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Carbon monoxide-based therapy ameliorates acute pancreatitis via TLR4 inhibition Xue J; Habtezion AJ Clin Invest 2014[Jan]; 124 (1): 437-47The 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.|Acute Disease[MESH]|Adoptive Transfer[MESH]|Animals[MESH]|Carbon Monoxide/pharmacology/*therapeutic use[MESH]|Cells, Cultured[MESH]|Female[MESH]|Humans[MESH]|Inflammation Mediators/metabolism[MESH]|Lipopolysaccharides/pharmacology[MESH]|Lymphocyte Antigen 96/metabolism[MESH]|Macrophages/metabolism[MESH]|Mice[MESH]|Mice, Inbred BALB C[MESH]|Mice, Inbred C57BL[MESH]|Mice, Knockout[MESH]|Organometallic Compounds/pharmacology/*therapeutic use[MESH]|Pancreas/immunology/metabolism/pathology[MESH]|Pancreatitis/*drug therapy/immunology[MESH]|Spleen/metabolism[MESH]|Toll-Like Receptor 4/antagonists & inhibitors/*metabolism[MESH]|Tumor Necrosis Factor-alpha/metabolism[MESH] |
