Induction of Heme Oxygenase by Cobalt-Protoporphyrin (Copp) in Small Bowel Donors Results in Decrease of Preservation/Reperfusion Injury and Improved Isograft Survival

Squiers, Elizabeth C.; Buelow, Roland; Szmalc, Frank S.; Iyer, Suhasini; Bruch, David; Tice, Diane G.

doi:10.1097/00007890-199905150-00462

Cited by 4 publications

(3 citation statements)

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“…Heme oxygenase‐1 has been shown to be up‐regulated by various causes of oxidative injury including IR [10,11]. Its induction, by pharmacologic or transfection means, has been shown to be protective in several in vivo rodent models including: heart allograft [23], small bowel allograft [24], liver allograft [25], renal IR [13], and renal allograft [14,15,18]. However, there is little data examining the long‐term beneficial effects of HO‐1 induction in renal allografts.…”

Section: Discussionmentioning

confidence: 99%

Peritransplant treatment with cobalt protoporphyrin attenuates chronic renal allograft rejection

Bédard¹,

Jiang²,

Parry³

et al. 2005

Transplant Int

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Summary Allogen‐independent injury contributes to chronic rejection in renal allografts and heme oxygenase‐1 (HO‐1) has been shown to be protective in a number of settings. This study evaluated the effect of renal allograft recipient HO‐1 up‐regulation on chronic rejection in a rat model. Rat (F344 to Lewis) renal transplantation recipients were grouped: (i) cyclosporine (CsA) alone (0.75 mg/kg s.c. × 10 day; n = 5); (ii) CsA + low dose cobalt protoporphyrin (CoPP) an HO‐1 inducer (0.5 mg/kg i.p. on days −5,0,5; n = 13) and (iii) CsA + high dose CoPP (5.0 mg/kg i.p. on days −5,0,5; n = 8). Renal function was assessed by serum creatinine levels on day 140. Histopathologic changes in allografts were graded. Morphometric analyses performed to objectively quantify the vascular changes and glomerulosclerosis. HO‐1 expression quantified by Western blot and both HO‐1 and endothelin (ET‐1) localized using immunohistochemistry. Recipients treated with CsA + high dose CoPP had significantly decreased cortical scarring, vascular hyalinization and intimal thickness. They also had a significant, dose dependant, reduction in luminal obliteration and glomerulosclerosis by morphometric analyses. This freedom from chronic rejection in recipients treated with CoPP translated into quiescent grafts at postoperative day 140 with immunostaining and Western blot demonstrating decreased level of HO‐1 versus controls (P = 0.012). In summary, the peritransplant up‐regulation of HO‐1 in renal allograft recipients significantly attenuates chronic rejection in rat renal allografts by inhibiting transplant vasculopathy.

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Section: Discussionmentioning

confidence: 99%

Peritransplant treatment with cobalt protoporphyrin attenuates chronic renal allograft rejection

Bédard¹,

Jiang²,

Parry³

et al. 2005

Transplant Int

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“…Treatment with cobalt-protoporphyrin (Co-PP), 4 which is known to up-regulate HO-1 expression, showed positive effects on long-term graft acceptance (16,17,19) and might therefore be an interesting approach for avoiding murine abortion. In this study, we hypothesized that up-regulating HO levels at the fetal-maternal interface from mice undergoing abortion would prevent fetal rejection possibly by modifying the Th1:Th2 production, by interfering with the NO synthase (NOS) system, or by preventing tissue damage, all these mechanisms are known to be associated with both the HO-1 pathway and pregnancy outcome.…”

mentioning

confidence: 99%

Protection from Abortion by Heme Oxygenase-1 Up-Regulation Is Associated with Increased Levels of Bag-1 and Neuropilin-1 at the Fetal-Maternal Interface

Sollwedel

Bertoja

Zenclussen

et al. 2005

The Journal of Immunology

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Tolerance mechanisms allowing pregnancy success resemble those involved in allograft acceptance. Heme oxygenase (HO) is a tissue-protective molecule, which allows graft acceptance and is known to have antiapoptotic effects on several cell types. We previously reported down-regulated levels of HO-1 and HO-2 in placenta from allopregnant mice undergoing abortion. In this study, we analyzed whether the up-regulation of HO-1 by cobalt-protoporphyrin (Co-PP) during implantation window can rescue mice from abortion. Induction of HO-1 by Co-PP treatment prevented fetal rejection, whereas the down-regulation of HOs by zinc-protoporphyrin application boosted abortion. The beneficial effect of HO-1 induction was not related to a local shift to Th2-profile or to a change in the NO system. Interestingly, the expression of the antiapoptotic/cytoprotective molecule Bag-1 as well as the levels of neuropilin-1, a novel marker for T regulatory cells, were up-regulated after Co-PP treatment. Our data strongly support a very important role for HO-1 in fetal allotolerance and suggest that HO-1 might be protective by up-regulating tissue protective molecules, i.e., Bag-1, and by activating T regulatory cells rather than by changing the local cytokine profile.

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“…In allograft models, induced expression of HO‐1 following gene therapy or treatment with protoporphyrins prolonged allograft survival and reduced arteriosclerosis and interstitial fibrosis (4). In ischemia/reperfusion models up‐regulation of HO‐1 protected liver, small bowel, lungs, heart and kidneys from injury and resulted in significantly improved long‐term graft function, even in transplants from marginal donors (5–8). However, the protective effects associated with elevated HO‐1 expression go beyond transplantation.…”

Section: Graft Protection By Hemoxygenase‐1 Overexpressionmentioning

confidence: 99%

Protection of Grafts by Hemoxygenase‐1 and its Toxic Product Carbon Monoxide

Buelow

Tullius

Volk

2001

American Journal of Transplantation

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Induction of Heme Oxygenase by Cobalt-Protoporphyrin (Copp) in Small Bowel Donors Results in Decrease of Preservation/Reperfusion Injury and Improved Isograft Survival

Cited by 4 publications

References 0 publications

Peritransplant treatment with cobalt protoporphyrin attenuates chronic renal allograft rejection

Peritransplant treatment with cobalt protoporphyrin attenuates chronic renal allograft rejection

Protection from Abortion by Heme Oxygenase-1 Up-Regulation Is Associated with Increased Levels of Bag-1 and Neuropilin-1 at the Fetal-Maternal Interface

Protection of Grafts by Hemoxygenase‐1 and its Toxic Product Carbon Monoxide

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