Daniel Wang
Pronouns: he/him
Research Mentor(s): Ramadan Ali
Research Mentor School/College/Department: Internal Medicine-Rheumatology / Medicine
Program:
Authors: Daniel Wang, Dinesh Khanna, Jason S. Knight, Ramadan Ali
Session: Session 7: 4:40 pm – 5:30 pm
Poster: 34
Abstract
Background/Purpose: Systemic sclerosis (SSc or scleroderma) is a disease characterized by vascular dysfunction, autoimmunity, and fibrosis. Many devastating complications such as digital ulcerations, scleroderma renal crisis, and pulmonary hypertension are the result of a deranged vasculature. Endothelial-to-mesenchymal transition (EndoMT) is an important driver of SSc. It is a process in which endothelial cells acquire myofibroblast-like features contributing to vascular dysfunction. Neutrophils and neutrophil extracellular traps (NETs) have recently been revealed to drive these vasculopathies. We hypothesize that NETs contribute to EndoMT in SSc and that anti-NET therapies might be a potential approach for combatting EndoMT. Methods: We conducted ELISAs to compare NET levels in plasma from SSc patients with vascular complications to an SSc control matched for age, sex, and disease duration but without vascular complications. To assess the effect of NETs on EndoMT, healthy human umbilical vein endothelial cells (HUVECs) were treated with plasma from SSc patients with vascular complications, plasma from SSc patients without vascular complications, or plasma from healthy controls in the presence or absence of NET-targeting agents. Gene expression of mesenchymal markers ACTA2 was measured by quantitative PCR. Results: We assessed plasma from SSc patients by ELISA and found higher levels of NETs in the plasma of SSc patients with vascular complications compared to SSc without vascular complications or healthy controls. We next assessed the potential role of NETs as inducers of EndoMT. We found that plasma from SSc patients with vascular complications increased the expression of mesenchymal markers ACTA2 in HUVECs compared to plasma from SSc patients without vascular complications. Notably, the addition of anti-NET therapies including anti-histone 4, DNase, and a neutrophil elastase inhibitor, significantly reduced NET-mediated EndoMT. Conclusion: Our data suggest that SSc patients with vascular complications have higher NET levels than a matched cohort without vascular complications. Our data also suggest that NETs can contribute to EndoMT and that anti-NET therapies might have the potential for combatting EndoMT and vascular disease in SSc.
