Atovaquone attenuates experimental colitis by reducing neutrophil infiltration of colonic mucosa.
Atovaquone attenuates experimental colitis by reducing neutrophil infiltration of colonic mucosa.
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DOI：
10.3389/fphar.2022.1011115
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发表时间：
2022
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
作者：
溃疡性结肠炎（UC）是一种慢性复发性疾病，其特征是中性粒细胞在结肠黏膜和管腔内异常积聚。尽管随着新型生物制剂和靶向免疫反应的小分子的发展，UC治疗取得了重大进展，但目前大多数治疗方法的成功仍然有限，存在重大的安全性问题。因此，有必要开发更多安全有效的治疗UC的方法。多年来，抗疟疾药物已被安全地用于解决组织炎症和相关病理。阿托伐醌是fda最近批准的一种抗疟疾药物，在体外显示出抗病毒和肿瘤抑制特性，但其在粘膜炎症中的作用尚未得到评估。通过临床前小鼠dss诱导的结肠炎模型，结合体内补补性腹膜炎和体外人中性粒细胞激活和趋化实验，我们研究了阿托瓦醌对疾病缓解和中性粒细胞运输的功能和机制影响。我们证明，阿托伐醌通过减少炎症结肠粘膜中性粒细胞的积累来促进dss诱导的小鼠结肠炎的消退。在机制上，我们发现阿托伐醌抑制了中性粒细胞中CD11b表达的诱导，降低了它们的极化和迁移能力。因此，我们的研究结果确定了阿托伐醌在促进粘膜炎症消退中的新作用，支持了这种fda批准的药物作为UC治疗药物的潜在重新用途的想法。
Ulcerative colitis (UC) is a chronic relapsing disease featuring aberrant accumulation of neutrophils in colonic mucosa and the luminal space. Although significant advances in UC therapy have been made with the development of novel biologics and small molecules targeting immune responses, success of most current therapies is still limited, with significant safety concerns. Thus, there is a need to develop additional safe and effective therapies for the treatment of UC. Antimalarial drugs have been safely used for many years to resolve tissue inflammation and the associated pathologies. Atovaquone is a recent FDA-approved antimalarial drug that has shown anti-viral and tumor-suppressive properties in vitro however, its role in mucosal inflammation has not been evaluated. Using pre-clinical murine DSS-induced colitis model combined with complementary in vivo peritonitis and ex vivo human neutrophil activation and chemotaxis assays we investigated functional and mechanistic impacts of atovaquone on disease resolution and neutrophil trafficking. We demonstrate that atovaquone promotes resolution of DSS-induced murine colitis by reducing neutrophil accumulation in the inflamed colonic mucosa. Mechanistically, we show that atovaquone suppressed induction of CD11b expression in neutrophils, reducing their polarization and migratory ability. Thus, our findings identify a new role of atovaquone in promoting resolution of mucosal inflammation, supporting the idea of potential repurposing of this FDA-approved drug as UC therapeutic.
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影响因子：
4.9
作者：
Lee SH;Kwon JE;Cho ML
通讯作者：
Cho ML
影响因子：
4
作者：
Rosales C
通讯作者：
Rosales C
影响因子：
20.3
作者：
Kumar, Sachin;Xu, Juying;Filippi, Marie-Dominique
通讯作者：
Filippi, Marie-Dominique
影响因子：
5.6
作者：
Lucafò M;Curci D;Franzin M;Decorti G;Stocco G
通讯作者：
Stocco G
DOI：
10.1186/1710-1492-2-3-98
发表时间：
2006-09-15
期刊：
Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology
影响因子：
--
作者：
Lacy P
通讯作者：
Lacy P