Department of Orthopaedics and Traumatology, Adam Malik General Hospital, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia.
Department of Pharmacology and Therapeutics School of Medicine, Universitas Sumatera Utara, Indonesia.
Biomed Res Int. 2023 Jan 27;2023:7421325. doi: 10.1155/2023/7421325. eCollection 2023.
Tuberculosis (TB) of the spine is a highly disruptive disease, especially in underdeveloped and developing countries. This condition requires standard TB treatment for 9-18 months, which increases patient risk of drug-resistant TB. Consequently, this raises the concern of adopting additional therapies to shorten the treatment duration, improve the efficacy of anti-TB drugs, and further decrease damage in the affected tissues and organs. Matrix metalloproteinase- (MMP-) 1 is a key regulator of the destruction of the extracellular matrix and associated proteins and is a new potential target for TB treatment research. In the present study, we investigated the effects of doxycycline as an MMP-1 inhibitor in patients with spondylitis TB.
Seventy-two New Zealand white rabbits with spondylitis TB were divided into 12 different groups based on incubation period (2, 4, 6, and 8 weeks) and doxycycline administration (without, 1 mg/kg body weight (BW), and 5 mg/kg BW). We observed the course of infection through the blood concentration changes and immunohistochemical examination of MMP-1, in addition to BTA staining, culture, polymerase chain reaction (PCR), and histopathological examination.
Treatment with once daily 5 mg/kg BW doxycycline significantly improved the blood MMP-1 level ( < 0.05) compared with the placebo and 1 mg/kg BW doxycycline. A significantly reduced ongoing infection and a higher healing rate were demonstrated in rabbits with a higher doxycycline dose through BTA staining, culture, PCR, and histopathology. Various degrees of vertebral endplates, vertebral body, and intervertebral disc destruction were observed in 32 rabbits with positive histopathological findings, in addition to positive inflammatory cell infiltration, characterized by numerous lymphocytes, macrophages, and epithelial cells, as well as abundant granulation tissue and necrotic substances proximal to the inoculated vertebral area. Bone and intervertebral disc destructions were more apparent in the untreated rabbits.
Our study demonstrated the potential of doxycycline as an adjunctive treatment in spondylitis TB. However, limitations remain regarding the differences in the pathogenesis and virulence of between rabbit and human systems, sample size, and the dose-dependent effect of doxycycline. Further studies are needed to address these issues.
脊柱结核（TB）是一种极具破坏性的疾病，特别是在欠发达和发展中国家。这种疾病需要标准的 TB 治疗 9-18 个月，这增加了患者发生耐药性 TB 的风险。因此，人们开始关注采用额外的治疗方法来缩短治疗时间，提高抗 TB 药物的疗效，并进一步减少受影响组织和器官的损伤。基质金属蛋白酶-（MMP-）1 是细胞外基质和相关蛋白破坏的关键调节剂，是 TB 治疗研究的一个新的潜在靶点。在本研究中，我们研究了强力霉素作为 MMP-1 抑制剂在脊柱结核患者中的作用。
72 只新西兰白兔患有脊柱结核，根据孵育期（2、4、6 和 8 周）和强力霉素给药（无、1mg/kg 体重和 5mg/kg 体重）将其分为 12 个不同的组。我们通过血液浓度变化和 MMP-1 的免疫组织化学检查，以及 BTA 染色、培养、聚合酶链反应（PCR）和组织病理学检查来观察感染过程。
与安慰剂和 1mg/kg BW 强力霉素相比，每日一次 5mg/kg BW 强力霉素治疗可显著降低血液 MMP-1 水平（<0.05）。通过 BTA 染色、培养、PCR 和组织病理学检查，在高剂量强力霉素的兔子中，感染的持续时间显著减少，愈合率更高。在 32 只组织病理学检查呈阳性的兔子中，观察到不同程度的椎体终板、椎体和椎间盘破坏，以及阳性炎症细胞浸润，特征为大量淋巴细胞、巨噬细胞和上皮细胞，以及大量肉芽组织和靠近接种椎体区域的坏死物质。未治疗的兔子中骨和椎间盘破坏更为明显。
本研究表明强力霉素作为脊柱结核辅助治疗的潜力。然而，仍然存在一些限制，包括兔与人系统的发病机制和毒力差异、样本量以及强力霉素的剂量依赖性效应等问题。需要进一步研究来解决这些问题。
