The antifibrotic drug pirfenidone promotes pulmonary cavitation and drug resistance in a mouse model of chronic tuberculosis
The antifibrotic drug pirfenidone promotes pulmonary cavitation and drug resistance in a mouse model of chronic tuberculosis
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DOI：
10.1172/jci.insight.86017
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发表时间：
2016-09-08
期刊：
影响因子：
8
通讯作者：
Bishai, William R.
中科院分区：
文献类型：
--
作者：
Ahidjo, Bintou A.;Maiga, Mariama C.;Bishai, William R.
吡非尼酮是最近批准用于治疗特发性肺纤维化（IPF）的抗纤维化药物。由于结核病（TB）的特征是肉芽肿性炎症伴实质破坏和替代性纤维化，因此我们试图确定添加吡非尼酮作为抗宿主治疗是否在TB的抗菌治疗期间提供有益效果。我们假设吡非尼酮的抗炎和抗纤维化特性将减少炎性肺损伤，并增加抗微生物药物在肉芽肿中的渗透，以加速治疗反应。使用慢性TB的鼠模型评估了TB药物治疗期间连续性吡非尼酮的有效性。将用标准疗法2 HRZ/4 HR（H，异烟肼; R，利福平;和Z，吡嗪酰胺）治疗的小鼠与含有吡非尼酮（Pf）的2种替代方案（2 HRZPf/4 HRPf和2 HRZPf/4 HR）进行比较。与我们的假设相反，连续使用吡非尼酮导致细菌清除率降低和复发率增加。这种治疗失败与异烟肼单耐药杆菌的出现、空化增加和显著的肺病理学密切相关。虽然抗纤维化药物可能最终被用作结核病的抗宿主定向治疗的一部分，但这项研究清楚地表明，必须谨慎行事。此外，随着吡非尼酮在临床实践中越来越广泛地使用，在地方性TB环境中需要增加患者监测。
Pirfenidone is a recently approved antifibrotic drug for the treatment of idiopathic pulmonary fibrosis (IPF). Because tuberculosis (TB) is characterized by granulomatous inflammation in conjunction with parenchymal destruction and replacement fibrosis, we sought to determine whether the addition of pirfenidone as an adjunctive, host-directed therapy provides a beneficial effect during antimicrobial treatment of TB. We hypothesized that pirfenidone's antiinflammatory and antifibrotic properties would reduce inflammatory lung damage and increase antimicrobial drug penetration in granulomas to accelerate treatment response. The effectiveness of adjunctive pirfenidone during TB drug therapy was evaluated using a murine model of chronic TB. Mice treated with standard therapy 2HRZ/4HR (H, isoniazid; R, rifampin; and Z, pyrazinamide) were compared with 2 alternative regimens containing pirfenidone (Pf) (2HRZPf/4HRPf and 2HRZPf/4HR). Contrary to our hypothesis, adjunctive pirfenidone use leads to reduced bacterial clearance and increased relapse rates. This treatment failure is closely associated with the emergence of isoniazid monoresistant bacilli, increased cavitation, and significant lung pathology. While antifibrotic agents may eventually be used as part of adjunctive host-directed therapy of TB, this study clearly demonstrates that caution must be exercised. Moreover, as pirfenidone becomes more widely used in clinical practice, increased patient monitoring would be required in endemic TB settings.