Abstract
The nuclear DNA binding protein high mobility group box 1 (HMGB1) has recently been suggested to act as a late mediator of septic shock. The effect of ((S)-6,7-dihydroxy-1-(4-hydroxynaphthylmethyl)-1,2,3,4-tetrahydroisoquinoline alkaloid, also known as THI-56, in an experimental model of sepsis was investigated. THI-56 exhibited potent anti-inflammatory properties in response to LPS in RAW 264.7 cells. In particular, THI-56 significantly inhibited the expression of inducible nitric oxide synthase (iNOS) and the release of HMGB1 in activated macrophages. THI-56 activated NE-F2-regulated factor 2 (Nrf-2)/heme oxygenase 1 (HO-1). The specific knockdown of the HO-1 gene by HO-1 siRNA significantly reversed the inhibitory effects of THI-56 on iNOS expression and HMGB1 release in LPS-stimulated macrophages. Importantly, THI-56 administration protected animals from death induced by either a lethal dose of LPS or cecal ligation and puncture (CLP). Furthermore, the ALT, AST, BUN, creatinine, and HMGB1 levels in the blood were significantly increased in CLP-induced septic mice, and the administration of THI-56 reduced these levels in a concentration-dependent and zinc protoporphyrin IX (ZnPPIX)-sensitive manner. In addition, the administration of THI-56 significantly ameliorated not only lung damage but also macrophage infiltration in the livers of CLP-induced septic mice, and these effects were also abrogated in the presence of ZnPPIX. Thus, we conclude that THI-56 significantly attenuates the proinflammatory response induced by LPS and reduces organ damage in a CLP-induced sepsis model through the upregulation of Nrf-2/HO-1.
Highlights
Sepsis is defined as a systemic inflammatory response syndrome resulting from a microbial infection
Heme oxygenase-1 (HO-1), a stress-responsive protein that can be induced by stimulants such as inflammatory cytokines, heat shock, heavy metals and oxidants, degrades heme into three products: Fe++, biliverdin, and carbon monoxide (CO)
THI-56 Significantly Attenuated iNOS/nitric oxide (NO) and high mobility group box 1 (HMGB1) Release in Macrophages Induced by LPS
Summary
Sepsis is defined as a systemic inflammatory response syndrome resulting from a microbial infection. The pathogenesis of sepsis is attributable, at least in part, to dysregulated systemic inflammatory responses characterized by the excessive accumulation of various proinflammatory mediators, such as tumor necrosis factor (TNF) or interleukin (IL)-1 [2], interferon-gamma (IFN-c) [3], and nitric oxide (NO) [4]. It has been demonstrated that a ubiquitous protein, high mobility group box 1 (HMGB1), is released by activated macrophages/ monocytes and functions as a late mediator of lethal endotoxemia and sepsis [5,6,7,8]. Heme oxygenase-1 (HO-1), a stress-responsive protein that can be induced by stimulants such as inflammatory cytokines, heat shock, heavy metals and oxidants, degrades heme into three products: Fe++, biliverdin, and carbon monoxide (CO). It seems plausible that the identification of HO-1-inducing agents can lead to the development of therapeutic interventions for inflammatory disorders such as sepsis
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