Biliverdin protects the functional integrity of a transplanted syngeneic small bowel

Nakao, Atsunori; Otterbein, Leo E.; Overhaus, Marcus; Sarady, Judit K.; Tsung, Allan; Kimizuka, Kei; Nalesnik, Michael A.; Kubo, Takashi; Uchiyama, Takashi; Liu, Fang; Murase, Noriko; Bauer, Anthony J.; Bach, Fritz H.

doi:10.1053/j.gastro.2004.05.059

Cited by 150 publications

(116 citation statements)

References 44 publications

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“…These include, severe sepsis [11,41,51], severe malaria [42], ischemia-reperfusion injury [2,14,31], rejection of transplanted organs [8], induction of immunological tolerance [61], autoimmune neuroinflammation [10], restenosis [4,37], myocardial infarction [27] and, as illustrated more recently, type 2 diabetes and obesity [23].…”

Section: Discussionmentioning

confidence: 99%

Therapeutic efficacy of naringin on cyclosporine (A) induced nephrotoxicity in rats: Involvement of hemeoxygenase-1

Chandramohan

Parameswari

2013

Pharmacological Reports

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Abstract:Background: Clinically, chronic nephrotoxicity may lead to renal functional impairment and progress to end stage renal failure. The renoprotective effect of a flavonoid naringin (NG) against cyclosporine A (CsA)-induced nephrotoxicity was investigated in this study. Methods: Nephrotoxicity was induced in male albino Wistar rats by injecting 25 mg/kg body weight of CsA for a period of 21 days. CsA-induced rats were also cotreated with 40 mg of NG/kg body weight, orally. Results: After the experimental period, the levels of lipid peroxides (TBARS) and hydroxyl radical (OH ) were found to be elevated, whereas the levels of SOD, catalase, glutathione, vitamin C, E and A were decreased in CsA-induced rats. NG co-treatment significantly decreased the levels of lipid peroxides and hydroxyl radicals and restored the levels of enzymic and non-enzymic antioxidants in renal tissues. Histological analysis revealed that CsA administration caused severe and widespread necrosis with dilatation of proximal tubules, vacuolization, tubular cell desquamation and intraluminal cast formation with massive infiltration of inflammatory cells. CsA-induced histopathological renal changes were minimal in animals which received NG treatment. The western blot and confocal microscopic expression of heme oxygenase-1 was restored by NG. In CsA-induced animals the expression was reduced compared to NG treated animals. Conclusions: The present study reveals that NG can act as effective renoprotective drug against CsA-induced toxicity.

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Section: Discussionmentioning

confidence: 99%

Therapeutic efficacy of naringin on cyclosporine (A) induced nephrotoxicity in rats: Involvement of hemeoxygenase-1

Chandramohan

Parameswari

2013

Pharmacological Reports

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“…HO-1 acts on heme and generates three products: biliverdin, carbon monoxide (CO), and Fe 2ϩ . Recent studies of these products have begun to shed light on the mechanisms of HO-1 action as a homeostatic gene (8,(22)(23)(24).…”

Section: Discussionmentioning

confidence: 99%

Cell Surface Biliverdin Reductase Mediates Biliverdin-induced Anti-inflammatory Effects via Phosphatidylinositol 3-Kinase and Akt

Węgiel

Baty

Gallo

et al. 2009

Journal of Biological Chemistry

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138

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Biliverdin reductase A (BVR) catalyzes the reduction of biliverdin (BV) to bilirubin (BR) in all cells. Others and we haveshown that biliverdin is a potent anti-inflammatory molecule, however, the mechanism by which BV exerts its protective effects is unclear. We describe and elucidate a novel finding demonstrating that BVR is expressed on the external plasma membrane of macrophages (and other cells) where it quickly converts BV to BR. The enzymatic conversion of BV to BR on the surface by BVR initiates a signaling cascade through tyrosine phosphorylation of BVR on the cytoplasmic tail. Phosphorylated BVR in turn binds to the p85␣ subunit of phosphatidylinositol 3-kinase and activates downstream signaling to Akt. Using bacterial endotoxin (lipopolysaccharide) to initiate an inflammatory response in macrophages, we find a rapid increase in BVR surface expression. One of the mechanisms by which BV mediates its protective effects in response to lipopolysaccharide is through enhanced production of interleukin-10 (IL-10) the prototypical anti-inflammatory cytokine. IL-10 regulation is dependent in part on the activation of Akt. The effects of BV on IL-10 expression are lost with blockade of Akt. Inhibition of surface BVR with RNA interference attenuates BV-induced Akt signaling and IL-10 expression and in vivo negates the cytoprotective effects of BV in models of shock and acute hepatitis. Collectively, our findings elucidate a potentially important new molecular mechanism by which BV, through the enzymatic activity and phosphorylation of surface BVR (BVR) surf modulates the inflammatory response.

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“…The cellular mechanisms underlie the anti-inflammatory action of CO that lead to inhibition of IL-1, IL-6, TNFα and MIP-1 expression involve the p38 MAPK as well as the JNK signaling pathway and the transcription factor AP-1 Ryter and Otterbein, 2004). Biliverdin has been shown to inhibit the activation of pro-inflammatory transcription factors including NFkB in vitro and in vivo and to decrease inflammatory mediators such as IL-6, TNFα and leukocyte infiltration (Foresti et al, 2004;Nakao et al, 2004;Sarady-Andrews et al, 2005) (Gibbs and Maines, 2007). Induction of HO-1 as well as administration of either CO or biliverdin or both have been shown to lessened tissue damage in various models of injury.…”

Section: Discussionmentioning

confidence: 99%

“…Numerous studies have shown that biliverdin/bilirubin benefit ischemiareperfusion injury and solid-organ transplantation, including chronic rejection, and islet transplantation (Fondevila et al, 2004;Nakao et al, 2004;Yamashita et al, 2004) and suggested it as a novel therapeutic approach to maximize the function and thus the availability of donor organs (Ollinger et al, 2007). In view of the cataractogenic and pressure elevation potential of the currently used glucocorticoids to prevent or treat graft rejection, biliverdin/ bilirubin might constitute an alternative treatment of choice.…”

Section: Discussionmentioning

confidence: 99%

Exacerbated corneal inflammation and neovascularization in the HO-2 null mice is ameliorated by biliverdin

Bellner

Vitto

Patil

et al. 2008

Experimental Eye Research

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Heme oxygenase (HO-1 and HO-2) represents an intrinsic cytoprotective and anti-inflammatory system based on its ability to modulate leukocyte migration and to inhibit expression of inflammatory cytokines and proteins. HO-2 deletion leads to unresolved corneal inflammation and chronic inflammatory complications including ulceration, perforation and neovascularization. We examined the consequences of HO-2 deletion on hemangiogenesis and lymphangiogenesis in the model of suture-induced inflammatory neovascularization. A 8.0 silk suture was placed at the corneal apex of wild type and HO-2 null mice. Neovascularization was assessed by vital microscopy and quantified by image analysis. Hemangiogenesis and lymphangiogenesis were determined by immunofluorescence staining using anti-CD31 and anti-LYVE-1 antibodies, respectively. Inflammation was quantified by histology and myeloperoxidase activity. The levels of HO-1 expression and inflammatory cytokines were determined by real time PCR and ELISA, respectively. Corneal sutures produced a consistent inflammatory response and a time-dependent neovascularization. The response in HO-2 null mice was associated with a greater increase compared to the wild type in the number of leukocytes (827600±129000 vs. 294500±57510; p<0.05), neovessels measured by vital microscopy (21.91±1.05 vs. 12.77±1.55 mm; p<0.001) 4 days after suture placement. Hemangiogenesis but not lymphangiogenesis was more pronounced in HO-2 null mice compared to wild type mice. Induction of HO-1 in sutured corneas was greatly attenuated in HO-2 null corneas and treatment with biliverdin diminished the exaggerated inflammatory and neovascular response in HO-2 null mice. The demonstration that the inflammatory responses, including expression of proinflammatory proteins, inflammatory cell influx and hemangiogenesis are exaggerated in HO-2 knockout mice strongly supports the notion that the HO system is critical for controlling the inflammatory and neovascular response in the cornea. Hence, pharmacological amplification of this system may constitute a novel therapeutic strategy for the treatment of corneal disorders associated with excessive inflammation and neovascularization.

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Biliverdin protects the functional integrity of a transplanted syngeneic small bowel

Cited by 150 publications

References 44 publications

Therapeutic efficacy of naringin on cyclosporine (A) induced nephrotoxicity in rats: Involvement of hemeoxygenase-1

Therapeutic efficacy of naringin on cyclosporine (A) induced nephrotoxicity in rats: Involvement of hemeoxygenase-1

Cell Surface Biliverdin Reductase Mediates Biliverdin-induced Anti-inflammatory Effects via Phosphatidylinositol 3-Kinase and Akt

Exacerbated corneal inflammation and neovascularization in the HO-2 null mice is ameliorated by biliverdin

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