Identification of P-Rex1 as an anti-inflammatory and anti-fibrogenic target for pulmonary fibrosis.
Identification of P-Rex1 as an anti-inflammatory and anti-fibrogenic target for pulmonary fibrosis.
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鉴定 P-Rex1 作为肺纤维化抗炎和抗纤维化靶点
DOI：
10.1038/srep25785
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发表时间：
2016-05-13
影响因子：
4.6
通讯作者：
Ye RD
中科院分区：
文献类型：
--
作者：
Liang Q;Cheng N;Zhang G;Liang Y;Qian F;Wu D;Ye RD
肺纤维化（PF）导致肺功能进行性且往往不可逆转的丧失，对健康构成威胁，目前尚无有效的治疗方法。我们检测了P-Rex1，一种PI3K和G蛋白βγ调节的Rac小GTPase的鸟嘌呤核苷酸交换因子（GEF），是否与PF有关。在博莱霉素诱导的PF模型中，缺乏P-Rex1的小鼠肺泡结构保存良好，存活率明显高于野生型（WT）小鼠。p-rex1 - / -小鼠表达的促炎细胞因子和趋化因子明显少于WT幼崽，肺组织中的白细胞浸润也减少。在WT小鼠肺成纤维细胞中检测到P-Rex1，其基因缺失可减弱tgf β-1刺激的肺成纤维细胞迁移、Rac1激活和p38 MAPK磷酸化。与WT对照组相比，p-rex1 - / -小鼠的α-平滑肌肌动蛋白、纤维连接蛋白和tgf - β-1的表达明显降低。缺乏gef的P-Rex1突变体的表达有效地阻断了smads依赖的转录激活，这表明P-Rex1是TGFβ-1信号传导的下游介质。这些发现表明P-Rex1是PF的一个新参与者，表明靶向P-Rex1可能同时阻断PF的炎症和纤维化过程。
Pulmonary fibrosis (PF) leads to progressive and often irreversible loss of lung functions, posing a health threat with no effective cure. We examined P-Rex1, a PI3K- and G protein βγ-regulated guanine nucleotide exchange factor (GEF) of the Rac small GTPase, for its potential involvement in PF. In a bleomycin-induced PF model, mice deficient in p-rex1 had well-preserved alveolar structure and survived significantly better than their wild type (WT) littermates. The p-rex1−/− mice expressed significantly less proinflammatory cytokines and chemokines and had reduced leukocyte infiltration in the lung tissue than their WT littermates. P-Rex1 was detected in lung fibroblasts of WT mice, and its genetic deletion attenuated TGFβ-1-stimulated lung fibroblast migration, Rac1 activation and p38 MAPK phosphorylation. The p-rex1−/− mice showed significantly reduced pathological changes including the expression of α-smooth muscle actin, fibronectin and TGFβ-1 compared with their WT controls. Expression of a GEF-deficient P-Rex1 mutant effectively blocked Smads-dependent transcriptional activation, suggesting that P-Rex1 is a downstream mediator of TGFβ-1 signaling. These findings identify P-Rex1 as a novel player of PF, suggesting that targeting P-Rex1 may simultaneously block the inflammatory and fibrogenic processes of PF.