Erythropoietin reduces the development of nonseptic shock induced by zymosan in mice*

Cuzzocrea, Salvatore; Paola, Rosanna Di; Mazzon, Emanuela; Patel, Nimesh S. A.; Genovese, Tiziana; Muià, Carmelo; Crisafulli, Concetta; Caputi, Achille P.; Thiemermann, Christoph

doi:10.1097/01.ccm.0000207346.56477.e8

Cited by 40 publications

(47 citation statements)

References 55 publications

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“…More recently, studies have indicated that EPO has cytoprotective effects in experimental models of inflammation and sepsis. In a murine model of zymosan-induced inflammation and organ failure, treatment with EPO attenuated lung, liver, and pancreatic injury; renal dysfunction; and mortality (15). Pretreatment with EPO before LPS administration in a rat model of lung injury attenuated histological lung injury and edema, and …”

Section: Discussionmentioning

confidence: 99%

“…EPO, a hematopoietic growth factor with antiapoptotic properties, has been shown to have cytoprotective effects in various organs and tissues (14,15,17). We previously demonstrated that EPO attenuates splenic and thymic apoptosis in an endotoxic sepsis model (18).…”

Section: Discussionmentioning

confidence: 99%

“…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)(15)(16)(17). We previously demonstrated that EPO decreases lipopolysaccharide (LPS)-induced thymic and splenic apoptosis (18).…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

et al. 2013

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“…Results from these studies are conflicting and appear dependent on variables in experimental conditions such as the inflammatory process under investigation (sepsis, infectious, ischemia-reperfusion), EPO dose level, and timing of EPO delivery. Anti-inflammatory (Cuzzocrea et al 2006;Aoshiba et al 2009), proinflammatory (Wu et al 2010), and a lack of immune-modulating effects (Solling et al 2011) have been reported. The increased neutrophils (AMG 114 high-and low-dose groups) and fibrinogen (high-dose group only) at 6 and/or 24 hr in the AMG 114 high-and low-dose groups, respectively, are features of an acute inflammatory response.…”

Section: Discussionmentioning

confidence: 99%

Cytokines Associated with Increased Erythropoiesis in Sprague-Dawley Rats Administered a Novel Hyperglycosylated Analog of Recombinant Human Erythropoietin

Andrews

Hamadeh

et al. 2013

Toxicol Pathol

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We previously reported an increased incidence of thrombotic toxicities in Sprague-Dawley rats administered the highest dose level of a hyperglycosylated analog of recombinant human erythropoietin (AMG 114) for 1 month as not solely dependent on high hematocrit (HCT). Thereafter, we identified increased erythropoiesis as a prothrombotic risk factor increased in the AMG 114 high-dose group with thrombotic toxicities, compared to a low-dose group with no toxicities but similar HCT. Here, we identified pleiotropic cytokines as prothrombotic factors associated with AMG 114 dose level. Before a high HCT was achieved, rats in the AMG 114 high, but not the low-dose group, had imbalanced hemostasis (increased von Willebrand factor and prothrombin time, decreased antithrombin III) coexistent with cytokines implicated in thrombosis: monocyte chemotactic protein 1 (MCP-1), MCP-3, tissue inhibitor of metalloproteinases 1, macrophage inhibitory protein-2, oncostatin M, T-cell-specific protein, stem cell factor, vascular endothelial growth factor, and interleukin-11. While no unique pathway to erythropoiesis stimulating agent-related thrombosis was identified, cytokines associated with increased erythropoiesis contributed to a prothrombotic intravascular environment in the AMG 114 highdose group, but not in lower dose groups with a similar high HCT.

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“…Zimosan, akut peritonit, septik olmayan şok ve artrit gibi enflamatuvar hastalıkları tetikleyen, bakteriyel ve endotoksik olmayan bir moleküldür (11)(12)(13)(14).…”

Section: Zimosanın Patofizyolojik Olaylardaki Rolüunclassified

Signal Transduction of Zymosan and Spleen Tyrosine Kinase

Ünsal¹,

Temiz²,

Tunçtan³

et al. 2014

MUSBED

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Zimosan sinyal iletisi ve dalak tirozin kinazıZimosan, Saccharomyces cerevisiae'nin hücre duvarından elde edilen, polisakkarit zincirlerinden oluşan bir bileşendir. Zimosan, başlıca 1,3-β-glukan, 1,6-β-glukan ve α-mannan gibi çapraz bağlı polisakkaritlerden oluşmaktadır. Zimosan, fungal sepsis, septik olmayan şok, çoklu organ yetmezliği, akut peritonit, irritabl bağırsak sendromu gibi enflamatuvar hastalıkların patojenezinde rol oynamakta ve ilgili deneysel modellerde kullanılmaktadır. Zimosanın monosit, makrofaj ve dendritik hücreler gibi immün sistem hücrelerindeki etkilerine toll-like receptor 2, dektin-1, mannoz ve kompleman reseptörleri gibi çeşitli reseptörler aracılık etmektedir. Dalak tirozin kinazı (Dtk), 72 kDa ağırlığında reseptör ile kenetli olmayan bir intraselüler tirozin kinazdır. Dtk'nin, mast hücreleri, nötrofiller, makrofajlar ve trombositler gibi tüm hematopoetik hücrelerde ve fibroblastlar, epitel, sinir ve damar endotel hücreleri gibi hematopoetik olmayan hücrelerde eksprese edildiği gösterilmiştir. Dtk, zimosanın dektin-1 reseptörü aracılığıyla oluşturduğu hücresel yanıtlara aracılık eden önemli bir kinazdır. Bu derlemede, zimosan sinyal iletisinde Dtk'nin rolü değerlendirilmiştir. Anahtar sözcükler: Zimosan, Dalak tirozin kinazı, dektin-1, enflamasyon ABS TRACT Signal transduction of zymosan and spleen tyrosine kinaseZymosan is a component produced by polysaccharide which is obtained from cell wall of Saccharomyces cerevisiae. Zymosan consists of crosslinked polysaccharides such as 1,3-β glucan, 1,6-β glucan, and α-mannan. Zymosan plays a role in inflammmatory diseases such as fungal sepsis, non-septic shock, multiple organ dysfunction syndrome, acute peritonitis, irritable bowel syndrome and it is used in related experimental models. Toll-like receptor 2, dectin-1, mannose, and compleman receptors mediate zymosan's effects on immune system cells such as monocytes, macrophages, and dendritic cells. Spleen tyrosine kinase (Syk) is a cytosolic, intracellular, 72-kDa protein tyrosine kinase. It is demonstrated that Syk is expressed in hematopoietic cells such as mast cells, neutrophils, macrophages, B cells, leukocytes, and platelets and in non-hematopoietic cells such as epithelial, fibroblast, neuronal cells, and vascular endothelial cells. Spleen tyrosine kinase is a critical kinase that mediates cellular responses through dectin-1 receptor by zymosan. In this review, the role of syk in is evaluated in the signal transduction of zymosan.

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Erythropoietin reduces the development of nonseptic shock induced by zymosan in mice*

Abstract: This study provides evidence, for the first time, that erythropoietin attenuates the degree of zymosan-induced nonseptic shock in mice.

Cited by 40 publications

References 55 publications

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

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

Cytokines Associated with Increased Erythropoiesis in Sprague-Dawley Rats Administered a Novel Hyperglycosylated Analog of Recombinant Human Erythropoietin

Signal Transduction of Zymosan and Spleen Tyrosine Kinase

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