Inhibition of Glutaminase 1 Attenuates Experimental Pulmonary Fibrosis
Inhibition of Glutaminase 1 Attenuates Experimental Pulmonary Fibrosis
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DOI：
10.1165/rcmb.2019-0051oc
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发表时间：
2019-10-01
影响因子：
6.4
通讯作者：
Liu, Gang
中科院分区：
文献类型：
--
作者：
Cui, Huachun;Xie, Na;Liu, Gang
细胞代谢异常在肺纤维化的发病机制中起着重要作用。在我们以前的系统性研究中，我们发现人肺肌成纤维细胞经历脱氨重编程，这是由脱氨酶（Gls）1的表达增加介导的。我们发现，增强的去甲氨酶通过促进人肺肌成纤维细胞中胶原蛋白的稳定来严格调节胶原蛋白的产生。我们的研究表明，肺成纤维细胞Gls 1是一个有前途的治疗靶点，这种疾病。在这项研究中，我们主要集中在描绘成纤维细胞Gls 1在小鼠肺纤维化模型中的体内作用，并确定Gls 1抑制在治疗这种病理学中的功效。我们现在表明，成纤维细胞Gls 1在纤维化小鼠肺中上调。我们目前的证据表明，小鼠与消融成纤维细胞Gls 1保护博莱霉素诱导的肺纤维化。我们表明Gls 1抑制剂CB-839在治疗博来霉素和转化生长因子β 1诱导的肺纤维化方面具有治疗效果。因此，我们的研究为推进Gls 1抑制剂，特别是CB-839，进入治疗这种疾病的下一阶段测试建立了坚实的理论基础。
It has been increasingly recognized lately that aberrant cellular metabolism plays an important role in the pathogenesis of pulmonary fibrosis. In our previous systemic studies, we found that human lung myofibroblasts undergo glutaminolytic reprogramming, which is mediated by an increased expression of glutaminase (Gls) 1. We showed that augmented glutaminolysis critically regulates collagen production by promoting its stabilization in human lung myofibroblasts. Our study indicates that lung fibroblast Gls1 is a promising therapeutic target for this disease. In this investigation, we primarily focused on delineating the in vivo role of fibroblast Gls1 in mouse models of pulmonary fibrosis and determining the efficacy of Gls1 inhibition in treating this pathology. We now show that fibroblast Gls1 is upregulated in fibrotic mouse lungs. We present evidence that mice with ablation of fibroblast Gls1 are protected from bleomycin-induced lung fibrosis. We show that the Gls1 inhibitor, CB-839, is therapeutically efficacious in treating both bleomycin- and transforming growth factor-beta 1-induced pulmonary fibrosis. Our study has thus established a solid rationale for advancing Gls1 inhibitors, particularly CB-839, to the next stage of testing in the treatment of this disease.