# Regulation of HMGB1 Release in Endotoxemia.

> **NIH NIH R01** · FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH · 2020 · $313,500

## Abstract

Project Abstract:
Despite recent advances in the antibiotic therapy and intensive care, bacterial infections and sepsis remain
widespread problems in critically ill patients, annually claiming > 225,000 victims in the U.S. alone. The
pathogenesis of sepsis remains obscure, but is partly mediated by bacterial toxins (e.g., lipopolysaccharide,
LPS), which stimulate macrophages/monocytes to sequentially release early (e.g., TNF and IFN-γ),
intermediate (e.g., the Serum Amyloid A, SAA), and late (e.g., HMGB1 and histones) pro-inflammatory
mediators. Our seminal discovery of HMGB1 as a late mediator of lethal systemic inflammation (LSI)
(Science, 285: 248-51, 1999) has prompted the investigation of various early cytokines (e.g., IFN-γ) and liver-
derived acute-phase proteins (e.g., fetuin-A and SAA) in the regulation of HMGB1 release. To search for other
endogenous HMGB1 regulators, we systematically monitored the dynamic changes of circulating HMGB1 and
other proteins in normal healthy subjects versus septic patients, and found a negative correlation between
levels of circulating HMGB1 and tetranectin (TN), a plasminogen-binding protein implicated in binding
plasminogen (PLMG) to activate the plasmin (PLM)-dependent fibrinolysis. Furthermore, we have generated
preliminary data that the highly purified recombinant TN dose-dependently attenuated the LPS/SAA-induced
HMGB1 release, but specifically stimulated the release of several neutrophil-attracting chemokines (CXCL1
and CXCL5) by primary human monocytes. In animal models of lethal endotoxemia and sepsis (induced by
cecal ligation and puncture, CLP), circulating TN levels were time-dependently decreased; whereas the
supplementation with highly purified recombinant TN conferred a significant protection. These exciting
findings raised several important questions regarding the intricate mechanisms underlying the TN-mediated
inhibition of HMGB1 release, as well as its significant protection against LSI. Accordingly, we propose to test: 1)
the novel hypothesis that TN divergently regulates HMGB1 release and neutrophil-attracting chemokine
expression through distinct mechanisms (Aim 1); 2) the under-appreciated role of TN in LSI by using gene
knockout or supplementation with recombinant TN or TN-specific peptide agonists (Aim 2); and 3) the novel
mechanisms by which TN or TN-specific peptide agonists affect the outcome of LSI (Aim 3). Collectively,
these proposed studies will improve our understanding of the pathophysiology of endotoxemia and sepsis, and
help to identify novel therapeutic strategies for the treatment of sepsis and other inflammatory diseases.

## Key facts

- **NIH application ID:** 10004057
- **Project number:** 5R01GM063075-15
- **Recipient organization:** FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
- **Principal Investigator:** Haichao Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $313,500
- **Award type:** 5
- **Project period:** 2002-07-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10004057

## Citation

> US National Institutes of Health, RePORTER application 10004057, Regulation of HMGB1 Release in Endotoxemia. (5R01GM063075-15). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10004057. Licensed CC0.

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