Control of lung vascular permeability and endotoxin-induced pulmonary oedema by changes in extracellular matrix mechanics
Control of lung vascular permeability and endotoxin-induced pulmonary oedema by changes in extracellular matrix mechanics
复制标题
DOI：
10.1038/ncomms2774
复制
发表时间：
2013-04-01
影响因子：
16.6
通讯作者：
Ingber, Donald E.
中科院分区：
文献类型：
--
作者：
Mammoto, Akiko;Mammoto, Tadanori;Ingber, Donald E.
血管通透性增加导致许多疾病，包括急性呼吸窘迫综合征、癌症和炎症。过去大多数关于血管屏障功能的工作都集中在可溶性调节剂上，如肿瘤坏死因子α。在这里，我们表明，肺血管通透性是由细胞外基质结构的变化机械控制。我们的研究表明，肺血管渗漏可以通过改变细胞外基质的顺应性在体外和通过操纵赖氨酰氧化酶介导的胶原交联在体内增加。细胞外基质硬度相对于正常水平的降低或增加破坏了连接的完整性并增加了血管渗漏。重要的是，内毒素诱导的血管通透性增加伴随着细胞外基质刚性和赖氨酰氧化酶活性的增加，这可以通过抑制赖氨酰氧化酶活性来防止。赖氨酰氧化酶和细胞外基质作为肺血管渗漏的关键调节因子的鉴定可能导致用于治疗肺水肿和由异常血管通透性引起的其他疾病的新治疗方法的发展。
Increased vascular permeability contributes to many diseases, including acute respiratory distress syndrome, cancer and inflammation. Most past work on vascular barrier function has focused on soluble regulators, such as tumour-necrosis factor-alpha. Here we show that lung vascular permeability is controlled mechanically by changes in extracellular matrix structure. Our studies reveal that pulmonary vascular leakage can be increased by altering extracellular matrix compliance in vitro and by manipulating lysyl oxidase-mediated collagen crosslinking in vivo. Either decreasing or increasing extracellular matrix stiffness relative to normal levels disrupts junctional integrity and increases vascular leakage. Importantly, endotoxin-induced increases of vascular permeability are accompanied by concomitant increases in extracellular matrix rigidity and lysyl oxidase activity, which can be prevented by inhibiting lysyl oxidase activity. The identification of lysyl oxidase and the extracellular matrix as critical regulators of lung vascular leakage might lead to the development of new therapeutic approaches for the treatment of pulmonary oedema and other diseases caused by abnormal vascular permeability.