RT期刊文章SR电子T1 TRIM33阻止肺纤维化的损害TGF-β1信号摩根富林明欧洲呼吸杂志乔和J FD欧元欧洲呼吸学会SP 1901346 10.1183/13993003.01346 -2019 A1 Pierre-Marie Boutanquoi A1 Olivier煤屑A1 Guillaume188bet官网地址比特拉阿莫A1皮埃尔西蒙Bellaye A1露塞尔Dondaine A1 Guillaume马吉安A1 Lenny Pommerolle A1 Aurelie Vadel A1的马克西米连Spanjaard A1奥列格Demidov A1 Arnaud Mailleux A1布鲁诺A1伽马安基丁酸马丁科尔布A1卡门·加里多A1弗朗索瓦丝Goirand A1菲利普Bonniaud年2020 UL //www.qdcxjkg.com/content/early/2020/03/12/13993003.01346 AB - 2019. -抽象原理特发性肺纤维化(IPF)是一种破坏性疾病的特点是myofibroblast异常增殖和细胞外基质(ECM)积聚在肺部。Transforming-growth-factor (TGF) -β1发起主要涉及SMADs profibrotic信号通路和小热休克蛋白αB-crystallin (HSPB5)。三方Motif-containing 33 (TRIM33)据报道,负调控TGF-β/ SMADs信号但它在纤维发生中的作用仍然是未知的。目的阐明TRIM33在IPF的角色。方法评估TRIM33表达式IPF患者和啮齿动物的肺纤维化模型。骨骨髓来源的巨噬细胞(BMDM),原发性肺成纤维细胞和3 d-lung组织切片Trim33-floxed小鼠中分离培养与TGF-β1或博来霉素(BLM)。Trim33表达被抑制,adenovirus-Cre重组酶(AdCre)。肺纤维化是评估hematopoietic-specific Trim33淘汰赛(KO)小鼠和Trim33-floxed老鼠收到AdCre BLM气管内的。结果TRIM33在肺泡巨噬细胞和成纤维细胞在IPF患者和啮齿动物肺纤维化。Trim33抑制在BMDM TGF-β1分泌增加BLM治疗。Hematopoietic-specific Trim33-KO敏感老鼠BLM-induced纤维化。原发性肺成纤维细胞和3 d-lung组织切片,Trim33-deficiency TGF-β1-downstream基因表达增加。 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.FootnotesThis manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.Conflict of interest: Dr. Boutanquoi has nothing to disclose.Conflict of interest: Dr. Burgy has nothing to disclose.Conflict of interest: Dr. Beltramo has nothing to disclose.Conflict of interest: Dr. Bellaye has nothing to disclose.Conflict of interest: Dr. DONDAINE has nothing to disclose.Conflict of interest: Dr. Marcion has nothing to disclose.Conflict of interest: Dr. Pommerolle has nothing to disclose.Conflict of interest: Dr. Vadel has nothing to disclose.Conflict of interest: Dr. Spanjaard has nothing to disclose.Conflict of interest: Dr. Demidov has nothing to disclose.Conflict of interest: Dr. MAILLEUX has nothing to disclose.Conflict of interest: Dr. Crestani reports personal fees and non-financial support from Astra-Zeneca, grants, personal fees and non-financial support from Boehringer Ingelheim, grants from MedImmune, grants, personal fees and non-financial support from Roche, personal fees and non-financial support from Sanofi, personal fees from Genzyme, outside the submitted work.Conflict of interest: Dr. Kolb reports grants and personal fees from Roche, grants and personal fees from Boehringer Ingelheim, grants from GSK, grants from Respivert, personal fees from Genoa, grants from Alkermes, grants from Pharmaxis, grants and personal fees from Prometic, personal fees from Indalo, personal fees from Third Pole, personal fees from Pieris, grants from Canadian Institute for Health Research, outside the submitted work.Conflict of interest: Dr. Garrido has nothing to disclose.Conflict of interest: Dr. Goirand has nothing to disclose.Conflict of interest: Dr. Bonniaud reports personal fees and other from Roche, personal fees and other from Boehringer , personal fees and other from Novartis, personal fees from TEVA, other from Chiesi, personal fees from AstraZeneca, other from Stallergene, outside the submitted work.