Ancient Chinese herbal medicine as a modern hope for the treatment of sepsis: Extract of Angelica sinensis as an antagonist for a newly discovered late mediator of sepsis, HMGB1

Abstract

Study objectives: Gram-negative bacterial infection and severe sepsis are the leading cause of death in ICUs, claiming approximately 225,000 victims annually in the United States alone. The high mortality of sepsis is mediated in part by bacterial endotoxin (lipopolysaccharide [LPS]), which stimulates macrophages to release excess amounts of proinflammatory cytokines (such as tumor necrosis factor [TNF] and interleukin-1 [IL-1]) during severe infection. If delivered early enough, anti-TNF therapy can be effective in animal models of systemic inflammation, but early treatment is difficult to achieve in the clinic. An alternative therapeutic strategy would be to identify macrophage mediators that may be clinically more accessible. We recently discovered that a ubiquitous protein, high motility group box 1 (HMGB1), is released late by activated macrophages, and functions as a late mediator of lethal endotoxemia and sepsis. Various Chinese herbals have been traditionally used either alone or in combination with others in the treatment of various inflammation diseases. We evaluate the immunomodulatory properties of Chinese herbals. Methods: Extract of 12 Chinese herbals was prepared and individually assayed for activity in inhibiting LPS-induced HMGB1 release in cultures of murine macrophage-like RAW 264.7 cells or human peripheral blood mononuclear cells (HuPBMCs). Subsequently, extract of selected herbals capable of inhibiting LPS-induced HMGB1 release was examined for efficacy in protecting animals (Balb/C mice, 20 to 25 g, 7 to 8 weeks old) against lethal sepsis induced by cecal ligation and puncture. Results: The extract of one Chinese herbal, Angelica sinensis , dose-dependently attenuated LPS-induced HMGB1 release in cultures of murine macrophages and HuPBMCs, with a maximal suppression of greater than 95%. Consistently, intraperitoneal administration of Angelica extract beginning as late as 24 hours after cecal ligation and puncture significantly increased animal survival rate from 25% in the control (saline solution) group (n=20 mice/group) to 70% in the herbal treatment group (n=20 mice/group, P Conclusion: Angelica sinensis , a widely used Chinese herbal supplement, holds potential as a therapeutic agent for the clinical management of human sepsis.