Recombinant Adenosine Deaminase Ameliorates Inflammation, Vascular Disease, and Fibrosis in Preclinical Models of Systemic Sclerosis
Recombinant Adenosine Deaminase Ameliorates Inflammation, Vascular Disease, and Fibrosis in Preclinical Models of Systemic Sclerosis
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重组腺苷脱氨酶可改善系统性硬化症临床前模型中的炎症、血管疾病和纤维化
DOI：
10.1002/art.41259
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发表时间：
2020
影响因子：
13.3
通讯作者：
Distler JHW
中科院分区：
文献类型：
--
作者：
Zhang Y;Layritz F;Wohlfahrt T;Chen CW;Soare A;Bergmann C;Ramming A;Groeber F;Reuter C;Fornasini G;Soukhareva N;Schreiber B;Ramamurthy S;Amann K;Schett G;Distler JHW
系统性硬化症（SSc）的特征是纤维化、血管疾病和炎症。腺苷信号传导在成纤维细胞活化中起核心作用。我们进行了这项研究，以评估腺苷消耗与聚乙二醇化腺苷脱氨酶（PEG-ADA）在SSc.MethodsThe临床前模型的治疗效果PEG-ADA对炎症，血管重塑和组织纤维化的影响进行了分析，在Fra-2小鼠和B10.D2→BALB/c（H-2d）硬皮病慢性移植物抗宿主病（GVHD）模型。PEG-ADA的作用在体外人全层皮肤模型中得到证实。ResultsPEG-ADA有效抑制肌成纤维细胞分化，减少肺纤维化34.3%（胶原蛋白表达减少）在Fra-2小鼠中，真皮纤维化减少51.8%（P= 0.0006; n = 6），肠纤维化减少17.7%（P= 0.0228; n = 6）。PEG-ADA的抗纤维化作用也在硬皮病慢性GVHD（降低38.4%）（P= 0.0063; n = 8）和人全层皮肤模型中得到证实。PEG-ADA治疗可减少炎症并纠正M2/Th 2/第2组先天淋巴细胞2偏向。此外，PEG-ADA抑制肺血管平滑肌细胞增殖（减少40.5%）（P< 0.0001; n = 6），并防止血管壁增厚（减少39.6%）（P= 0.0028; n = 6）和肺动脉闭塞（减少63.9%）（P= 0.0147; n = 6）。PEG-ADA处理抑制微血管内皮细胞凋亡（减少65.4%）（P= 0.0001; n = 6），并减弱毛细血管稀疏（减少32.5%）（P= 0.0199; n = 6）。RNA测序表明，PEG-ADA治疗使Fra-2小鼠中与纤维化、血管病变和炎症相关的多个通路正常化。结论PEG-ADA治疗可改善SSc的3个主要特征，且剂量相关且耐受性良好。这些发现可能具有直接的翻译意义，因为PEG‐ADA已被美国食品药品监督管理局批准用于治疗ADA缺乏型重度联合免疫缺陷病患者。
ObjectiveSystemic sclerosis (SSc) is characterized by fibrosis, vascular disease, and inflammation. Adenosine signaling plays a central role in fibroblast activation. We undertook this study to evaluate the therapeutic effects of adenosine depletion with PEGylated adenosine deaminase (PEG‐ADA) in preclinical models of SSc.MethodsThe effects of PEG‐ADA on inflammation, vascular remodeling, and tissue fibrosis were analyzed in Fra‐2 mice and in a B10.D2→BALB/c (H‐2d) model of sclerodermatous chronic graft‐versus‐host disease (GVHD). The effects of PEG‐ADA were confirmed in vitro in a human full‐thickness skin model.ResultsPEG‐ADA effectively inhibited myofibroblast differentiation and reduced pulmonary fibrosis by 34.3% (with decreased collagen expression) (P= 0.0079; n = 6), dermal fibrosis by 51.8% (P= 0.0006; n = 6), and intestinal fibrosis by 17.7% (P= 0.0228; n = 6) in Fra‐2 mice. Antifibrotic effects of PEG‐ADA were also demonstrated in sclerodermatous chronic GVHD (reduced by 38.4%) (P= 0.0063; n = 8), and in a human full‐thickness skin model. PEG‐ADA treatment decreased inflammation and corrected the M2/Th2/group 2 innate lymphoid cell 2 bias. Moreover, PEG‐ADA inhibited proliferation of pulmonary vascular smooth muscle cells (reduced by 40.5%) (P< 0.0001; n = 6), and prevented thickening of the vessel walls (reduced by 39.6%) (P= 0.0028; n = 6) and occlusions of pulmonary arteries (reduced by 63.9%) (P= 0.0147; n = 6). Treatment with PEG‐ADA inhibited apoptosis of microvascular endothelial cells (reduced by 65.4%) (P= 0.0001; n = 6) and blunted the capillary rarefication (reduced by 32.5%) (P= 0.0199; n = 6). RNA sequencing demonstrated that treatment with PEG‐ADA normalized multiple pathways related to fibrosis, vasculopathy, and inflammation in Fra‐2 mice.ConclusionTreatment with PEG‐ADA ameliorates the 3 cardinal features of SSc in pharmacologically relevant and well‐tolerated doses. These findings may have direct translational implications, as PEG‐ADA has already been approved by the Food and Drug Administration for the treatment of patients with ADA‐deficient severe combined immunodeficiency disease.
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影响因子：
16.6
作者：
Zehender A;Huang J;Györfi AH;Matei AE;Trinh-Minh T;Xu X;Li YN;Chen CW;Lin J;Dees C;Beyer C;Gelse K;Zhang ZY;Bergmann C;Ramming A;Birchmeier W;Distler O;Schett G;Distler JHW
通讯作者：
Distler JHW
DOI：
--
发表时间：
2018
期刊：
--
影响因子：
--
作者：
Zhongsheng Peng;P. Borea;T. Wilder;H. Yee;L. Chiriboga;M. Blackburn;G. Azzena;G. Resta;B. Cronstein
通讯作者：
Zhongsheng Peng;P. Borea;T. Wilder;H. Yee;L. Chiriboga;M. Blackburn;G. Azzena;G. Resta;B. Cronstein
影响因子：
32.4
作者：
McHedlidze T;Waldner M;Zopf S;Walker J;Rankin AL;Schuchmann M;Voehringer D;McKenzie AN;Neurath MF;Pflanz S;Wirtz S
通讯作者：
Wirtz S
影响因子：
20.3
作者：
Zarek, Paul E.;Huang, Ching-Tai;Powel, Jonathan D.
通讯作者：
Powel, Jonathan D.
DOI：
--
发表时间：
2000
期刊：
--
影响因子：
--
作者：
G. Haskó;D. Kuhel;Jiang-fan Chen;M. Schwarzschild;E. Deitch;J. Mabley;A. Marton;C. Szabó
通讯作者：
G. Haskó;D. Kuhel;Jiang-fan Chen;M. Schwarzschild;E. Deitch;J. Mabley;A. Marton;C. Szabó