National Institute for Research in Tuberculosis, National Institute of Health, International Center for Excellence in Research, Chennai, India.
National Institute for Research in Tuberculosis (NIRT), Chennai, India.
Front Immunol. 2020 Mar 11;11:419. doi: 10.3389/fimmu.2020.00419. eCollection 2020.
Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinase (TIMPs) are potential regulators of tuberculosis (TB) pathology. Whether they are candidates for non-sputum-based biomarkers for pulmonary TB (PTB) and extra-pulmonary TB (EPTB) is not fully understood. Hence, to examine the association of MMPs and TIMPs with PTB and EPTB, we have measured the circulating levels of MMPs (MMP-1, 2, 3, 7, 8, 9, 12, and 13) and TIMPs (TIMP-1, 2, 3, and 4) in PTB, EPTB and compared them with latent tuberculosis (LTB) or healthy control (HC) individuals. We have also assessed their circulating levels before and after the completion of anti-tuberculosis treatment (ATT). Our data describes that systemic levels of MMP-1, 8, 9, 12 were significantly increased in PTB compared to EPTB, LTB, and HC individuals. In contrast, MMP-7 was significantly reduced in PTB compared to EPTB individuals. Likewise, the systemic levels of MMP-1, 7, 13 were significantly increased in EPTB in comparison to LTB and HC individuals. In contrast, MMP-8 was significantly reduced in EPTB individuals compared to LTB and HC individuals. In addition, the systemic levels of TIMP-1, 2, 3 were significantly diminished and TIMP-4 levels were significantly enhanced in PTB compared to EPTB, LTB, and HC individuals. The circulating levels of TIMP-2 was significantly reduced and TIMP-3 was significantly elevated in EPTB individuals in comparison with LTB and HCs. Some of the MMPs (7, 8, 9, 12, 13 in PTB and 1, 7, 8, 9 in EPTB) and TIMPs (1, 2, 3, 4 in PTB and 4 in EPTB) were significantly modulated upon treatment completion. ROC analysis showed that MMP-1, 9 and TIMP-2, 4 could clearly discriminate PTB from EPTB, LTB and HCs and MMP-13 and TIMP-2 could clearly discriminate EPTB from LTB and HCs. Additionally, multivariate analysis also indicated that these alterations were independent of age and sex in PTB and EPTB individuals. Therefore, our data demonstrates that MMPs and TIMPs are potential candidates for non-sputum-based biomarkers for differentiating PTB and EPTB from LTB and HC individuals.
基质金属蛋白酶（MMPs）和金属蛋白酶组织抑制剂（TIMPs）是结核病（TB）病理学的潜在调节剂。它们是否可作为肺结核（PTB）和肺外结核（EPTB）的无痰生物标志物尚不完全清楚。因此，为了研究 MMPs 和 TIMPs 与 PTB 和 EPTB 的相关性，我们测量了 PTB、EPTB 患者循环中的 MMPs（MMP-1、2、3、7、8、9、12 和 13）和 TIMPs（TIMP-1、2、3 和 4）的水平，并将其与潜伏性结核（LTB）或健康对照（HC）个体进行了比较。我们还评估了他们在完成抗结核治疗（ATT）前后的循环水平。我们的数据表明，与 EPTB、LTB 和 HC 个体相比，系统中 MMP-1、8、9、12 的水平在 PTB 中显著升高。相反，与 EPTB 个体相比，MMP-7 在 PTB 中显著降低。同样，与 LTB 和 HC 个体相比，EPTB 患者中 MMP-1、7、13 的系统水平显著升高。相反，与 LTB 和 HC 个体相比，EPTB 个体中 MMP-8 的水平显著降低。此外，与 EPTB、LTB 和 HC 个体相比，PTB 患者中 TIMP-1、2、3 的水平显著降低，TIMP-4 的水平显著升高。EPTB 患者中 TIMP-2 的水平显著降低，TIMP-3 的水平显著升高。一些 MMPs（PTB 中的 7、8、9、12、13 和 EPTB 中的 1、7、8、9）和 TIMPs（PTB 中的 1、2、3、4 和 EPTB 中的 4）在治疗完成后显著发生变化。ROC 分析表明，MMP-1、9 和 TIMP-2、4 可以清楚地区分 PTB 与 EPTB、LTB 和 HC，而 MMP-13 和 TIMP-2 可以清楚地区分 EPTB 与 LTB 和 HC。此外，多变量分析还表明，这些改变在 PTB 和 EPTB 个体中独立于年龄和性别。因此，我们的数据表明，MMPs 和 TIMPs 是区分 PTB 和 EPTB 与 LTB 和 HC 个体的无痰生物标志物的潜在候选物。
