Erythropoietin and its derivative protect the intestine from severe ischemia/reperfusion injury in the rat

Mori, Satoshi; Sawada, Tokihiko; Okada, Toshie; Kubota, Keiichi

doi:10.1016/j.surg.2007.12.013

Cited by 50 publications

(42 citation statements)

References 41 publications

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“…This indicates that reduction of apoptotic cell death mediated by EPO may account for some protection that is not dependent on microvascular blood flow. This observation is in line with EPO administration that reduced apoptotic cell death and recovery of the impaired microcirculation following ischemia-reperfusion injury of the intestine, 38 liver 36 and testes. 39 This indicates that a reduced apoptotic cell death contributing to final tissue survival is most probably dependent on ischemia followed by reperfusion.…”

Section: Epo Enos Ischemic Damage and Skin F Rezaeian Et Alsupporting

confidence: 81%

Erythropoietin-induced upregulation of endothelial nitric oxide synthase but not vascular endothelial growth factor prevents musculocutaneous tissue from ischemic damage

Rezaeian

Wettstein

Egger

et al. 2010

Laboratory Investigation

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Recent findings have attested the protective effects of erythropoietin (EPO) in ischemically challenged organs. We therefore aimed at elaborating the underlying mechanism of EPO-mediated protection in musculocutaneous tissue undergoing persistent ischemia after acute injury. Mice were assigned to five experimental groups equipped with a randomly perfused flap fixed in a dorsal skinfold chamber, whereas the sixth group did not undergo flap preparation: EPO, L-Name, EPO and L-Name, EPO and bevacizumab, untreated flap, and nonischemic chamber (control). Intravital fluorescence microscopic analysis of microhemodynamics, apoptotic cell death, macromolecular leakage and angiogenesis was carried out over a 10-day period. Further, immunohistochemical analysis was used to study the protein expression of endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF). Increased expression of eNOS in EPO-administered mice correlated with significant arteriolar dilation and thus increased blood flow resulting in a maintained functional capillary density (FCD) at day 10. In addition, EPO induced a VEGF upregulation, which was associated with newly formed capillaries. In addition, EPO was able to reduce ischemia-induced apoptotic cell death and finally to significantly reduce flap necrosis. In contrast, coadministration of L-Name abolished EPO-mediated tissue protection by abrogating the dilatory effect resulting in reduced FCD and tissue survival, without counteracting angiogenesis and apoptotic cell death, whereas additional administration of bevacizumab did not influence the beneficial effect of EPO on flap survival despite abrogating angiogenesis. Macromolecular leakage was found to be increased in all treatment groups. This study shows that EPO administration prevents musculocutaneous tissue from ischemic necrosis as a consequence of an eNOS-dependent arteriolar hyperperfusion maintaining capillary perfusion, thus representing a promising approach to pharmacologically protect ischemically challenged tissue.

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Section: Epo Enos Ischemic Damage and Skin F Rezaeian Et Alsupporting

confidence: 81%

Erythropoietin-induced upregulation of endothelial nitric oxide synthase but not vascular endothelial growth factor prevents musculocutaneous tissue from ischemic damage

Rezaeian

Wettstein

Egger

et al. 2010

Laboratory Investigation

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“…In models of ischemia-reperfusion injury, protective effects of EPO may be mediated by the inhibition of several proinflammatory cytokines, including IL-6 and tumor necrosis factor-α (TNF-α) (24,29). Although in our study animals in the EPO group had slightly lower IL-6 and IL-10 cytokine levels than control animals, we were not able to show a statistically significant decrease.…”

Section: Erythropoietin In Experimental Sepsiscontrasting

confidence: 75%

“…Antiapoptotic and tissue protective effects of EPO have been demonstrated most vigorously in models of ischemia-reperfusion injury affecting the brain, intestine, heart, and kidney, among other organs and tissues (14,(24)(25)(26). More recently, studies have indicated that EPO has cytoprotective effects in experimental models of inflammation and sepsis.…”

Section: Discussionmentioning

confidence: 99%

Erythropoietin prevents lymphoid apoptosis but has no effect on survival in experimental sepsis

et al. 2013

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Background: Lymphoid apoptosis in sepsis is associated with poor outcome, and prevention of apoptosis frequently improves survival in experimental models of sepsis. Recently, erythropoietin (EPO) was shown to protect against lipopolysaccharide (LPS)-induced mortality. As cecal ligation and puncture (CLP) is a clinically more relevant model of sepsis, we evaluated the effect of EPO on CLP-induced lymphoid tissue apoptosis and mortality. Methods: Young Wistar rats were subjected to polymicrobial sepsis by CLP. EPO (5,000 U/kg intraperitoneal) was administered 30 min before CLP and then 1 and 4 h after CLP. Spleen, thymus, and small intestine were harvested at 24 h and assessed for apoptosis by terminal deoxynucleotidyl transferase nick-end labeling (TUNEL) and caspase-3 staining. A separate group of animals was followed up for mortality. results: Splenic, thymic, and intestinal apoptosis was increased after CLP; administration of EPO significantly decreased apoptosis as determined by TUNEL and caspase-3 staining. Final survival in the CLP mortality study was 30% in both saline and EPO groups. conclusion: Our results provide the first evidence that EPO attenuates lymphoid apoptosis in the CLP model of sepsis. However, EPO is not associated with a survival benefit in the CLP model of sepsis. s epsis can be described as the systemic maladaptive response of the body to invasion by pathogenic microorganisms (1). It is an important cause of morbidity and mortality in children and adults worldwide. Patients with sepsis often present with evidence of infection, circulatory, and respiratory failure. This presentation is usually caused by an initial, severe proinflammatory response. If appropriate and timely treatment can be instituted, patients may survive this stage; however, an antiinflammatory response frequently follows the proinflammatory phase (2).Apoptosis has been implicated in the development of the anti-inflammatory phase during sepsis (3). Several studies have demonstrated increased lymphocyte apoptosis in animals and humans with sepsis and its relation to poor outcome (2,4-6). Although initial findings were in adults, lymphopenia and apoptosis-associated depletion of lymphoid organs also have a role in sepsis-related death in critically ill children and neonates (7,8).Uptake of apoptotic cells by phagocytic cells leads to production of anti-inflammatory cytokines or anergy, whereas uptake of necrotic cells causes secretion of proinflammatory cytokines. Therefore, in contrast to necrosis, apoptotic cell death does not produce inflammation but rather an immunosuppressive state (9). The importance of apoptosis in sepsis has been revealed by multiple experimental studies that demonstrated that prevention of lymphocyte apoptosis increases survival (10-13).Among the candidates for a therapeutic approach is erythropoietin (EPO), a hematopoietic growth factor shown to have antiapoptotic and cytoprotective effects in both animal and human models of hypoxia-ischemia (14-17). We previously demonstrated that EPO decreases ...

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“…For example, both asialoEPO and a small peptide mimic of EPO (pyroglutamate helix B surface peptide [pHBSP] [62]) have plasma half-lives of only ~2 min. Yet both are highly effective in preventing injury in a wide range of neurological and other acute injuries after only a single parenteral dose (32,(64)(65)(66).…”

Section: Development Of Tissue-protective Receptor-specific Ligandsmentioning

confidence: 99%

The Receptor That Tames the Innate Immune Response

Brines

Cerami

2011

Mol Med

115

101

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Erythropoietin and its derivative protect the intestine from severe ischemia/reperfusion injury in the rat

Cited by 50 publications

References 41 publications

Erythropoietin-induced upregulation of endothelial nitric oxide synthase but not vascular endothelial growth factor prevents musculocutaneous tissue from ischemic damage

Erythropoietin-induced upregulation of endothelial nitric oxide synthase but not vascular endothelial growth factor prevents musculocutaneous tissue from ischemic damage

Erythropoietin prevents lymphoid apoptosis but has no effect on survival in experimental sepsis

The Receptor That Tames the Innate Immune Response

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