Small GTPase RAB6 deficiency promotes alveolar progenitor cell renewal and attenuates PM2.5-induced lung injury and fibrosis.
Small GTPase RAB6 deficiency promotes alveolar progenitor cell renewal and attenuates PM2.5-induced lung injury and fibrosis.
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小 GTP 酶 RAB6 缺乏促进肺泡祖细胞更新并减轻 PM2.5 诱导的肺损伤和纤维化
DOI：
10.1038/s41419-020-03027-2
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发表时间：
2020-10-04
影响因子：
9
通讯作者：
Li X
中科院分区：
文献类型：
--
作者：
Yang L;Liu G;Li X;Xia Z;Wang Y;Lin W;Zhang W;Zhang W;Li X
特发性肺纤维化(IPF)是一种进行性间质性肺疾病，以慢性非特异性间质性炎症和广泛的胶原纤维沉积为特征，导致肺功能的破坏。研究表明，暴露在细颗粒物(PM2.5)中会增加患IPF的风险。为了从PM2.5所致的肺损伤中恢复过来，需要对肺泡上皮细胞进行修复和再生，以维持肺功能。2型肺泡上皮细胞(AEC2)是成人肺中的干细胞，通过复杂的信号转导参与肺修复过程。我们以前的研究表明，RAB6是肺癌中低表达的RAS家族成员，它抑制肺癌干细胞的自我更新，但在PM2.5诱导的肺纤维化中，RAB6是否以及如何调节AEC2细胞的增殖和自我更新尚不清楚。在这里，我们证明了RAB6基因敲除可以抑制PM2.5损伤小鼠的肺纤维化、氧化应激和AEC2细胞死亡。此外，RAB6基因敲除可减少Dickkopf1(DKK1)的自分泌，激活PM2.5损伤的AEC2细胞的增殖、自我更新和Wnt/β-catenin信号转导。RAB6过表达可增加AEC2细胞DKK1的自分泌，抑制细胞的增殖、自我更新和Wnt/β-catenin信号转导。此外，DKK1抑制剂还能促进RAB6高表达的AEC2细胞的增殖、自我更新和WNT/β-连环蛋白信号转导，减轻PM2.5诱导的小鼠肺纤维化。这些数据证实RAB6是DKK1自分泌和Wnt/β-catenin信号的调节者，调节AEC2细胞的增殖和自我更新，提示RAB6的破坏可能促进AEC2细胞的增殖和自我更新，以促进PM2.5损伤后的肺修复。
Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease characterized by chronic non-specific inflammation of the interstitial lung and extensive deposition of collagen fibers leading to destruction of lung function. Studies have demonstrated that exposure to fine particulate matter (PM2.5) increases the risk of IPF. In order to recover from PM2.5-induced lung injury, alveolar epithelial cells need to be repaired and regenerated to maintain lung function. Type 2 alveolar epithelial cells (AEC2) are stem cells in the adult lung that contribute to the lung repair process through complex signaling. Our previous studies demonstrated that RAB6, a RAS family member lowly expressed in lung cancer, inhibited lung cancer stem cell self-renewal, but it is unclear whether or not and how RAB6 may regulate AEC2 cell proliferation and self-renewal in PM2.5-induced pulmonary fibrosis. Here, we demonstrated that knockout of RAB6 inhibited pulmonary fibrosis, oxidative stress, and AEC2 cell death in PM2.5-injured mice. In addition, knockout of RAB6 decreased Dickkopf 1(DKK1) autocrine and activated proliferation, self-renewal, and wnt/β-catenin signaling of PM2.5-injured AEC2 cells. RAB6 overexpression increased DKK1 autocrine and inhibited proliferation, self-renewal and wnt/β-catenin signaling in AEC2 cells in vitro. Furthermore, DKK1 inhibitors promoted proliferation, self-renewal and wnt/β-catenin signaling of RAB6 overexpressing AEC2 cells, and attenuated PM2.5-induced pulmonary fibrosis in mice. These data establish RAB6 as a regulator of DKK1 autocrine and wnt/β-catenin signal that serves to regulate AEC2 cell proliferation and self-renewal, and suggest a mechanism that RAB6 disruption may promote AEC2 cell proliferation and self-renewal to enhance lung repair following PM2.5 injury.
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影响因子：
8.8
作者：
Landeira D;Bagci H;Malinowski AR;Brown KE;Soza-Ried J;Feytout A;Webster Z;Ndjetehe E;Cantone I;Asenjo HG;Brockdorff N;Carroll T;Merkenschlager M;Fisher AG
通讯作者：
Fisher AG
Wnt/Dkk负反馈失衡促进慢性胰腺炎胰腺星状细胞持续激活
影响因子：
3.7
作者：
Hu Y;Wan R;Yu G;Shen J;Ni J;Yin G;Xing M;Chen C;Fan Y;Xiao W;Xu G;Wang X;Hu G
通讯作者：
Hu G
影响因子：
82.9
作者：
Liang J;Zhang Y;Xie T;Liu N;Chen H;Geng Y;Kurkciyan A;Mena JM;Stripp BR;Jiang D;Noble PW
通讯作者：
Noble PW
大气PM2.5亚慢性暴露对大鼠肝脏纤维化、炎症、内质网应激和细胞凋亡的影响
影响因子：
2.1
作者：
Li, Ruijin;Zhang, Mei;Cai, Zongwei
通讯作者：
Cai, Zongwei
影响因子：
6.8
作者：
Qiu, Yi-Ning;Wang, Guo-Hui;Zhang, Ke-Zhong
通讯作者：
Zhang, Ke-Zhong