| First Author | Xue J | Year | 2014 |
| Journal | J Clin Invest | Volume | 124 |
| Issue | 1 | Pages | 437-47 |
| PubMed ID | 24334457 | Mgi Jnum | J:207616 |
| Mgi Id | MGI:5559250 | Doi | 10.1172/JCI71362 |
| Citation | Xue J, et al. (2014) Carbon monoxide-based therapy ameliorates acute pancreatitis via TLR4 inhibition. J Clin Invest 124(1):437-47 |
| abstractText | 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. |
