Leukotriene B4: A potential mediator and biomarker for cardiac allograft vasculopathy.

Autor: Wang D; Transplant and Stem Cell Immunobiology (TSI) Lab, Department of Surgery, Division of Cardiothoracic Surgery, University of California, San Francisco, San Francisco, California., Tediashvili G; Transplant and Stem Cell Immunobiology (TSI) Lab, Department of Surgery, Division of Cardiothoracic Surgery, University of California, San Francisco, San Francisco, California., Kim D; Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California., Hu X; Transplant and Stem Cell Immunobiology (TSI) Lab, Department of Surgery, Division of Cardiothoracic Surgery, University of California, San Francisco, San Francisco, California., Luikart H; Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California., Renne T; Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland; Center for Thrombosis and Hemostasis (CTH), Johannes Gutenberg University Medical Center, Mainz, Germany., Tian A; Pulmonary and Critical Medicine, Stanford University and Palo Alto Veteran Institute of Research (PAVIR), Stanford, California., Nadeau KC; Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts., Velden J; Evotec AG, Manfred Eigen Campus, Hamburg, Germany., Schrepfer S; Transplant and Stem Cell Immunobiology (TSI) Lab, Department of Surgery, Division of Cardiothoracic Surgery, University of California, San Francisco, San Francisco, California., Khush KK; Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California. Electronic address: kiran@stanford.edu.
Jazyk: angličtina
Zdroj: The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation [J Heart Lung Transplant] 2024 Aug; Vol. 43 (8), pp. 1336-1347. Date of Electronic Publication: 2024 Apr 24.
DOI: 10.1016/j.healun.2024.04.004
Abstrakt: Background: Cardiac allograft vasculopathy (CAV) remains the leading cause of long-term graft failure and mortality after heart transplantation. Effective preventive and treatment options are not available to date, largely because underlying mechanisms remain poorly understood. We studied the potential role of leukotriene B4 (LTB4), an inflammatory lipid mediator, in the development of CAV.
Methods: We used an established preclinical rat CAV model to study the role of LTB4 in CAV. We performed syngeneic and allogeneic orthotopic aortic transplantation, after which neointimal proliferation was quantified. Animals were then treated with Bestatin, an inhibitor of LTB4 synthesis, or vehicle control for 30 days post-transplant, and evidence of graft CAV was determined by histology. We also measured serial LTB4 levels in a cohort of 28 human heart transplant recipients with CAV, 17 matched transplant controls without CAV, and 20 healthy nontransplant controls.
Results: We showed that infiltration of the arterial wall with macrophages leads to neointimal thickening and a rise in serum LTB4 levels in our rat model of CAV. Inhibition of LTB4 production with the drug Bestatin prevents development of neointimal hyperplasia, suggesting that Bestatin may be effective therapy for CAV prevention. In a parallel study of heart transplant recipients, we found nonsignificantly elevated plasma LTB4 levels in patients with CAV, compared to patients without CAV and healthy, nontransplant controls.
Conclusions: This study provides key evidence supporting the role of the inflammatory cytokine LTB4 as an important mediator of CAV development and provides preliminary data suggesting the clinical benefit of Bestatin for CAV prevention.
(Copyright © 2024 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE