Tuberculosis, Pulmonary Cavitation, and Matrix Metalloproteinases
Tuberculosis, Pulmonary Cavitation, and Matrix Metalloproteinases
复制标题
DOI：
10.1164/rccm.201311-2106pp
复制
发表时间：
2014-07-01
影响因子：
24.7
通讯作者：
Friedland, Jon S.
中科院分区：
文献类型：
--
作者：
Ong, Catherine W. M.;Elkington, Paul T.;Friedland, Jon S.
结核病（TB）是一种全球性的慢性传染病，正面临着耐药菌株的出现，而治疗这种感染的新药很少。肺空洞是确诊疾病的标志，与非常高的细菌负荷相关。空化可能导致痰培养转化延迟、耐药性出现和感染传播。宿主对结核分枝杆菌的免疫反应与驱动结核腔的发展有关。TB的特征在于基质降解表型，其中蛋白水解基质金属蛋白酶（MMP）的活性相对不受金属蛋白酶的特异性组织抑制剂的对抗。由单核细胞衍生的细胞、嗜中性粒细胞和基质细胞分泌的蛋白酶，特别是MMP，参与细胞募集和组织损伤，并可能引起空化。MMP活性通过促炎趋化因子和细胞因子增强，通过复杂的信号传导途径严格调节，并导致基质破坏。MMP浓度在人TB中升高，并且与肺组织破坏的临床和放射学标记物密切相关。在临床前和临床试验中靶向MMPs的免疫调节疗法是结核病治疗的潜在突破。针对空洞型结核病患者的策略有可能提高治愈率并减少疾病传播。
Tuberculosis (TB), a chronic infectious disease of global importance, is facing the emergence of drug-resistant strains with few new drugs to treat the infection. Pulmonary cavitation, the hallmark of established disease, is associated with very high bacillary burden. Cavitation may lead to delayed sputum culture conversion, emergence of drug resistance, and transmission of the infection. The host immunological reaction to Mycobacterium tuberculosis is implicated in driving the development of TB cavities. TB is characterized by a matrix-degrading phenotype in which the activity of proteolytic matrix metalloproteinases (MMPs) is relatively unopposed by the specific tissue inhibitors of metalloproteinases. Proteases, in particular MMPs, secreted from monocyte-derived cells, neutrophils, and stromal cells, are involved in both cell recruitment and tissue damage and may cause cavitation. MMP activity is augmented by proinflammatory chemokines and cytokines, is tightly regulated by complex signaling paths, and causes matrix destruction. MMP concentrations are elevated in human TB and are closely associated with clinical and radiological markers of lung tissue destruction. Immunomodulatory therapies targeting MMPs in preclinical and clinical trials are potential adjuncts to TB treatment. Strategies targeting patients with cavitary TB have the potential to improve cure rates and reduce disease transmission.