Single bolus injection of bilirubin improves the clinical outcome in a mouse model of endotoxemia

Cardiovascular Research Center and Department of Pharmacology, University of Virginia, Charlottesville, Virginia, USA.
Shock (Impact Factor: 3.05). 12/2007; 28(5):582-8. DOI: 10.1097/shk.0b013e31804d41dd
Source: PubMed


Increasing serum levels of biliverdin and bilirubin was shown to be beneficial in settings of inflammation. Bilirubin was shown to be protective in LPS-induced lung injury in rats; however, the exact mechanism remains elusive. Here, we investigated whether a single bolus injection of bilirubin would exert anti-inflammatory effects in a mouse model of endotoxemia. Mice were challenged with sublethal doses (2 mg/kg body weight) of LPS, and the effects of intravenously administered bilirubin (40 mg/kg body weight) were assessed. In contrast to control animals, bilirubin-treated animals fully recovered from endotoxin shock within 24 h. Bilirubin treatment improved the clinical score significantly at all time points assessed, attenuated weight loss, and improved LPS-induced anorexia. Furthermore, bilirubin treatment inhibited LPS-induced leukocyte-endothelial interactions and leukocyte accumulation in various tissues. Expression of inflammatory genes, including endothelial adhesion molecules, but also IL-1beta and TNF-alpha, was significantly reduced in bilirubin-treated animals. Moreover, bilirubin inhibited LPS-induced expression of inflammatory genes in isolated cultured aortic endothelial cells and in bone marrow-derived macrophages. These data show that single-dose administration of bilirubin attenuates tissue injury induced by endotoxin, and that bilirubin, in addition to its antioxidant effects, also exerts potent anti-inflammatory activity.

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    • "HO-1 is part of the hemoglobin degradation system resulting in the generation of anti-inflammatory carbon monoxide and bilirubin. Bilirubin proved to be protective in murine endotoxemia [36]. CO on the other hand inhibited LPS-mediated inflammatory responses of macrophages [33]. "
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    ABSTRACT: Sepsis still remains a major cause for morbidity and mortality in patients. The molecular mechanisms underlying the disease are still enigmatic. A great number of therapeutic approaches have failed and treatment strategies are limited to date. Among those few admitted for clinical intervention, intensive insulin treatment has proven to be effective in the reduction of disease related complications in critically ill patients. Insulin effectively reduces glucose levels and thereby contributes to protection. On the other hand insulin is a potent signaling pathway activator. One of those is the PI3K signaling axis. Activation of PI3K is known to limit pro-inflammatory gene expression. Here we can show that in a mouse model of insulin hypersensitivity induced by the deletion of the PI3K antagonist PTEN, specifically in hepatic tissue, significant protection is conferred in murine models of lethal endotoxemia and sepsis. Acute inflammatory responses are diminished, glucose metabolism normalized and vascular activation is reduced. Furthermore we investigated the hepatic gene expression profile of relevant anti-inflammatory genes in PTEN deficient mice and found marked upregulation of PPARγ and HO-1. We conclude from our data that insulin hypersensitivity via sustained activation of the PI3K signaling pathway exerts protective effects in acute inflammatory processes.
    PLoS ONE 06/2013; 8(6):e67013. DOI:10.1371/journal.pone.0067013 · 3.23 Impact Factor
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    • "The majority of the effects ascribed to BV are mimicked with BR, however the signaling pathways are vastly different including the effects on BVR. BR blocks iNOS expression as well as proinflammatory cytokine expression during endotoxemia (Wang et al., 2004; Lanone et al., 2005), improving the outcome in a lethal models of endotoxemia in rodents (Sarady-Andrews et al., 2005; Kadl et al., 2007; Wegiel et al., 2009). Some of the beneficial signaling and modification effects ascribed to BVR in response to BV, are also observed in response to BR (Baranano et al., 2002). "
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    ABSTRACT: Biliverdin (BV) has emerged as a cytoprotective and important anti-inflammatory molecule. Conversion of BV to bilirubin (BR) is catalyzed by biliverdin reductase (BVR) and is required for the downstream signaling and nuclear localization of BVR. Recent data by others and us make clear that BVR is a critical regulator of innate immune responses resulting from acute insult and injury and moreover, that a lack of BVR results in an enhanced proinflammatory phenotype. In macrophages, BVR is regulated by its substrate BV which leads to activation of the PI3K-Akt-IL-10 axis and inhibition of TLR4 expression via direct binding of BVR to the TLR4 promoter. In this review, we will summarize recent findings on the role of BVR and the bile pigments in inflammation in context with its activity as an enzyme, receptor, and transcriptional regulator.
    Frontiers in Pharmacology 03/2012; 3:47. DOI:10.3389/fphar.2012.00047 · 3.80 Impact Factor
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    • "inverse correlation between plasma bilirubin levels and various diseases (Vítek et al., 2002, 2006; Wiedemann et al., 2003; Sedlak et al., 2004; Lin et al., 2006). It displays anti-inflammatory activity in animal models of endotoxemia, septicemia and ischemia reperfusion injury (Fondevila et al., 2004; Wang et al., 2004; Keshavan et al., 2005; Lanone et al., 2005; Nakao et al., 2005; Overhaus et al., 2006; Kadl et al., 2007). Some of the proposed mechanisms of bilirubin including its ability to down-regulate expression of adhesion molecules, inhibit infiltration of inflammatory cells and production of nitric oxide (NO), and to reduce production of various inflammatory factors. "
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    ABSTRACT: Nonspecific inflammatory response is the major cause for failure of islet grafts at the early phase of intraportal islet transplantation (IPIT). Bilirubin, a natural product of heme catabolism, has displayed anti-oxidative and anti-inflammatory activities. The present study has demonstrated that bilirubin protected islet grafts by inhibiting nonspecific inflammatory response in a syngeneic rat model of IPIT. The inflammation-induced cell injury was mimicked by exposing cultured rat insulinoma INS-1 cells to cytokines (IL-1β, TNF-α and IFN-γ) in in vitro assays. At appropriate lower concentrations, bilirubin significantly attenuated the reduced cell viability and enhanced cell apoptosis induced by cytokines, and protected the insulin secretory function of INS-1 cells. Diabetic inbred male Lewis rats induced by streptozotocin underwent IPIT at different islet equivalents (IEQs) (optimal dose of 1000, and suboptimal doses of 750 or 500), and bilirubin was administered to the recipients every 12 h, starting from one day before transplantation until 5 days after transplantation. Administration of bilirubin improved glucose control and enhanced glucose tolerance in diabetic recipients, and reduced the serum levels of inflammatory mediators including IL-1β, TNF-α, soluble intercellular adhesion molecule 1, monocyte chemoattractant protein-1 and NO, and inhibited the infiltration of Kupffer cells into the islet grafts, and restored insulin-producing ability of transplanted islets.
    Experimental and Molecular Medicine 09/2010; 42(11):739-48. DOI:10.3858/emm.2010.42.11.075 · 3.45 Impact Factor
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