.
急性肺损伤仍然是一种具有挑战性的临床病症，需要开发新型、安全且有效的治疗方法。预防巨噬细胞M1极化是应对过度炎症的一个可行途径。我们开展了一项表型筛选活动，以鉴定能有效抑制脂多糖（LPS）诱导的一氧化氮（NO）合成和白细胞介素6（IL-6）分泌的氮杂嘧啶化合物。我们鉴定出先导化合物，其抑制IL-6分泌的半数抑制浓度（IC）为3.72 μM，无明显细胞毒性，与地塞米松相比，对巨噬细胞吞噬作用的抑制作用最小。在LPS诱导的急性肺损伤小鼠模型中，腹腔注射30 mg/kg可改善焦虑样行为，抑制IL-6释放，并限制中性粒细胞浸润和肺水肿。组织学研究证实了该化合物的保护活性。用该化合物治疗可防止CD68巨噬细胞迁移和出血的发生。因此，我们已经确定了一种有前景的治疗急性肺损伤的药理学方法，这可能为开发针对细菌和病毒感染的细胞因子介导并发症的新药带来希望。
