Effect of an MMP-9/MMP-12 inhibitor on smoke-induced emphysema and airway remodelling in guinea pigs
Effect of an MMP-9/MMP-12 inhibitor on smoke-induced emphysema and airway remodelling in guinea pigs
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DOI：
10.1136/thx.2006.068353
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发表时间：
2007-08-01
期刊：
影响因子：
10
通讯作者：
Wright, Joanne L.
中科院分区：
文献类型：
--
作者：
Churg, Andrew;Wang, Rona;Wright, Joanne L.
背景资料：基质金属蛋白酶（MMP）被认为在香烟烟雾诱导的肺气肿的发病机制中是重要的，但该假设仅在小鼠中得到证实，并且其对其他物种，特别是人类的适用性是不确定的。MMPs在烟雾诱导的小气道重塑中的作用尚不清楚。方法：研究了MMP-9/MMP-12双重抑制剂AZ11557272对每天暴露于香烟烟雾长达6个月的豚鼠慢性阻塞性肺疾病（COPD）的解剖学和功能变化的影响。在任何时候，吸烟诱导的灌洗液炎性细胞、灌洗液锁链素（弹性蛋白分解的标志物）和血清肿瘤坏死因子α（TNF α）的增加均被AZ11557272完全消除。在6个月时，肺容量和空域大小增加。AZ11557272使压力-容积曲线恢复到对照水平，使吸烟引起的总肺容量、残气量和肺活量增加减少约70%，并使吸烟引起的空域扩大逆转约70%。表面与体积比与灌洗液锁链素和血清TNF α水平之间存在非常强的相关性。AZ11557272防止烟雾介导的小气道壁厚度增加，但没有防止烟雾诱导的平均肺动脉pressure. Conclusions增加：MMP-9/MMP-12抑制剂可以大大改善形态肺气肿，小气道重塑和这些病变的功能后果在非鼠物种。这些发现加强了MMP是人类COPD解剖学变化的重要介质的观点，并表明MMP-9和MMP-12可能是潜在的干预靶点。
Background: Matrix metalloproteases (MMPs) are believed to be important in the pathogenesis of cigarette smoke-induced emphysema, but this hypothesis has only been proved in the mouse and its applicability to other species, particularly humans, is uncertain. The role of MMPs in smoke-induced small airway remodelling is unknown.Methods: The effects of a dual MMP-9/MMP-12 inhibitor, AZ11557272, on the development of anatomical and functional changes of chronic obstructive pulmonary disease (COPD) in guinea pigs exposed daily to cigarette smoke for up to 6 months were examined.Results: At all times, smoke-induced increases in lavage inflammatory cells, lavage desmosine (a marker of elastin breakdown) and serum tumour necrosis factor alpha (TNF alpha) were completely abolished by AZ11557272. At 6 months there was an increase in lung volumes and airspace size. AZ11557272 returned the pressure-volume curve to control levels, decreased smoke-induced increases in total lung capacity, residual volume and vital capacity by about 70%, and also reversed smoke-induced airspace enlargement by about 70%. There was a very strong correlation between surface to volume ratio and both lavage desmosine and serum TNFa levels. AZ11557272 protected against smoke-mediated increases in small airway wall thickness but did not prevent smoke-induced increases in mean pulmonary artery pressure.Conclusions: An MMP-9/MMP-12 inhibitor can substantially ameliorate morphological emphysema, small airway remodelling and the functional consequences of these lesions in a non-murine species. These findings strengthen the idea that MMPs are important mediators of the anatomical changes behind COPD in humans, and suggest that MMP-9 and MMP-12 may be potential intervention targets.