谷氨酰胺分解
博莱霉素
特发性肺纤维化
基因敲除
肺纤维化
癌症研究
化学
肺
纤维化
下调和上调
炎症
医学
病理
谷氨酰胺
免疫学
内科学
细胞凋亡
化疗
生物化学
氨基酸
基因
作者
Naqi Lian,Huanhuan Jin,Weijie Zhu,Chen‐Yan Zhang,Yuewen Qi,Miao Jiang,Jing Mao,Xinyu Lu,Fengming Zhao,Beili Xi,Qi Xu,Yu Li
标识
DOI:10.1016/j.acthis.2022.151961
摘要
Idiopathic pulmonary fibrosis (IPF) represents a fatal pulmonary disease. Its mechanisms remain unclear and effective therapies are urgently needed. Glutaminolysis is involved in IPF pathology, but little is known about the role of ASCT2 responsible for cellular uptake of glutamine in IPF. We investigated the role of ASCT2 and its therapeutic implication in IPF through knockdown of ASCT2 in mice.Mouse IPF model was established through a single intratracheal administration of bleomycin, and lentivirus-coated ASCT2 siRNA was administrated into mice via caudal vein for knockdown of ASCT2. Mouse blood and lung tissues were collected for biochemical, histological, and molecular examinations.ASCT2 siRNA significantly lowered ASCT2 expression in mouse lung tissues. Knockdown of ASCT2 reduced pulmonary levels of glutamic acid, α-ketoglutarate, glutathione and ATP, mitigated pulmonary histological injury, and reduced serum concentrations of pulmonary injury parameters including SP-A, SP-D, KL-6 and CCL18 in IPF mice. Moreover, serum levels of fibrotic parameters HA, LN, PC-III and IV-C were lowered by ASCT2 depletion. Collagen production and pulmonary hydroxyproline levels were also decreased by ASCT2 siRNA in IPF mice, which was concomitant with downregulation of α-smooth muscle actin, collagen type Iα1 and transforming growth factor-β receptor II. Furthermore, ASCT2 deficiency downregulated the mRNA and protein expression of inflammatory cytokines IL-1β and TNF-α as well as macrophage marker F4/80 in lung tissues of IPF mice.Inhibition of ASCT2 effectively mitigated pulmonary injury, fibrosis and inflammation in mice with bleomycin-induced IPF. ASCT2 could be a novel therapeutic target for treatment of IPF.
科研通智能强力驱动
Strongly Powered by AbleSci AI