Neutrophil extracellular traps promote fibrous vascular occlusions in chronic thrombosis

医学 中性粒细胞胞外陷阱 血栓形成 病理 细胞外 炎症 内科学 心脏病学 生物 细胞生物学
作者
Smriti Sharma,Thomas M. Hofbauer,Anna S. Ondracek,Stela Chausheva,Arman Alimohammadi,Tyler Artner,Adelheid Panzenboeck,Johanna Rinderer,Inbal Shafran,Andreas Mangold,Robert Winker,Evelyne Wohlschläger‐Krenn,Bernhard Moser,Shahrokh Taghavi,Walter Klepetko,Klaus T. Preissner,Iréne Lang
出处
期刊:Blood [Elsevier BV]
卷期号:137 (8): 1104-1116 被引量:109
标识
DOI:10.1182/blood.2020005861
摘要

Abstract Acute pulmonary embolism generally resolves within 6 months. However, if the thrombus is infected, venous thrombi transform into fibrotic vascular obstructions leading to chronic deep vein thrombosis and/or chronic thromboembolic pulmonary hypertension (CTEPH), but precise mechanisms remain unclear. Neutrophils are crucial in sequestering pathogens; therefore, we investigated the role of neutrophil extracellular traps (NETs) in chronic thrombosis. Because chronic pulmonary thrombotic obstructions are biologically identical to chronic deep venous thrombi, the murine inferior vena cava ligation model was used to study the transformation of acute to chronic thrombus. Mice with staphylococcal infection presented with larger thrombi containing more neutrophils and NETs but less resolution. Targeting NETs with DNase1 diminished fibrosis and promoted thrombus resolution. For translational studies in humans, we focused on patients with CTEPH, a severe type of deep venous and pulmonary artery fibrotic obstruction after thrombosis. Neutrophils, markers of neutrophil activation, and NET formation were increased in CTEPH patients. NETs promoted the differentiation of monocytes to activated fibroblasts with the same cellular phenotype as fibroblasts from CTEPH vascular occlusions. RNA sequencing of fibroblasts isolated from thrombo-endarterectomy specimens and pulmonary artery biopsies revealed transforming growth factor-β (TGF-β) as the central regulator, a phenotype which was replicated in mice with fibroblast-specific TGF-β overactivity. Our findings uncover a role of neutrophil-mediated inflammation to enhance TGF-β signaling, which leads to fibrotic thrombus remodeling. Targeting thrombus NETs with DNases may serve as a new therapeutic concept to treat thrombosis and prevent its sequelae.
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