Evaluation of Standard Chemotherapy in the Guinea Pig Model of Tuberculosis
Evaluation of Standard Chemotherapy in the Guinea Pig Model of Tuberculosis
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DOI：
10.1128/aac.01521-09
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发表时间：
2010-05-01
影响因子：
4.9
通讯作者：
Orme, Ian M.
中科院分区：
文献类型：
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作者：
Ordway, Diane J.;Shanley, Crystal A.;Orme, Ian M.
本研究的目的是双重的。首先，我们在豚鼠结核病模型中评估标准化疗，以确定这种动物物种是否可以有效地用于此目的。其次，鉴于豚鼠和人类疾病病理学的相似性，我们希望评估其他参数，包括磁共振成像，显微镜检查，细胞因子表达和淋巴细胞表型，对药物治疗感染的反应。这项研究表明，传统的利福平-异烟肼-吡嗪酰胺化疗显着减少了结核分枝杆菌的高毒力Erdman K 01菌株的数量，大多数杆菌在一个月内被消除。尽管如此，在至少3到4个月的时间里，仍然可以在肺部和其他组织中检测到细菌。通过磁共振成像在宏观水平上可以清楚地观察到肺和淋巴结中的非坏死性肉芽肿的消退。显微镜下，大多数肺部和肺外炎症自发消退，留下由营养不良性钙化和纤维化组成的残留病变，标志着原发病变的坏死部位。残留的钙化病变，也与肺淋巴管炎，包含抗酸杆菌，即使在积极的化疗。这些病变内存在完整的细胞外杆菌，表明这些可能是疾病再激活的主要部位。化疗降低了T细胞流入感染组织的水平，并伴随着TH 1细胞因子表达的大量持续增加。化疗还阻止了肺组织中高水平的白细胞介素-10和Foxp 3阳性细胞的出现，这些细胞是调节性T细胞的已知标志物。
The purpose of this study was 2-fold. First, we evaluated standard chemotherapy in the guinea pig model of tuberculosis to determine if this animal species could productively be used for this purpose. Second, given the similarities of the pathology of disease in guinea pigs and humans, we wished to evaluate additional parameters, including magnetic resonance imaging, microscopy, and cytokine expression and lymphocyte phenotypes, in response to an infection treated with drug therapy. This study shows that conventional rifampin-isoniazid-pyrazinamide chemotherapy significantly decreased the numbers of the highly virulent Erdman K01 strain of Mycobacterium tuberculosis, with most of the bacilli being eliminated in a month. Despite this result, bacteria could still be detected in the lungs and other tissues for at least another 3 to 4 months. Resolution of the nonnecrotic granulomas in the lungs and lymph nodes could be clearly visualized by magnetic resonance imaging at the macroscopic level. Microscopically, the majority of the pulmonary and extrapulmonary inflammation resolved spontaneously, leaving residual lesions composed of dystrophic calcification and fibrosis marking the site of necrosis of the primary lesion. Residual calcified lesions, which were also associated with pulmonary lymphangitis, contained acid-fast bacilli even following aggressive chemotherapy. The presence of intact extracellular bacilli within these lesions suggests that these could serve as the primary sites of disease reactivation. The chemotherapy reduced the level of T-cell influx into infected tissues and was accompanied by a large and sustained increase in TH1 cytokine expression. Chemotherapy also prevented the emergence in lung tissues of high levels of interleukin-10 and Foxp3-positive cells, known markers of regulatory T cells.