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Carbon monoxide–based therapy ameliorates acute pancreatitis via TLR4 inhibition
Jing Xue, Aida Habtezion
Jing Xue, Aida Habtezion
Published December 16, 2013
Citation Information: J Clin Invest. 2014;124(1):437-447. https://doi.org/10.1172/JCI71362.
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Research Article Gastroenterology

Carbon monoxide–based therapy ameliorates acute pancreatitis via TLR4 inhibition

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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

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Figure 1

CORM-2 treats CDE-induced AP.

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CORM-2 treats CDE-induced AP.
(A) Balb/c mice were treated with 8 mg/kg ...
(A) Balb/c mice were treated with 8 mg/kg CORM-2 or VE control i.v. 24 hours after CDE feeding, then sacrificed at 72 hours. (B) Mouse survival over time. (C and D) Amylase (C) and lipase (D) results from sera collected at 72 hours. (E) Representative H&E-stained pancreatic sections. ED, edema; N, necrosis; Hem, hemorrhage. Scale bar: 100 μm. (F) Pancreas histology scores. (G and H) Pancreatic trypsin activity (G) and lung MPO measurements (H). Data are mean ± SEM of at least 3 independent experiments (n ≥ 5 per group).
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