Targeting of αv integrin identifies a core molecular pathway that regulates fibrosis in several organs.
Targeting of αv integrin identifies a core molecular pathway that regulates fibrosis in several organs.
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肌成纤维细胞是组织纤维化过程中积聚的细胞外基质成分的主要来源，而肝星状细胞(HSCs)是肝脏中肌成纤维细胞的主要来源。到目前为止，还没有强大的系统来从基因上操纵这些细胞。我们报道了PDGFRb-Cre高效灭活小鼠HSCs基因。我们使用这个系统删除了αv整合素亚基，因为多个αv整合素被认为是多个器官纤维化的中心介质。肝星状细胞αv整合素亚基缺失对四氯化碳诱导的小鼠肝纤维化有保护作用，而αvβ3、αvβ5或αvβ6的整体缺失或αvβ8的条件性缺失对HSC无保护作用。PDGFRb-Cre能有效靶向多个器官的肌成纤维细胞，利用该系统去除αv整合素在肺和肾纤维化模型中也具有保护作用。关键是，一种新的小分子(CWHM12)对αv整合素的药理阻断可以减轻肝和肺纤维化，即使在纤维化建立后给予也是如此。这些数据确定了调节纤维化的核心途径，并表明所有αv整合素的药理学靶向可能在治疗广泛的纤维化疾病患者中具有临床实用价值。
Myofibroblasts are the major source of extracellular matrix components that accumulate during tissue fibrosis, and hepatic stellate cells (HSCs) are the major source of myofibroblasts in the liver. To date, robust systems to genetically manipulate these cells have not existed. We report that Pdgfrb-Cre inactivates genes in murine HSCs with high efficiency. We used this system to delete the αv integrin subunit because of the suggested role of multiple αv integrins as central mediators of fibrosis in multiple organs. Depletion of the αv integrin subunit in HSCs protected mice from CCl4-induced hepatic fibrosis, whereas global loss of αvβ3, αvβ5 or αvβ6 or conditional loss of αvβ8 on HSCs did not. Pdgfrb-Cre effectively targeted myofibroblasts in multiple organs, and depletion of αv integrins using this system was also protective in models of pulmonary and renal fibrosis. Critically, pharmacological blockade of αv integrins by a novel small molecule (CWHM 12) attenuated both liver and lung fibrosis, even when administered after fibrosis was established. These data identify a core pathway that regulates fibrosis, and suggest that pharmacological targeting of all αv integrins may have clinical utility in the treatment of patients with a broad range of fibrotic diseases.
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影响因子：
2.9
作者：
ABE, M;HARPEL, JG;RIFKIN, DB
通讯作者：
RIFKIN, DB
影响因子：
3.2
作者：
BREUSS, JM;GILLETT, N;PYTELA, R
通讯作者：
PYTELA, R
影响因子：
6.3
作者：
Ikura, Y;Morimoto, H;Sakurai, M
通讯作者：
Sakurai, M
影响因子：
10.5
作者：
FASSLER, R;MEYER, M
通讯作者：
MEYER, M
DOI：
10.1073/pnas.82.24.8681
发表时间：
1985-12-01
影响因子：
11.1
作者：
FRIEDMAN, SL;ROLL, FJ;BISSELL, DM
通讯作者：
BISSELL, DM