A unique esophageal extracellular matrix proteome alters normal fibroblast function in severe eosinophilic esophagitis.
A unique esophageal extracellular matrix proteome alters normal fibroblast function in severe eosinophilic esophagitis.
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独特的食管外基质组蛋白质组在严重的嗜酸性食管炎中改变了正常的成纤维细胞功能。
DOI：
10.1016/j.jaci.2021.01.023
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发表时间：
2021-08
期刊：
影响因子：
--
通讯作者：
Aceves SS
中科院分区：
文献类型：
--
作者：
Hsieh LY;Chiang AWT;Duong LD;Kuo CC;Dong SX;Dohil R;Kurten R;Lewis NE;Aceves SS
嗜酸性粒细胞性食管炎（EoE）是一种慢性Th2疾病，并发组织纤维化和食管腔通畅丧失。纤维狭窄性食道对治疗反应不佳，但促纤维化的治疗靶点在很大程度上尚不清楚。利用蛋白质组学和原代细胞作为确定相关促纤维化因子的新方法。我们利用原代食管EoE和正常成纤维细胞、它们的衍生细胞外基质（ECM）、成纤维细胞在自体和拮抗ECM上培养的方法，以及蛋白质组学来阐明EoE - ECM蛋白对细胞功能失调的影响。我们将正常或严重EoE食管的食管成纤维细胞培养在自体和对立细胞外基质（ECM）上。EoE - ECM蛋白组改变了正常食管成纤维细胞蛋白的表达。蛋白质组学分析表明，血栓反应蛋白-1 （TSP-1）仅在EoE ECM中检测到，在EoE ECM蛋白-蛋白相互作用组中处于中心位置，在活跃的EoE活检中显著升高，并诱导成纤维细胞胶原I的产生。EoE成纤维细胞分泌一种独特的ECM蛋白质组，反映其体内状态，诱导正常成纤维细胞表达I型胶原和α-平滑肌肌动蛋白。在EoE中，TSP-1是一种以前未被发现的促纤维化分子。这种在自体与拮抗ECM上培养组织成纤维细胞的新方法，对于识别以前未被发现的EoE和潜在的其他纤维化疾病的疾病特异性药物ECM靶点具有临床应用价值。通过对在自体或相反衍生物细胞外基质上培养的病变和正常食管成纤维细胞的蛋白质组学分析，发现并证实了血栓反应蛋白-1是EoE纤维化的致病介质。
Eosinophilic esophagitis (EoE) is a chronic Th2 disorder complicated by tissue fibrosis and loss of esophageal luminal patency. The fibrostenotic esophagus does not respond well to therapy but pro-fibrotic therapeutic targets are largely unclear. To utilize proteomics and primary cell as a novel approach to determine relevant pro-fibrotic factors. We utilized primary esophageal EoE and normal fibroblasts, their derivative extracellular matrixes (ECMs), an approach of fibroblast culture on autologous versus opposing ECM, and proteomics to elucidate EoE ECM proteins that dysregulate cellular function. We cultured esophageal fibroblasts from normal or severe EoE esophagi on autologous versus opposing extracellular matrix (ECM). The EoE ECM proteome shifted normal esophageal fibroblast protein expression. Proteomic analysis demonstrated that thrombospondin-1 (TSP-1) is detected only in the EoE ECM, is central in the EoE ECM protein-protein interactome, is significantly elevated in active EoE biopsies, and induces fibroblast collagen I production. EoE fibroblasts secrete a unique ECM proteome that reflects their in vivo state and induces collagen I and α-smooth muscle actin protein expression from normal fibroblasts. TSP-1 is a previously unappreciated pro-fibrotic molecule in EoE. The novel approach of culturing tissue fibroblasts on autologous versus opposing ECM has clinical utility for identifying previously unappreciated disease-specific druggable ECM targets in EoE and, potentially other, fibrotic disorders. Using proteomics analyses of diseased and normal esophageal fibroblasts cultured on autologous or opposing derivative extracellular matrixes, thrombospondin-1 was discovered and validated as a pathogenic mediator of fibrosis in EoE.
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影响因子：
7.7
作者：
Dellon ES;Kim HP;Sperry SL;Rybnicek DA;Woosley JT;Shaheen NJ
通讯作者：
Shaheen NJ
影响因子：
15.9
作者：
Parker, Matthew W.;Rossi, Daniel;Bitterman, Peter B.
通讯作者：
Bitterman, Peter B.
影响因子：
6.9
作者：
Belotti, Dorina;Capelli, Chiara;Taraboletti, Giulia
通讯作者：
Taraboletti, Giulia
DOI：
10.1097/mpg.0000000000000668
发表时间：
2015-08
影响因子：
2.9
作者：
Beppu L;Yang T;Luk M;Newbury RO;Palmquist J;Dohil R;Kurten RC;Broide DH;Aceves SS
通讯作者：
Aceves SS
影响因子：
4
作者：
Feizi A;Gatto F;Uhlen M;Nielsen J
通讯作者：
Nielsen J