Bedaquiline and Pyrazinamide Treatment Responses Are Affected by Pulmonary Lesion Heterogeneity in Mycobacterium tuberculosis Infected C3HeB/FeJ Mice.
Bedaquiline and Pyrazinamide Treatment Responses Are Affected by Pulmonary Lesion Heterogeneity in Mycobacterium tuberculosis Infected C3HeB/FeJ Mice.
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Bedaquiline和吡嗪酰胺治疗反应受肺病变异质性的影响，感染了C3HEB/FEJ小鼠。
DOI：
10.1021/acsinfecdis.5b00127
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发表时间：
2016-04-08
影响因子：
5.3
通讯作者：
Lenaerts AJ
中科院分区：
文献类型：
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作者：
Irwin SM;Prideaux B;Lyon ER;Zimmerman MD;Brooks EJ;Schrupp CA;Chen C;Reichlen MJ;Asay BC;Voskuil MI;Nuermberger EL;Andries K;Lyons MA;Dartois V;Lenaerts AJ
BALB/c 和 Swiss 小鼠通常用于验证结核病药物治疗方案的有效性，尽管这些小鼠品系未能形成表现出干酪样坏死的类人肺肉芽肿。人类肉芽肿内的微环境条件可能会对药物功效产生负面影响，这可能不会反映在传统小鼠模型中发现的非坏死性病变中。 C3HeB/FeJ 小鼠模型已被越来越多地使用，因为它会产生缺氧、干酪样坏死肉芽肿，这可能更接近地模拟人类肺肉芽肿中发现的病理生理状况。在这里，我们检查了 BALB/c 和 C3HeB/FeJ 小鼠对单独和联合施用贝达喹啉 (BDQ) 和吡嗪酰胺 (PZA) 的治疗反应。 BALB/c 小鼠对两种药物始终表现出高度一致的治疗反应，而 C3HeB/FeJ 小鼠则表现出由反应性小鼠和反应性较差小鼠组成的双峰反应。对 BALB/c 和 C3HeB/FeJ 小鼠解剖病变的血浆药代动力学分析表明，PZA 以相似的效率渗透两种小鼠品系的病变类型。然而，C3HeB/FeJ 肉芽肿坏死干酪膜的 pH 值确定为 7.5，在标准实验室体外生长条件下，该范围内的 PZA 基本上无效。 BDQ 优先积聚在两种小鼠品系肺部的高细胞区域内，尽管当剂量为 25 mg/kg 时，BDQ 在中央皮膜内的浓度有所降低，但仍具有生物学相关性。 C3HeB/FeJ 小鼠模型中不同的肺部病理学导致的不同治疗反应揭示了可能影响治疗效果的几个因素，可以在临床试验中进一步评估。
BALB/c and Swiss mice are routinely used to validate the effectiveness of tuberculosis drug regimens, although these mouse strains fail to develop human-like pulmonary granulomas exhibiting caseous necrosis. Microenvironmental conditions within human granulomas may negatively impact drug efficacy, and this may not be reflected in non-necrotizing lesions found within conventional mouse models. The C3HeB/FeJ mouse model has been increasingly utilized as it develops hypoxic, caseous necrotic granulomas which may more closely mimic the pathophysiological conditions found within human pulmonary granulomas. Here, we examined the treatment response of BALB/c and C3HeB/FeJ mice to bedaquiline (BDQ) and pyrazinamide (PZA) administered singly and in combination. BALB/c mice consistently displayed a highly uniform treatment response to both drugs, while C3HeB/FeJ mice displayed a bimodal response composed of responsive and less-responsive mice. Plasma pharmacokinetic analysis of dissected lesions from BALB/c and C3HeB/FeJ mice revealed that PZA penetrated lesion types from both mouse strains with similar efficiency. However, the pH of the necrotic caseum of C3HeB/FeJ granulomas was determined to be 7.5, which is in the range where PZA is essentially ineffective under standard laboratory in vitro growth conditions. BDQ preferentially accumulated within the highly cellular regions in the lungs of both mouse strains, although it was present at reduced but still biologically relevant concentrations within the central caseum when dosed at 25 mg/kg. The differential treatment response which resulted from the heterogeneous pulmonary pathology in the C3HeB/FeJ mouse model revealed several factors which may impact treatment efficacy, and could be further evaluated in clinical trials.