Reversing established sepsis with antagonists of endogenous high-mobility group box 1

Proceedings of the National Academy of Sciences of the United States of America - Tập 101 Số 1 - Trang 296-301 - 2004
Huan Yang1, Mahendar Ochani1, Jianhua Li1, Xiaoling Qiang1, Mahira Tanovic1, Helena Erlandsson Harris1, Srinivas M. Susarla1, Luis Ulloa1, Hong Wang1, Robert DiRaimo1, Christopher J. Czura1, Haichao Wang1, Jesse Roth1, H. Shaw Warren1, Mitchell P. Fink1, Matthew J. Fenton1, Jan Andersson1, Kevin J. Tracey1
1Laboratory of Biomedical Science, North Shore-Long Island Jewish Research Institute, 350 Community Drive, Manhasset, NY 11030; Center for Molecular Medicine, Karolinska Hospital, 171 76 Stockholm, Sweden; Infectious Disease Unit, Massachusetts General Hospital, East 149 13th Street, Charlestown, MA 02129; Department of Critical Care Medicine, University of Pittsburgh Medical School, 3550 Terrace Street, Pittsburgh, PA 15261; Division of Pulmonary and Critical Care, University of Maryland School of...

Tóm tắt

Despite significant advances in intensive care therapy and antibiotics, severe sepsis accounts for 9% of all deaths in the United States annually. The pathological sequelae of sepsis are characterized by a systemic inflammatory response, but experimental therapeutics that target specific early inflammatory mediators [tumor necrosis factor (TNF) and IL-1β] have not proven efficacious in the clinic. We recently identified high mobility group box 1 (HMGB1) as a late mediator of endotoxin-induced lethality that exhibits significantly delayed kinetics relative to TNF and IL-1β. Here, we report that serum HMGB1 levels are increased significantly in a standardized model of murine sepsis, beginning 18 h after surgical induction of peritonitis. Specific inhibition of HMGB1 activity [with either anti-HMGB1 antibody (600 μg per mouse) or the DNA-binding A box (600 μg per mouse)] beginning as late as 24 h after surgical induction of peritonitis significantly increased survival (nonimmune IgG-treated controls = 28% vs. anti-HMGB1 antibody group = 72%, P < 0.03; GST control protein = 28% vs. A box = 68%, P < 0.03). Animals treated with either HMGB1 antagonist were protected against the development of organ injury, as evidenced by improved levels of serum creatinine and blood urea nitrogen. These observations demonstrate that specific inhibition of endogenous HMGB1 therapeutically reverses lethality of established sepsis indicating that HMGB1 inhibitors can be administered in a clinically relevant time frame.

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Proceedings of the National Academy of Sciences of the United States of America

Tập 101 Số 1

296-301

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