title: 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
authors: J
authors: Xue
authors: Aida
authors: A
authors: Habtezion
mesh_terms: D000208:Acute Disease; D019264:Adoptive Transfer; D000818:Animals; D002248:Carbon Monoxide / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D051218:Lymphocyte Antigen 96 / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009942:Organometallic Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D010179:Pancreas / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010195:Pancreatitis / Q000188:drug therapy* / Q000276:immunology; D013154:Spleen / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D018836:Inflammation Mediators; D008070:Lipopolysaccharides; C411728:Ly96 protein, mouse; D051218:Lymphocyte Antigen 96; D009942:Organometallic Compounds; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C447082:tricarbonyldichlororuthenium (II) dimer; D002248:Carbon Monoxide