November 12, 2014
Notes: Xu, Wei
Research Support, Non-U.S. Gov’t
Hepatogastroenterology. 2013 Sep;60(126):1504-8.
Reference Type: Journal Article
Record Number: 4827Author: Xue, J. and Habtezion, A.
Title: Carbon monoxide-based therapy ameliorates acute pancreatitis via TLR4 inhibition
Journal: J Clin Invest
Date: Jan 2
Short Title: Carbon monoxide-based therapy ameliorates acute pancreatitis via TLR4 inhibition
Alternate Journal: The Journal of clinical investigation
ISSN: 1558-8238 (Electronic)
Accession Number: 24334457
Keywords: Acute Disease
Carbon Monoxide/pharmacology/*therapeutic use
Lymphocyte Antigen 96/metabolism
Mice, Inbred BALB C
Mice, Inbred C57BL
Organometallic Compounds/pharmacology/*therapeutic use
Toll-Like Receptor 4/antagonists & inhibitors/*metabolism
Tumor Necrosis Factor-alpha/secretion
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-alpha 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.