A Nonerythropoietic Peptide that Mimics the 3D Structure of Erythropoietin Reduces Organ Injury/Dysfunction and Inflammation in Experimental Hemorrhagic Shock

Patel, Nimesh S. A.; Nandra, Kiran K.; Brines, Michael; Collino, Massimo; Wong, W.S. Fred; Kapoor, Amar; Benetti, Elisa; Goh, Fera Y.; Fantozzi, Roberto; Cerami, Anthony; Thiemermann, Christoph

doi:10.2119/molmed.2011.00053

Cited by 29 publications

(22 citation statements)

References 54 publications

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“…Phosphorylation of JAK-2 results in potent anti-inflammatory and anti-apoptotic effects. ARA290 influences downstream pathways of JAK-2, such as activation of pro-survival pathway Akt and inhibition of pro-inflammatory pathways p38 mitogen activated protein kinase, glycogen synthase kinase-3β and nuclear factor-κβ [20-22]. In this study design it was not possible to measure activation of these pathways as tissue samples suitable for western blot analysis were obtained seven days post-reperfusion.…”

Section: Discussionmentioning

confidence: 99%

ARA290, a non-erythropoietic EPO derivative, attenuates renal ischemia/reperfusion injury

et al. 2013

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BackgroundIn contrast with various pre-clinical studies, recent clinical trials suggest that high dose erythropoietin (EPO) treatment following kidney transplantation does not improve short-term outcome and that it even increases the risk of thrombotic events. ARA290 is a non-erythropoietic EPO derivative and does not increase the risk of cardiovascular events, but potentially has cytoprotective capacities in prevention of renal ischemia/reperfusion injury.MethodsEight female Dutch Landrace pigs were exposed to unilateral renal ischemia for 45 minutes with simultaneous cannulation of the ureter of the ischemic kidney. ARA290 or saline was administered by an intravenous injection at 0, 2, 4 and 6 hours post-reperfusion. The animals were sacrificed seven days post-reperfusion.ResultsARA290 increased glomerular filtration rate during the observation period of seven days. Furthermore, ARA290 tended to reduce MCP-1 and IL-6 expression 15 minutes post-reperfusion. Seven days post-reperfusion ARA290 reduced interstitial fibrosis.ConclusionsThe improvement in renal function following renal ischemia/reperfusion and reduced structural damage observed in this study by ARA290 warrants further investigation towards clinical application.

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Section: Discussionmentioning

confidence: 99%

ARA290, a non-erythropoietic EPO derivative, attenuates renal ischemia/reperfusion injury

et al. 2013

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“…We have used a well-characterized rat model of HS to investigate the early development of the renal and glomerular dysfunction, and liver and neuromuscular injury associated with severe hemorrhage and resuscitation (Nandra et al, 2012; Patel et al, 2011). Having discovered that EPO pre-treatment does indeed attenuate the organ injury and dysfunction induced by HS, we investigated the potential mechanism(s) behind this protective effect by evaluating the ability of EPO to mobilize EPCs and its effects on the activation of various cellular signaling pathways [in particular phosphorylation of Akt on Ser473, phosphorylation of glycogen synthase kinase-3β (GSK-3β) on Ser9, phosphorylation of eNOS on Ser1177 and activation of nuclear factor-κB (NF-κB, measured as nuclear translocation of the p65 subunit)].…”

Section: Introductionmentioning

confidence: 99%

Pharmacological preconditioning with erythropoietin attenuates the organ injury and dysfunction induced in a rat model of hemorrhagic shock

Nandra

Collino

Rogazzo

et al. 2013

Disease Models &Amp; Mechanisms

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SUMMARYPre-treatment with erythropoietin (EPO) has been demonstrated to exert tissue-protective effects against ‘ischemia-reperfusion’-type injuries. This protection might be mediated by mobilization of bone marrow endothelial progenitor cells (EPCs), which are thought to secrete paracrine factors. These effects could be exploited to protect against tissue injury induced in cases where hemorrhage is foreseeable, for example, prior to major surgery. Here, we investigate the effects of EPO pre-treatment on the organ injury and dysfunction induced by hemorrhagic shock (HS). Recombinant human EPO (1000 IU/kg/day i.p.) was administered to rats for 3 days. Rats were subjected to HS on day 4 (pre-treatment protocol). Mean arterial pressure was reduced to 35±5 mmHg for 90 minutes, followed by resuscitation with 20 ml/kg Ringer’s lactate for 10 minutes and 50% of the shed blood for 50 minutes. Rats were sacrificed 4 hours after the onset of resuscitation. EPC (CD34+/flk-1+ cell) mobilization was measured following the 3-day pre-treatment with EPO and was significantly increased compared with rats pre-treated with phosphate-buffered saline. EPO pre-treatment significantly attenuated organ injury and dysfunction (renal, hepatic and neuromuscular) caused by HS. In livers from rats subjected to HS, EPO enhanced the phosphorylation of Akt (activation), glycogen synthase kinase-3β (GSK-3β; inhibition) and endothelial nitric oxide synthase (eNOS; activation). In the liver, HS also caused an increase in nuclear translocation of p65 (activation of NF-κB), which was attenuated by EPO. This data suggests that repetitive dosing with EPO prior to injury might protect against the organ injury and dysfunction induced by HS, by a mechanism that might involve mobilization of CD34+/flk-1+ cells, resulting in the activation of the Akt-eNOS survival pathway and inhibition of activation of GSK-3β and NF-κB.

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“…Modifying EPO molecules to enhance their beneficial effects and reduce negative side effects will help to expand the scope for application of EPO therapy. However, it is still far from becoming part of routine clinical practice 72 …”

Section: Pharmacologic Interventionmentioning

confidence: 99%

“…However, it is still far from becoming part of routine clinical practice. 72 It is also relevant to discuss manipulation of the seeded cells using gene transfection. Nanotechnology may help to modify the basic structure of the scaffold.…”

Section: Epomentioning

confidence: 99%

Tissue-Engineered Airway: A Regenerative Solution

Jungebluth

Moll

Baiguera

et al. 2011

Clin Pharmacol Ther

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The use of synthetic degradable or permanent polymers and biomaterials has not yet helped to achieve successful clinical whole-airway replacement. A novel, clinically successful approach involves tissue engineering (TE) replacement using three-dimensional biologic scaffolds composed of allogeneic extracellular scaffolds derived from nonautologous sources and recellularized with autologous stem cells or differentiated cells. In this paper, we discuss this novel approach and review information that can lead to a better understanding of stem cell recruitment and/or mobilization and site-specific tissue protection, which can be pharmacologically boosted in humans.

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A Nonerythropoietic Peptide that Mimics the 3D Structure of Erythropoietin Reduces Organ Injury/Dysfunction and Inflammation in Experimental Hemorrhagic Shock

Cited by 29 publications

References 54 publications

ARA290, a non-erythropoietic EPO derivative, attenuates renal ischemia/reperfusion injury

ARA290, a non-erythropoietic EPO derivative, attenuates renal ischemia/reperfusion injury

Pharmacological preconditioning with erythropoietin attenuates the organ injury and dysfunction induced in a rat model of hemorrhagic shock

Tissue-Engineered Airway: A Regenerative Solution

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