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首页> 外文期刊>The journal of clinical investigation >MMP-1 drives immunopathology in human tuberculosis and transgenic mice
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MMP-1 drives immunopathology in human tuberculosis and transgenic mice

机译：MMP-1驱动人类结核病和转基因小鼠的免疫病理学

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Mycobacterium tuberculosis can cause lung tissue damage to spread, but the mechanisms driving this immunopathology are poorly understood. The breakdown of lung matrix involves MMPs, which have a unique ability to degrade fibrillar collagens at neutral pH. To determine whether MMPs play a role in the immunopathology of tuberculosis (TB), we profiled MMPs and their inhibitors, the tissue inhibitor of metalloproteinases (TIMPs), in sputum and bronchoalveolar lavage fluid from patients with TB and symptomatic controls. MMP-1 concentrations were significantly increased in both HIV-negative and HIV-positive patients with TB, while TIMP concentrations were lower in HIV-negative TB patients. In primary human monocytes, M. tuberculosis infection selectively upregulated MMP1 gene expression and secretion, and Ro32-3555, a specific MMP inhibitor, suppressed M. tuberculosis –driven MMP-1 activity. Since the mouse MMP-1 ortholog is not expressed in the lung and mice infected with M. tuberculosis do not develop tissue destruction equivalent to humans, we infected transgenic mice expressing human MMP-1 with M. tuberculosis to investigate whether MMP-1 caused lung immunopathology. In the MMP-1 transgenic mice, M. tuberculosis infection increased MMP-1 expression, resulting in alveolar destruction in lung granulomas and significantly greater collagen breakdown. In , MMP-1 may drive tissue destruction in TB and represents a therapeutic target to limit immunopathology.
机译：结核分枝杆菌可引起肺组织损伤扩散，但导致这种免疫病理的机制了解甚少。肺基质分解涉及MMP，MMP具有在中性pH下降解原纤维胶原蛋白的独特能力。为了确定MMP在结核病（TB）的免疫病理学中是否起作用，我们对来自TB患者和有症状对照的痰液和支气管肺泡灌洗液中的MMP及其抑制剂，金属蛋白酶的组织抑制剂（TIMPs）进行了分析。 HIV阴性和HIV阳性结核病患者的MMP-1浓度均显着增加，而HIV阴性结核病患者TIMP浓度较低。在原代人单核细胞中，结核分枝杆菌感染选择性上调了MMP1基因的表达和分泌，而特定的MMP抑制剂Ro32-3555抑制了结核分枝杆菌驱动的MMP-1活性。由于小鼠MMP-1直系同源基因在肺中不表达，并且感染结核分枝杆菌的小鼠未发生与人类相当的组织破坏，因此我们用结核分枝杆菌感染了表达人MMP-1的转基因小鼠，以研究MMP-1是否引起了肺免疫病理学。在MMP-1转基因小鼠中，结核分枝杆菌感染增加了MMP-1的表达，导致肺肉芽肿中的肺泡破坏和胶原蛋白分解明显增加。在MMP-1中，MMP-1可能会导致TB组织破坏，并成为限制免疫病理的治疗靶标。

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