Phosphodiesterase-4 Inhibition Combined with Isoniazid Treatment of Rabbits with Pulmonary Tuberculosis Reduces Macrophage Activation and Lung Pathology
Phosphodiesterase-4 Inhibition Combined with Isoniazid Treatment of Rabbits with Pulmonary Tuberculosis Reduces Macrophage Activation and Lung Pathology
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DOI：
10.1016/j.ajpath.2011.03.039
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发表时间：
2011-07-01
影响因子：
6
通讯作者：
Kaplan, Gilla
中科院分区：
文献类型：
--
作者：
Subbian, Selyakumar;Tsenova, Liana;Kaplan, Gilla
结核病（TB）是世界范围内发病率和死亡率最高的疾病。即使在成功地用微生物治愈了结核病之后，许多患者仍会留下残留的肺损伤，这可能导致慢性呼吸障碍，并且由于再感染结核分枝杆菌而增加结核病发作的风险。促炎细胞因子肿瘤坏死因子- α和其他几种炎症标志物水平的升高，以及基质金属蛋白酶的表达，与结核病患者肺纤维化、组织损伤和治疗效果差的风险增加有关。在这项研究中，我们使用兔肺结核模型来评估辅助免疫调节对异烟肼抗生素治疗结果的影响，使用磷酸二酯酶-4抑制剂抑制先天免疫反应。我们的数据显示，与单独使用抗生素相比，用磷酸二酯酶-4抑制剂CC-3052加异烟肼联合治疗结核分枝杆菌感染的家兔，可以显著降低免疫发病的程度，这是通过对感染组织的组织学分析和参与炎症、纤维化和肺部伤口愈合的基因表达来确定的。抗生素和CC-3052联合治疗不仅能减轻疾病，还能提高肺部的细菌清除率。这些发现支持了辅助免疫调节改善肺结核治疗和降低慢性呼吸损伤风险的潜力。(Ant。中华疾病杂志，2011,39 (3):289301；做的!: 10.1016.j.ajpath.2011.03.039)
Tuberculosis (TB) is responsible for significant morbidity and mortality worldwide. Even after successful microbiological cure of TB, many patients are left with residual pulmonary damage that can lead to chronic respiratory impairment and greater risk of additional TB episodes due to reinfection with Mycobacterium tuberculosis. Elevated levels of the proinflammatory cytokine tumor necrosis factor-alpha and several other markers of inflammation, together with expression of matrix metalloproteinases, have been associated with increased risk of pulmonary fibrosis, tissue damage, and poor treatment outcomes in TB patients. In this study, we used a rabbit model of pulmonary TB to evaluate the impact of adjunctive immune modulation, using a phosphodiesterase-4 inhibitor that dampens the innate immune response, on the outcome of treatment with the antibiotic isoniazid. Our data show that cotreatment of M. tuberculosis infected rabbits with the phosphodiesterase-4 inhibitor CC-3052 plus isoniazid significantly reduced the extent of immune pathogenesis, compared with antibiotic alone, as determined by histologic analysis of infected tissues and the expression of genes involved in inflammation, fibrosis, and wound healing in the lungs. Combined treatment with an antibiotic and CC-3052 not only lessened disease but also improved bacterial clearance from the lungs. These findings support the potential for adjunctive immune modulation to improve the treatment of pulmonary TB and reduce the risk of chronic respiratory impairment. (Ant., Pathol 2011, 179:289301; DO!: 10.1016.j.ajpath.2011.03.039)