The Polyanionic Drug Suramin Neutralizes Histones and Prevents Endotheliopathy
Abstract
Drugs are needed to protect against the neutrophil-derived histones responsible for endothelial injury in acute inflammatory conditions such as trauma and sepsis. Heparin and other polyanions can neutralize histones but challenges with dosing or side effects such as bleeding limit clinical application. In this study, we demonstrate that suramin, a widely available polyanionic drug, completely neutralizes the toxic effects of individual histones, but not citrullinated histones from neutrophil extracellular traps. The sulfate groups on suramin form stable electrostatic interactions with hydrogen bonds in the histone octamer with a dissociation constant of 250 nM. In cultured endothelial cells (Ea.Hy926), histone-induced thrombin generation was significantly decreased by suramin. In isolated murine blood vessels, suramin abolished aberrant endothelial cell calcium signals and rescued impaired endothelial-dependent vasodilation caused by histones. Suramin significantly decreased pulmonary endothelial cell ICAM-1 expression and neutrophil recruitment caused by infusion of sublethal doses of histones in vivo. Suramin also prevented histone-induced lung endothelial cell cytotoxicity in vitro and lung edema, intra-alveolar hemorrhage, and mortality in mice receiving a lethal dose of histones. Protection of vascular endothelial function from histone-induced damage is a novel mechanism of action for suramin with therapeutic implications for conditions characterized by elevated histone levels.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jul 05, 2023
- Source ID
- 10.4049/jimmunol.2200703
Entities
People
- Adrian M. Sackheim
- Beth Bouchard
- Devdoot Majumdar
- Jianing Li
- Jonathan E. Boyson
- Kalev Freeman
- Laurel Haines
- Mark T Nelson
- Matthew E. Poynter
- Michael A. Lawson
- Nuria Villalba
- Swapnil K Sonkusare
- Yen-lin Chen
- Yong-Tao Ma
Organizations
- American Chemical Society
- Horizon Europe
- National Heart, Lung, and Blood Institute
- National Institute of Allergy and Infectious Diseases
- National Institute of General Medical Sciences
- National Institute of Neurological Disorders and Stroke
- National Institute on Aging
- Office of the Director
- United States Department of Defense
- University of Manchester
- University of Vermont
- University of Virginia