Key Laboratory of Animal Epidemiology and Zoonosis, Ministry of Agriculture, National Animal Transmissible Spongiform Encephalopathy Laboratory, College of Veterinary Medicine, China Agricultural University, Beijing, China.
Cell Prolif. 2019 Jul;52(4):e12649. doi: 10.1111/cpr.12649. Epub 2019 Jun 14.
Mycobacterium tuberculosis (Mtb) leads to approximately 1.5 million human deaths every year. In pulmonary tuberculosis (TB), Mtb must drive host tissue destruction to cause pulmonary cavitation and dissemination in the tissues. Matrix metalloproteinases (MMPs) are endopeptidases capable of degrading all components of pulmonary extracellular matrix (ECM). It is well established that Mtb infection leads to upregulation of MMPs and also causes disturbance in the balance between MMPs and tissue inhibitors of metalloproteinases (TIMPs), thus altering the extracellular matrix deposition. In TB, secretion of MMPs is mainly regulated by NF-κB, p38 and MAPK signalling pathways. In addition, recent studies have demonstrated the immunomodulatory roles of MMPs in Mtb pathogenesis. Researchers have proposed a new regimen of improved TB treatment by inhibition of MMP activity to hinder matrix destruction and to minimize the TB-associated morbidity and mortality. The proposed regimen involves adjunctive use of MMP inhibitors such as doxycycline, marimastat and other related drugs along with front-line anti-TB drugs to reduce granuloma formation and bacterial load. These findings implicate the possible addition of economical and well-tolerated MMP inhibitors to current multidrug regimens as an attractive mean to increase the drug potency. Here, we will summarize the recent advancements regarding expression of MMPs in TB, their immunomodulatory role, as well as their potential as therapeutic targets to control the deadly disease.
结核分枝杆菌（Mtb）每年导致约 150 万人死亡。在肺结核（TB）中，Mtb 必须驱动宿主组织破坏，导致肺部空洞和组织内播散。基质金属蛋白酶（MMPs）是能够降解肺细胞外基质（ECM）所有成分的内肽酶。众所周知，Mtb 感染会导致 MMPs 的上调，也会导致 MMPs 和金属蛋白酶组织抑制剂（TIMPs）之间的平衡失调，从而改变细胞外基质的沉积。在 TB 中，MMPs 的分泌主要受 NF-κB、p38 和 MAPK 信号通路调节。此外，最近的研究表明 MMPs 在 Mtb 发病机制中具有免疫调节作用。研究人员提出了一种新的改良 TB 治疗方案，通过抑制 MMP 活性来阻碍基质破坏，最大限度地降低与 TB 相关的发病率和死亡率。该方案涉及联合使用 MMP 抑制剂，如强力霉素、马立司他和其他相关药物以及一线抗 TB 药物，以减少肉芽肿形成和细菌负荷。这些发现表明，在当前的多药方案中加入经济且耐受性良好的 MMP 抑制剂可能是提高药物疗效的一种有吸引力的手段。在这里，我们将总结 MMPs 在 TB 中的表达、它们的免疫调节作用以及它们作为治疗靶点控制致命疾病的潜力方面的最新进展。
