Selectin-Mediated Interactions Regulate Cytokine Networks and Macrophage Heme Oxygenase-1 Induction in Cardiac Allograft Recipients

Coito, Ana J.; Shaw, Gray D.; Li, Jiye; Ke, Bibo; Ma, Jeffrey; Busuttil, Ronald W.; Kupiec‐Weglinski, Jerzy W.

doi:10.1038/labinvest.3780395

Cited by 24 publications

(15 citation statements)

References 32 publications

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“…In the present study, treatment with hemin led to a significant decrease in serum IFN-g concentrations of MRL/ lpr mice, suggesting that suppressive effects on IFN-g production are partly involved in the reduction of IgG anti-dsDNA antibody level and directly contribute to improvement of renal lesions in HO-1 induction therapy. Although the relationship between HO-1 expression and IFN-g synthesis has been controversial, upregulation of HO-1 led to reduction of IFN-g synthesis in some experimental systems [38][39][40][41]. Treatment with cobalt protoporphyrin, an HO-1 inducer, decreases production of IL-10, IFN-g and TNF in mouse allogeneic mixed lymphocyte reaction [38].…”

Section: Discussionmentioning

confidence: 99%

Chemical induction of HO-1 suppresses lupus nephritis by reducing localiNOS expression and synthesis of anti-dsDNA antibody

Takeda

Takeno

Iwasaki

et al. 2004

Clinical and Experimental Immunology

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SUMMARYThere is accumulating evidence that haem oxygenase (HO)-1 plays a protective role in various disorders. The beneficial efficacy of HO-1 induction therapy has been shown in renal diseases such as glomerulonephritis, interstitial nephritis and drug induced nephrotoxicity. However, involvement of HO-1 in the development of autoimmune renal diseases remains uncertain. To assess the clinical efficacy of HO-1 induction therapy for lupus glomerulonephritis, MRL/ lpr mice were intraperitoneally injected with 100 m mol/kg hemin, a potent HO-1 inducer, or PBS as controls, once a week from 6 weeks of age to 21-24 weeks-old. We found that treatment with hemin led to a significant reduction of proteinuria and remarkable amelioration of glomerular lesions accompanied by decreased immune depositions. In addition, the circulating IgG anti-double-stranded DNA antibody level was significantly decreased in hemin treated mice when compared with controls. A single intraperitoneal injection with hemin resulted in reduction of inducible nitric oxide synthase expression in the kidney and spleen, and serum interferong level. Our results suggest that HO-1 induction therapy ameliorates lupus nephritis by suppressing nitric oxide (NO) dependent inflammatory responses and attenuating production of pathogenic autoantibodies.Keywords haem oxygenase-1 (HO-1) MRL/ lpr inducible nitric oxide synthase ( i NOS) interferon-gamma (IFN-g )

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Section: Discussionmentioning

confidence: 99%

Chemical induction of HO-1 suppresses lupus nephritis by reducing localiNOS expression and synthesis of anti-dsDNA antibody

Takeda

Takeno

Iwasaki

et al. 2004

Clinical and Experimental Immunology

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“…30 Reverse transcription was performed using 4 g of total RNA in a first-strand cDNA synthesis reaction with SuperScript II RNaseH reverse transcriptase (Life Technologies Inc.) as recommended by the manufacturer. The cDNA product was amplified by PCR using primers specific for rat cytokines and ␤-actin as previously described 29 or for rat MMP-9, MMP-2, tissue inhibitor of metalloproteinases (TIMP)-1, and TIMP-2, which were obtained from BI-OMOL Research Laboratories (Plymouth Meeting, PA). Relative quantities of mRNA were determined using a densitometer (Kodak Digital Science 1D Analysis Software, Rochester, NY).…”

Section: Rna Extraction and Reverse Transcriptasepolymerase Chain Reamentioning

confidence: 99%

Fibronectin-α4β1 Integrin Interactions Regulate Metalloproteinase-9 Expression in Steatotic Liver Ischemia and Reperfusion Injury

Moore

Shen

Gao

et al. 2007

The American Journal of Pathology

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Ischemia/reperfusion injury is a major cause of the highly dysfunctional rate observed in marginal steatotic orthotopic liver transplantation. In this study, we document that the interactions between fibronectin, a key extracellular matrix protein, and its integrin receptor ␣4␤1, expressed on leukocytes, specifically up-regulated the expression and activation of metalloproteinase-9 (MMP-9, gelatinase B) in a wellestablished steatotic rat liver model of ex vivo ice-cold ischemia followed by isotransplantation. The presence of the active form of MMP-9 was accompanied by massive intragraft leukocyte infiltration, high levels of proinflammatory cytokines, such as interleukin-1␤ and tumor necrosis factor-␣, and impaired liver function. Interestingly, MMP-9 activity in steatotic liver grafts was, to a certain extent, independent of the expression of its natural inhibitor, the tissue inhibitor of metalloproteinases-1. Moreover, the blockade of fibronectin-␣4␤1-integrin interactions inhibited the expression/activation of MMP-9 in steatotic orthotopic liver transplantations without significantly affecting the expression of metalloproteinase-2 (MMP-2, gelatinase A). Finally, we identified T lymphocytes and monocytes/macrophages as major sources of MMP-9 in steatotic liver grafts. Hence, these findings reveal a novel aspect of the function of fibronectin-␣4␤1 integrin interactions that holds significance for the successful use of marginal steatotic livers in transplantation. Orthotopic liver transplantation (OLT) is an effective therapeutic modality for end-stage liver disease. The critical shortage of human donor livers has provided the rationale to identify methods that would allow successful utilization of marginal steatotic donor grafts, which are characterized by higher dysfunction rate compared with nonsteatotic OLTs. 1,2Ischemia/reperfusion (I/R) insult, an antigen-independent event associated with leukocyte adhesion/migration and release of cytokines and free radicals, plays a major role in post-I/R organ injury suffered by OLTs.3,4 Leukocyte recruitment to sites of inflammatory stimulation in liver, which is a venous-driven vascular bed with slow flow rates, is poorly understood and may require distinct cascade of adhesive events compared with other organs with higher flow rates. Fibronectin (FN), a large glycoprotein with a central role in cellular adhesion and migration, is likely a key extracellular matrix (ECM) protein involved in these events. 5The role of FN in leukocyte adhesion, migration, and activation has been extensively reported.6 -8 Moreover, we have previously shown that the so-called cellular FN, which is the most potent form of FN in promoting cell spreading and migration, 9,10 is virtually absent in naïve steatotic livers, and it is expressed very early on the sinusoidal endothelium during cold ischemia, before steatotic OLT and leukocyte recruitment at the graft site. 11Leukocyte transmigration across endothelial and ECM barriers is dependent on both adhesive and focal matrix degradation mechani...

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“…RNA was extracted from livers with Trizol (Life Technologies, Inc., Grand Island, NY) using a Polytron RT-3000 (Kinematica AG, Littau-Luzern, Switzerland) as described. 14 Reverse transcription was performed using 4 g of total RNA in a first-strand complementary DNA synthesis reaction with SuperScript II RNaseH Reverse Transcriptase (Life Technologies, Inc.). One microliter of the resulting reverse transcriptase product was used for polymerase chain reaction amplification.…”

Section: Liver Cold Ischemia Model Followed By Ex Vivomentioning

confidence: 99%

Biliverdin therapy protects rat livers from ischemia and reperfusion injury

et al. 2004

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Heme oxygenase (HO-1) provides a cellular defense mechanism during oxidative stress and catalyzes the rate-limiting step in heme metabolism that produces biliverdin (BV). The role of BV and its potential use in preventing ischemia/reperfusion injury (IRI) had never been studied. This study was designed to explore putative cytoprotective functions of BV during hepatic IRI in rat liver models of ex vivo perfusion and orthotopic liver transplantation (OLT) after prolonged periods of cold ischemia. In an ex vivo hepatic IRI model, adjunctive BV improved portal venous blood flow, increased bile production, and decreased hepatocellular damage. These findings were correlated with amelioration of histological features of IRI, as assessed by Suzuki's criteria. Following cold ischemia and syngeneic OLT, BV therapy extended animal survival from 50% in untreated controls to 90% to 100%. This effect correlated with improved liver function and preserved hepatic architecture. Additionally, BV adjuvant after OLT decreased endothelial expression of cellular adhesion molecules (P-selectin and intracellular adhesion molecule 1), and decreased the extent of infiltration by neutrophils and inflammatory macrophages. BV also inhibited expression of inducible nitric oxide synthase and proinflammatory cytokines (interleukin 1␤, tumor necrosis factor ␣, and interleukin 6) in OLTs. Finally, BV therapy promoted an increased expression of antiapoptotic molecules independently of HO-1 expression, consistent with BV being an important mediator through which HO-1 prevents cell death. In conclusion, this study documents and dissects potent cytoprotective effects of BV in well-established rat models of hepatic IRI. Our results provide the rationale for a novel therapeutic approach using BV to maximize the function and thus the availability of donor organs. (HEPATOLOGY 2004;40:1333-1341 I schemia and reperfusion injury (IRI), an antigen-independent component of the insult to the liver during "harvesting," represents an important problem affecting liver transplantation. IRI causes up to 10% of early liver failures and can lead to a higher incidence of acute and chronic rejection. 1 Moreover, with the increasing donor shortage, more functionally "suboptimal" or "marginal" livers are being used. Such livers are more susceptible to the damage caused by IRI compared with normal livers. 2 Indeed, minimizing the adverse effects of IRI could significantly increase the number of patients that successfully undergo liver transplantation.Liver IRI is mediated by several processes that lead to hepatocellular damage, which is triggered when the liver is transiently deprived of oxygen during the organ procurement for transplantation, and later reoxygenated during reperfusion. The structural changes promoted by cold ischemia and reperfusion become more prominent with increased storage time. 3 The sinusoidal endothelial cells are very sensitive to IRI, thus affecting the delicate balance that maintains homeostasis in the microcirculation with

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Selectin-Mediated Interactions Regulate Cytokine Networks and Macrophage Heme Oxygenase-1 Induction in Cardiac Allograft Recipients

Cited by 24 publications

References 32 publications

Chemical induction of HO-1 suppresses lupus nephritis by reducing localiNOS expression and synthesis of anti-dsDNA antibody

Chemical induction of HO-1 suppresses lupus nephritis by reducing localiNOS expression and synthesis of anti-dsDNA antibody

Fibronectin-α4β1 Integrin Interactions Regulate Metalloproteinase-9 Expression in Steatotic Liver Ischemia and Reperfusion Injury

Biliverdin therapy protects rat livers from ischemia and reperfusion injury

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