The αvβ1 integrin plays a critical in vivo role in tissue fibrosis.
The αvβ1 integrin plays a critical in vivo role in tissue fibrosis.
复制标题
DOI：
10.1126/scitranslmed.aaa5094
复制
发表时间：
2015-05-20
影响因子：
17.1
通讯作者：
Sheppard D
中科院分区：
文献类型：
--
作者：
Reed NI;Jo H;Chen C;Tsujino K;Arnold TD;DeGrado WF;Sheppard D
整合素是一种跨膜异二聚体受体，具有多种生物学功能，在许多人类疾病中发挥重要作用。利用整合素亚单位敲除小鼠和抑制性抗体进行的研究已经确定了几乎每一种整合素异二聚体的重要作用，并导致了一些潜在有用的治疗药物的开发。一个值得注意的例外是αvβ1整合素。αv和β1亚基分别存在于许多二聚体对中，这使得通过单个亚基的遗传失活来推断αvβ1的特定作用具有挑战性，并且αvβ1复合体特异性阻断抗体尚不存在。因此，我们开发了一种有效的、高度特异的αvβ1小分子抑制剂来探索这种未被研究的整合素的功能。我们发现，αvβ1在活化的成纤维细胞上高表达，直接与转化生长因子β1的潜伏期相关肽结合，并介导转化生长因子β1的激活。这种αvβ1抑制剂的治疗性交付减轻了博莱霉素引起的肺纤维化和四氯化碳引起的肝纤维化，表明基于这种先导化合物的药物可能广泛用于治疗以过度组织纤维化为特征的疾病。
Integrins are transmembrane heterodimeric receptors that contribute to diverse biological functions and play critical roles in many human diseases. Studies using integrin subunit knockout mice and inhibitory antibodies have identified important roles for nearly every integrin heterodimer and led to the development of a number of potentially useful therapeutics. One notable exception is the αvβ1 integrin. αv and β1 subunits are individually present in numerous dimer pairs, making it challenging to infer specific roles for αvβ1 by genetic inactivation of individual subunits, and αvβ1 complex–specific blocking antibodies do not yet exist. We therefore developed a potent and highly specific small-molecule inhibitor of αvβ1 to probe the function of this understudied integrin. We found that αvβ1, which is highly expressed on activated fibroblasts, directly binds to the latency-associated peptide of transforming growth factor–β1 (TGFβ1) and mediates TGFβ1 activation. Therapeutic delivery of this αvβ1 inhibitor attenuated bleomycin-induced pulmonary fibrosis and carbon tetrachloride–induced liver fibrosis, suggesting that drugs based on this lead compound could be broadly useful for treatment of diseases characterized by excessive tissue fibrosis.
登录
查看更多内容
影响因子：
2.9
作者：
ABE, M;HARPEL, JG;RIFKIN, DB
通讯作者：
RIFKIN, DB
影响因子：
16.8
作者：
Dong, Xianchi;Hudson, Nathan E.;Springer, Timothy A.
通讯作者：
Springer, Timothy A.
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
7.2
作者：
Munger, John S.;Sheppard, Dean
通讯作者：
Sheppard, Dean
影响因子：
4
作者：
Lu, M;Munger, JS;Schnapp, LM
通讯作者：
Schnapp, LM