Carbon monoxide-based therapy ameliorates acute pancreatitis via TLR4 inhibition.

Abstract

The protective role of hemeoxygenase-1 (HO-1) in various inflammatory conditions is mediated in part by its products, carbon monoxide (CO) and biliverdin. Here we investigated a therapeutic role for CO and CO-primed cells in acute pancreatitis (AP). In a mouse model of AP, treatment with CO-releasing molecule-2 (CORM-2) decreased mortality, pancreatic damage, and lung injury. CORM-2 decreased systemic inflammatory cytokines, suppressed systemic and pancreatic macrophage TNF-α secretion, and inhibited macrophage TLR4 receptor complex expression. In both human and mouse cells, CORM-2 inhibited endogenous and exogenous ligand-dependent TLR4 activation, which indicates that CORM-2 could be therapeutic for both early and late stages of AP, which involve sterile- and endotoxin-mediated inflammation, respectively. Mice engrafted with TLR4-deficient hematopoietic cells were protected against caerulein-induced AP. In the absence of leukocyte TLR4 expression, CORM-2 did not confer additional protection, which indicates that CORM-2-dependent effects are mediated via suppression of macrophage TLR4 activation. We determined that CO was directly responsible for the protective effects of CORM-2 in AP, as inactive forms of CORM-2 were ineffective. Importantly, adoptive transfer of CORM-2-primed cells reduced AP. Such a therapeutic approach would translate the beneficial effects of CO-based therapies, avoiding CO- or CO-RM-mediated toxicities in AP and a wide range of diseases.

• Authors: Jing Xue, Aida Habtezion
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 124 Issue 1 Pg. 437-47 (Jan 2014) ISSN: 1558-8238 [Electronic] United States
• PMID: 24334457 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Inflammation Mediators
• Lipopolysaccharides
• Ly96 protein, mouse
• Lymphocyte Antigen 96
• Organometallic Compounds
• Tlr4 protein, mouse
• Toll-Like Receptor 4
• Tumor Necrosis Factor-alpha
• tricarbonyldichlororuthenium (II) dimer
• Carbon Monoxide

Topics

• Acute Disease
• Adoptive Transfer
• Animals
• Carbon Monoxide (pharmacology, therapeutic use)
• Cells, Cultured
• Female
• Humans
• Inflammation Mediators (metabolism)
• Lipopolysaccharides (pharmacology)
• Lymphocyte Antigen 96 (metabolism)
• Macrophages (metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Knockout
• Organometallic Compounds (pharmacology, therapeutic use)
• Pancreas (immunology, metabolism, pathology)
• Pancreatitis (drug therapy, immunology)
• Spleen (metabolism)
• Toll-Like Receptor 4 (antagonists & inhibitors, metabolism)
• Tumor Necrosis Factor-alpha (metabolism)