TY -的T1 TRIM33阻止肺纤维化的影响转化生长因子-β1信号JF -欧洲呼吸杂志乔-和J - 10.1183/13993003.01346 -2019欧元六世55 - 6 SP - 1901346 AU Boutanquoi Pierre-Marie AU -细粉,奥利弗盟——比特拉阿莫,纪尧姆AU - Bellaye,皮埃尔西蒙盟——Dondaine露塞尔AU -马吉安,Guillaume AU - Pommerolle, Lenny AU - Vadel, Aurélie AU - Spanjaard, Maximilien AU - Demidov, Oleg AU - Mailleux, Arnaud AU - Crestani, Bruno AU - Kolb, Martin AU - Garrido, Carmen AU - Goirand, Françoise AU - Bonniaud，特发性肺纤维化(IPF)是一种破坏性疾病，其特征是肺内肌成纤维细胞增殖和细胞外基质异常积聚。转化生长因子(TGF)-β1启动关键的促纤维化信号通路，涉及SMAD通路和小热休克蛋白B5 (HSPB5)。Tripartite motif-containing 33 (TRIM33)被报道负调控TGF-β/SMAD信号，但其在纤维形成中的作用尚不清楚。本研究的目的是阐明TRIM33在IPF中的作用。方法检测IPF患者和鼠肝纤维化模型肺组织中TRIM33的表达。从Trim33-floxed小鼠中分离骨髓源性巨噬细胞(BMDM)、原代肺成纤维细胞和3D肺组织切片，并用TGF-β1或博莱霉素(BLM)培养。用腺病毒Cre重组酶(AdCre)抑制Trim33的表达。在造血特异性Trim33敲除小鼠和气管内接受AdCre和BLM的Trim33-floxed小鼠中评估肺纤维化。结果TRIM33在IPF患者和啮齿动物纤维化肺的肺泡巨噬细胞和成纤维细胞中过表达。 Trim33 inhibition in BMDM increased TGF-β1 secretion upon BLM treatment. Haematopoietic-specific Trim33 knockout sensitised mice to BLM-induced fibrosis. In primary lung fibroblasts and 3D lung tissue slices, Trim33 deficiency increased expression of genes downstream of TGF-β1. In mice, AdCre-Trim33 inhibition worsened BLM-induced fibrosis. In vitro, HSPB5 was able to bind directly to TRIM33, thereby diminishing its protein level and TRIM33/SMAD4 interaction.Conclusion Our results demonstrate a key role of TRIM33 as a negative regulator of lung fibrosis. Since TRIM33 directly associates with HSPB5, which impairs its activity, inhibitors of TRIM33/HSPB5 interaction may be of interest in the treatment of IPF.TRIM33 has a protective role against fibrogenesis, inhibiting the TGF-β1 pathway through a direct association with HSPB5. Interactions between TRIM33, SMAD4 and HSPB5 may represent key targets to prevent the progression of pulmonary fibrosis. http://bit.ly/3aVCuxc ER -