Heme-Oxygenase-1 Induction and Carbon Monoxide-Releasing Molecule Inhibit Lipopolysaccharide (LPS)-Induced High-Mobility Group Box 1 Release in Vitro and Improve Survival of Mice in LPS- and Cecal Ligation and Puncture-Induced Sepsis Model in Vivo

Abstract

We examined our hypothesis that heme-oxygenase-1 (HO-1)-derived carbon monoxide (CO) inhibits the release of highmobility group box 1 (HMGB1) in RAW264.7 cells activated with lipopolysaccharide (LPS) in vitro and in LPS-or cecal ligation and puncture (CLP)-induced septic mice in vivo, so that HO-1 induction or CO improves survival of sepsis in rodents. We found that pretreatment with HO-1 inducers (hemin, cobalt protoporphyrin IX) or transfection of HO-1 significantly inhibited HMGB1 release, which was blocked by HO-1 small interfering RNA, in cells activated by LPS. Carbon monoxide-releasing molecule 2 (CORM-2) but not bilirubin or deferoxamine inhibited HMGB1 release in LPS-activated macrophages. Oxyhemoglobin reversed the effect of HO-1 inducers on HMGB1 release. Translocation of HMGB1 from nucleus to cytosol was significantly inhibited by HO-1 inducers, CORM-2, or HO-1 transfection. Neutralizing antibodies to tumor necrosis factor (TNF)-␣, interleukin (IL)-1␤, interferon-␤, and N -nitro-L-arginine methyl ester hydrochloride but not N-[2-(cyclohexyloxyl)-4-nitrophenyl]-methane sulfonamide (NS-398) significantly inhibited HMGB1 release in LPS-activated cells. Production of TNF-␣, IL-1␤, and IFN-␤ was significantly reduced by pretreatment of HO-1 inducers, CORM-2, or HO-1 transfection in LPS-activated cells. Plasma levels of HMGB1 in mice challenged with LPS or CLP were significantly reduced by the administration of HO-1 inducers or CORM-2, which was accompanied by either reduction (pretreatment) or no change (delayed administration) of serum TNF-␣ and IL-1␤ levels. Regardless of pretreatment or delayed administration, CORM-2 and hemin rescued mice from lethal endotoxemia and sepsis induced by LPS or CLP. Taken together, we concluded that HO-1-derived CO reduces HMGB1 release in LPS-activated cells and LPS-or CLP-induced animal model of sepsis.Sepsis is defined as a systemic inflammatory response syndrome from a microbial infection that results from excessive stimulation of the host immune system by pathogen components to produce various proinflammatory cytokines, and their overproduction causes systemic inflammation that can lead to the lethal multiple organ damage (Oberholzer et al., 2001). High-mobility group box 1 (HMGB1) is a chromatin-binding protein that participates in maintaining nucleosome structure and regulation of gene transcription (Landsman and Bustin, 1993). Various evidence indicated that HMGB1 is a necessary and sufficient late mediator of severe sepsis (Wang et al., 1999;Yang et al., 2004). Once released, HMGB1 can bind to cell-surface receptors, such as the receptor for advanced glycation end products and Toll-like receptors 2 and 4, and mediate various cellular responses, chemotactic cell movement, and release of proinflammatory Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org. doi:10.1124/mol.109.055137.ABBREVIATIONS: HMGB1, high-mobility group box 1; HO-1, heme-oxygenase-1; CORM-2, carbon monoxide-releasing molecule II; LPS, lip...

Carbon monoxide (CO)-releasing molecule-derived CO regulates tissue factor and plasminogen activator inhibitor type 1 in human endothelial cells

“…In contrast, enhanced induction of HO-1 and the administration of CORM-2 inhibit thrombus formation and affect the protein C system in sepsis [38]. CORM-2 reduces HMGB1 release in macrophages and septic animal models [9,39]. Our study showed that CORM-2 moderates TNF-α-induced TF and PAI-1 up-regulation.…”

“…Numerous reports have demonstrated CO-dependent protection in animal models of inflammatory syndromes, including sepsis [9] and colitis [10]. Inhalation of CO significantly suppresses ischemic induction of PAI-1 expression and the accumulation of fibrin in mice [11].…”

Heme Oxygenase-1 and Carbon Monoxide Promote Burkholderia pseudomallei Infection

“…CO may effectively interact with several intracellular heme-containing targets (e.g., soluble guanylate cyclase, cytochrome c oxidase, NADPH oxidase, potassium channels) to transduce important signals within cells. Several studies demonstrated that CO derived from CORMs can protect mice from lethal endotoxemia and polymicrobial sepsis induced by CLP (28,(70)(71)(72)(73). Recently, CORMs have been described to exert bactericidal (CORM-2, -3) or bacteriostatic (CORM-A1) activities against P. aeruginosa growth in vitro.…”

Acteoside Improves Survival in Cecal Ligation an Puncture-Induced Septic Mice via Blocking of High Mobility Group Box 1 Release

“…We first showed direct evidence that acteoside contributes to the reduction of HMGB1 and NO production by inducing HO-1 in macrophages. Other studies suggested that HMGB1 mediates cognitive impairment in sepsis survivors (Chavan et al, 2012;Huang et al, 2010) and that HO-1 inhibits the release of HMGB1 in Raw264.7 cells activated by LPS and in LPS-or CLP-induced septic mice (Tsoyi et al, 2009). Next, we assessed the signaling pathway through which acteoside induces HO-1.…”

“…Anti-HMGB1 antibodies and HMGB1 inhibitors significantly improve survival in septic animals, suggesting that HMGB1 is a possible therapeutic target in sepsis (Barnay-Verdier et al, 2011;Sama et al, 2004). Heme oxygenase-1 (HO-1), a stress-responsive protein induced by stimulants (inflammatory cytokines, heat shock, heavy metals, and oxidants) (Jang et al, 2012;Tsoyi et al, 2009) decreases circulating HMGB1 levels in animal models of sepsis and improves patient survival, demonstrating its therapeutic potential in inflammatory disorders . In addition, it is well known that the inducers of HO-1 expression inhibits the expression of the inflammatory genes (cyclooxygenase-2 and inducible nitric oxide synthase), and subsequently decreases PGE 2 and NO production (Oh et al, 2006;Suh et al, 2006).…”