Department of Pediatrics, University of California, San Diego, La Jolla, Calif; Division of Allergy Immunology, University of California, San Diego, La Jolla, Calif.
Department of Pediatrics, University of California, San Diego, La Jolla, Calif; Department of Bioengineering, University of California, San Diego, La Jolla, Calif.
J Allergy Clin Immunol. 2021 Aug;148(2):486-494. doi: 10.1016/j.jaci.2021.01.023. Epub 2021 Feb 6.
Eosinophilic esophagitis (EoE) is a chronic T2 disorder complicated by tissue fibrosis and loss of esophageal luminal patency. The fibrostenotic esophagus does not respond well to therapy, but profibrotic therapeutic targets are largely unclear.
Our aim was to utilize proteomics and primary cells as a novel approach to determine relevant profibrotic factors.
We utilized primary esophageal EoE and normal fibroblasts, their derivative extracellular matrixes (ECMs), an approach of fibroblast culture on autologous versus nonautologous ECM, and proteomics to elucidate EoE ECM proteins that dysregulate cellular function.
We cultured esophageal fibroblasts from normal esophagi and esophagi from patients with severe EoE on autologous versus nonautologous ECM. The EoE ECM proteome shifted normal esophageal fibroblast protein expression. Proteomic analysis demonstrated that thrombospondin-1 is detected only in the EoE ECM, is central in the EoE ECM protein-protein interactome, is found at significantly elevated levels in biopsy specimens from patients with active EoE, and induces fibroblast collagen I production.
Fibroblasts from patients with EoE 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. Thrombospondin-1 is a previously unappreciated profibrotic molecule in EoE.
嗜酸性食管炎（EoE）是一种慢性 T2 疾病，伴有组织纤维化和食管腔通畅性丧失。纤维狭窄性食管对治疗反应不佳，但大部分促纤维化治疗靶点尚不清楚。
我们旨在利用蛋白质组学和原代细胞作为一种新方法来确定相关的促纤维化因素。
我们利用原发性食管 EoE 和正常成纤维细胞、它们的衍生细胞外基质（ECM）、成纤维细胞在自体与非自体 ECM 上的培养方法以及蛋白质组学来阐明 EoE ECM 蛋白，这些蛋白会使细胞功能失调。
我们在自体与非自体 ECM 上培养来自正常食管和重度 EoE 患者的食管成纤维细胞。EoE ECM 蛋白质组改变了正常食管成纤维细胞的蛋白表达。蛋白质组学分析表明，只有在 EoE ECM 中检测到血小板反应蛋白-1，它是 EoE ECM 中蛋白质-蛋白质相互作用网络的核心，在活动性 EoE 患者的活检标本中水平显著升高，并诱导成纤维细胞胶原 I 产生。
EoE 患者的成纤维细胞分泌一种独特的 ECM 蛋白质组，反映其体内状态，并诱导正常成纤维细胞产生胶原 I 和α-平滑肌肌动蛋白蛋白。血小板反应蛋白-1是 EoE 中一种以前未被认识的促纤维化分子。
