Inhibition of Transforming Growth Factor β Worsens Elastin Degradation in a Murine Model of Kawasaki Disease
Inhibition of Transforming Growth Factor β Worsens Elastin Degradation in a Murine Model of Kawasaki Disease
复制标题
DOI：
10.1016/j.ajpath.2010.11.054
复制
发表时间：
2011-03-01
影响因子：
6
通讯作者：
Rabinovitch, Marlene
中科院分区：
文献类型：
--
作者：
Alvira, Cristina M.;Guignabert, Christophe;Rabinovitch, Marlene
川崎病(KD)是一种以冠状动脉炎为特征的急性炎症性疾病。然而，增加冠状动脉病变易感性的因素尚不清楚。由于转化生长因子β促进弹性蛋白合成并抑制蛋白分解，我们假设，与在马凡综合征患者形成的动脉瘤中观察到的益处相反，抑制转化生长因子β会加重炎症诱导的冠状动脉病变。在注射干酪乳杆菌壁提取物(LCWE)诱导冠状动脉炎症的KD小鼠模型上，我们发现干酪乳杆菌壁提取物(LCWE)从第2天开始增加冠状动脉平滑肌细胞中的转化生长因子-β信号，并持续到第14天，这是冠状动脉炎症的高峰点。到42天时，LCWE引起内外弹力板的碎裂。通过注射中和抗体阻断转化生长因子-β，可加剧LCCWE介导的弹性蛋白断裂，并在不增加炎症反应的情况下导致中层弹性蛋白的全面丧失。我们将这些增加的病理特征归因于蛋白水解性抑制物、纤溶酶原激活物抑制物-1的减少，以及与单独使用LCWE相比，基质金属蛋白酶9的活性增加了三倍。因此，我们的数据表明，在与KD相关的冠脉炎中，转化生长因子-β通过抑制纤溶酶介导的基质金属蛋白酶9的激活来抑制弹性蛋白的降解。因此，马凡综合征患者使用的阻断转化生长因子-β的策略不太可能是有益的，而可能是有害的。(Am J Pathol 2011,178：1210-1220；DOI。10.1016/j.ajpath.2010.11.054)
Kawasaki disease (KD) is an acute inflammatory illness marked by coronary arteritis. However, the factors increasing susceptibility to coronary artery lesions are unknown. Because transforming growth factor (TGF) beta increases elastin synthesis and suppresses proteolysis, we hypothesized that, in contrast to the benefit observed in aneurysms forming in those with Marfan syndrome, inhibition of TGF-beta would worsen inflammatory-induced coronary artery lesions. By using a murine model of KD in which injection of Lactobacillus casei wall extract (LCWE) induces coronary arteritis, we show that LCWE increased TGF-beta signaling in the coronary smooth muscle cells beginning at 2 days and continuing through 14 days, the point of peak coronary inflammation. By 42 days, LCWE caused fragmentation of the internal and external elastic lamina. Blocking TGF-beta by administration of a neutralizing antibody accentuated the LCWE-mediated fragmentation of elastin and induced an overall loss of medial elastin without increasing the inflammatory response. We attributed these increased pathological characteristics to a reduction in the proteolytic inhibitor, plasminogen activator inhibitor-1, and an associated threefold increase in matrix metalloproteinase 9 activity compared with LCWE alone. Therefore, our data demonstrate that in the coronary arteritis associated with KD, TGF-beta suppresses elastin degradation by inhibiting plasmin-mediated matrix metalloproteinase 9 activation. Thus, strategies to block TGF-beta, used in those with Marfan syndrome, are unlikely to be beneficial and could be detrimental. (Am J Pathol 2011, 178:1210-1220; DOI. 10.1016/j.ajpath.2010.11.054)