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Salvatore Cuzzocrea - One of the best experts on this subject based on the ideXlab platform.
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Effect of NADPH-oxidase inhibitors in the experimental model of Zymosan-induced shock in mice
Free radical research, 2011Co-Authors: Daniela Impellizzeri, Rosanna Di Paola, Emanuela Mazzon, Placido Bramanti, Irene Paterniti, Salvatore CuzzocreaAbstract:AbstractThe aim of this study was to investigate the effects of NADPH-oxidase inhibitors, in a mouse model of Zymosan. Zymosan-induced shock was induced in mice by administration of Zymosan (500 mg/kg, i.p.). The pharmacological treatment was the administration of apocynin (5 mg/kg 10% DMSO i.p.) and diphenylene iodonium chloride (DPI) (1 mg/kg i.v.) 1 h and 6 h after Zymosan administration. MOF and systemic inflammation in mice was assessed 18 h after administration of Zymosan. NADPH-oxidase inhibitors caused a significant reduction of the (1) peritoneal exudate formation, (2) neutrophil infiltration, (3) multiple organ dysfunction syndrome, (4) nitrotyrosine, (5) poly (ADP-ribose) (PAR), (6) cytokine formation, (7) adhesion molecule expression, (8) nuclear factor (NF-κB) expression and (9) apoptosis induced by Zymosan. Moreover, NADPH-oxidase inhibitors treatment significantly reduced the systemic toxicity, the loss in body weight and the mortality caused by Zymosan. This study has shown that NADPH-oxid...
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Fumonisin b1 reduces the development of multiple organ failure induced by Zymosan in mice.
Shock (Augusta Ga.), 2009Co-Authors: Salvatore Cuzzocrea, Rosanna Di Paola, Emanuela Mazzon, Tiziana Genovese, Concetta Crisafulli, Emanuela Esposito, Placido Bramanti, Daniela SalveminiAbstract:Ceramide is a major proapoptotic mediator released in response to numerous stimuli, including oxidative stress and cytokines. The role of ceramide in the pathophysiology of inflammation is just emerging, and the potential relevance of this pathway in nonseptic shock is not known. The aim of this study was to investigate the effects of fumonisin B1 (FB1), a specific inhibitor of ceramide synthase, on the development of nonseptic shock in mice caused by Zymosan. CD1 mice received either Zymosan (500 mg/kg, administered i.p. as a suspension in saline) or vehicle (0.25 mL per mouse saline). Fumonisin B1 (3 mg/kg, i.p.) was administered 1 and 6 h after Zymosan administration. Organ failure and systemic inflammation in mice were assessed 18 h after administration of Zymosan and/or FB1. Treatment of mice with FB1 attenuated peritoneal exudate formation and the migration of polymorphonuclear cells caused by Zymosan. Fumonisin B1 also attenuated plasma markers of lung, liver and pancreatic injury, and renal dysfunction caused by Zymosan and the increase in myeloperoxidase activity in the intestine caused by Zymosan. Immunohistochemical analyses for the presence of ceramide and nitrotyrosine revealed positive staining in intestinal tissue obtained from Zymosan-injected mice. The degree of staining for ceramide and nitrotyrosine was markedly reduced in tissue sections obtained from Zymosan-injected mice that had received FB1. In addition, administration of Zymosan caused a severe illness in the mice characterized by a systemic toxicity, significant loss of body weight, and 80% mortality within 12 days. Treatment with FB1 significantly reduced systemic toxicity, weight loss, and mortality caused by Zymosan. This study provides evidence that FB1 attenuates the degree of Zymosan-induced nonseptic shock in mice.
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Erythropoietin reduces the development of nonseptic shock induced by Zymosan in mice.
Critical care medicine, 2006Co-Authors: Salvatore Cuzzocrea, Rosanna Di Paola, Emanuela Mazzon, Nimesh S. A. Patel, Tiziana Genovese, Carmelo Muià, Concetta Crisafulli, Achille P. Caputi, Christoph ThiemermannAbstract:Objective: Erythropoietin is a potent stimulator of erythroid progenitor cells, and its expression is enhanced by hypoxia. In the present study, we investigated the effects of erythropoietin (1000 IU/kg subcutaneously) on the development of nonseptic shock caused by Zymosan. Design: Prospective, randomized study. Setting: University-based research laboratory. Subjects: Male CD mice. Interventions: Mice received either intraperitoneally Zymosan (500 mg/kg, administered intraperitoneally as a suspension in saline) or vehicle (0.25 mL/mouse saline). Erythropoietin was administered at the dose of 1000 IU/kg subcutaneously, 1 and 6 hrs after Zymosan administration. Organ failure and systemic inflammation in mice was assessed 18 hrs after administration of Zymosan and/or erythropoietin. Measurements and Main Results: Treatment of mice with erythropoietin (1000 IU/kg subcutaneously, 1 and 6 hrs after Zymosan administration) attenuated the peritoneal exudation and the migration of polymorphonuclear cells caused by Zymosan. Erythropoietin also attenuated the lung, liver, and pancreatic injury and renal dysfunction caused by Zymosan as well as the increase in myeloperoxidase activity caused by Zymosan in the lung and intestine. Immunohistochemical analysis for nitrotyrosine and poly(ADP-ribose) revealed positive staining in lung and intestine tissues obtained from Zymosan-treated mice. The degree of staining for nitrotyrosine and poly(ADP-ribose) was markedly reduced in tissue sections obtained from Zymosan-treated mice, which received erythropoietin. In addition, administration of Zymosan caused severe illness in the mice characterized by a systemic toxicity, significant loss of body weight, and a 70% mortality rate at the end of observation period (7 days). Treatment with erythropoietin significantly reduced the development of systemic toxicity, the loss in body weight, and the mortality caused by Zymosan. Conclusions: This study provides evidence, for the first time, that erythropoietin attenuates the degree of Zymosan-induced nonseptic shock in mice.
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Role of 5-lipoxygenase in the multiple organ failure induced by Zymosan
Intensive Care Medicine, 2004Co-Authors: Salvatore Cuzzocrea, Rosanna Di Paola, Tiziana Genovese, Ivana Serraino, Laura Dugo, Antonietta Rossi, Domenico Britti, Giuseppe Sciarra, Angelina De Sarro, Achille P. CaputiAbstract:Objective This study investigated the role of 5-lipoxygenase in the pathogenesis of multiple organ failure (MOF) induced by Zymosan. Design Male mice with a targeted disruption of the 5-lipoxygenase gene (5-LOKO) and littermate wild-type (WT) controls (5-LOWT) were used to evaluate the role of 5-lipoxygenase (5-LO) in the pathogenesis of MOF. Setting University research laboratory. Interventions and measurements MOF was induced by peritoneal injection of Zymosan (500 mg/kg i.p. as a suspension in saline) in 5-LOWT and in 5-LOKO mice. MOF was assessed 18 h after administration of Zymosan and monitored for 12 days (for loss of body weight and mortality). Results A severe inflammatory process induced by Zymosan administration in WT mice coincided with the damage of lung and small intestine, as assessed by histological examination. Myeloperoxidase activity indicative of neutrophil infiltration and lipid peroxidation were significantly increased in Zymosan-treated WT mice. Zymosan in the WT mice also induced a significant increase in the plasma level of nitrite/nitrate. Immunohistochemical examination demonstrated a marked increase in the immunoreactivity to ICAM-1 and P-selectin in the lung and intestine of Zymosan-treated WT mice. In contrast, the degree of (a) peritoneal inflammation and tissue injury, (b) upregulation/expression of P-selectin and ICAM-1, and (c) neutrophil infiltration were markedly reduced in intestine and lung tissue obtained from Zymosan-treated 5-LO deficient mice. Zymosan-treated 5-LOKO showed also a significantly decreased mortality. Conclusions These findings clearly demonstrate that 5-LO exerts a role in Zymosan-induced nonseptic shock.
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rosiglitazone a ligand of the peroxisome proliferator activated receptor γ reduces the development of nonseptic shock induced by Zymosan in mice
Critical Care Medicine, 2004Co-Authors: Salvatore Cuzzocrea, Rosanna Di Paola, Nimesh S. A. Patel, Tiziana Genovese, Laura Dugo, Francesco Fulia, Prabal K. Chatterjee, Barbara Pisano, Angela Ianaro, Elisabetta CuzzocreaAbstract:OBJECTIVE Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors that are related to retinoid, steroid, and thyroid hormone receptors. The PPAR-gamma receptor subtype appears to play a pivotal role in the regulation of cellular proliferation and inflammation. Rosiglitazone (Avandia) is a PPAR-gamma agonist (the most potent PPAR-gamma agonist of the thiazolidinedione antidiabetics). In the present study, we investigated the effects of rosiglitazone on the development of nonseptic shock caused by Zymosan in mice. DESIGN Experimental study. SETTING University laboratory. SUBJECTS Male CD mice. INTERVENTIONS We investigated the effects of rosiglitazone (3 mg/kg) on the development of nonseptic shock caused by Zymosan (500 mg/kg, administered intraperitoneally as a suspension in saline) in mice. MEASUREMENTS AND MAIN RESULTS Organ failure and systemic inflammation in rats were assessed 18 hrs after administration of Zymosan and/or rosiglitazone and monitored for 12 days (for loss of body weight and mortality rate). Treatment of mice with rosiglitazone (3 mg/kg intraperitoneally, 1 and 6 hrs after Zymosan) attenuated the peritoneal exudation and the migration of polymorphonuclear cells caused by Zymosan. Rosiglitazone also attenuated the lung, liver, and pancreatic injury and renal dysfunction caused by Zymosan as well as the increase in myeloperoxidase activity and malondialdehyde concentrations caused by Zymosan in the lung and intestine. Immunohistochemical analysis for inducible nitric oxide synthase, nitrotyrosine, and poly(adenosine diphosphate-ribose) revealed positive staining in lung and intestine tissues obtained from Zymosan-treated mice. The degree of staining for nitrotyrosine, inducible nitric oxide synthase, and poly(adenosine diphosphate-ribose) was markedly reduced in tissue sections obtained from Zymosan-treated mice that received rosiglitazone. To elucidate whether the protective effects of rosiglitazone are related to activation of the PPAR-gamma receptor, we also investigated the effect of a PPAR-gamma antagonist, GW 9662, on the protective effects of rosiglitazone. GW 9662 (1 mg/kg administered intraperitoneally 30 mins before treatment with rosiglitazone) significantly antagonized the effect of the PPAR-gamma agonist and thus abolished the protective effect. CONCLUSIONS This study provides evidence, for the first time, that rosiglitazone attenuates the degree of Zymosan-induced nonseptic shock in mice.
Nathalie Busso - One of the best experts on this subject based on the ideXlab platform.
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TLR2 modulates inflammation in Zymosan-induced arthritis in mice.
Arthritis research & therapy, 2005Co-Authors: Matthias Frasnelli, David Tarussio, Veronique Chobaz-péclat, Nathalie BussoAbstract:The interplay between the innate and acquired immune systems in chronic inflammation is not well documented. We have investigated the mechanisms of inflammation in murine Zymosan-induced arthritis (ZIA) in the light of recent data on the roles of Toll-like receptor 2 (TLR2) and Dectin-1 in the activation of monocyte/macrophages by Zymosan. The severity of inflammation, joint histology, lymphocyte proliferation and antibody production in response to Zymosan were analyzed in mice deficient in TLR2 and complement C3, and the effects of Dectin-1 inhibition by laminarin were studied. In comparison with wild-type animals, TLR2-deficient mice showed a significant decrease in the early (day 1) and late phases (day 24) of joint inflammation. C3-deficient mice showed no differences in technetium uptake or histological scoring. TLR2-deficient mice also showed a significant decrease in lymph node cell proliferation in response to Zymosan and a lower IgG antibody response to Zymosan at day 25 in comparison with wild-type controls, indicating that TLR2 signalling has a role in the development of acquired immune responses to Zymosan. Although laminarin, a soluble beta-glucan, was able to significantly inhibit Zymosan uptake by macrophages in vitro, it had no effect on ZIA in vivo. These results show that ZIA is more prolonged than was originally described and involves both the innate and acquired immune pathways. C3 does not seem to have a major role in this model of joint inflammation.
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TLR2 modulates inflammation in Zymosan-induced arthritis in mice
Arthritis Research & Therapy, 2005Co-Authors: Matthias Frasnelli, David Tarussio, Veronique Chobaz-péclat, Nathalie BussoAbstract:The interplay between the innate and acquired immune systems in chronic inflammation is not well documented. We have investigated the mechanisms of inflammation in murine Zymosan-induced arthritis (ZIA) in the light of recent data on the roles of Toll-like receptor 2 (TLR2) and Dectin-1 in the activation of monocyte/macrophages by Zymosan. The severity of inflammation, joint histology, lymphocyte proliferation and antibody production in response to Zymosan were analyzed in mice deficient in TLR2 and complement C3, and the effects of Dectin-1 inhibition by laminarin were studied. In comparison with wild-type animals, TLR2-deficient mice showed a significant decrease in the early (day 1) and late phases (day 24) of joint inflammation. C3-deficient mice showed no differences in technetium uptake or histological scoring. TLR2-deficient mice also showed a significant decrease in lymph node cell proliferation in response to Zymosan and a lower IgG antibody response to Zymosan at day 25 in comparison with wild-type controls, indicating that TLR2 signalling has a role in the development of acquired immune responses to Zymosan. Although laminarin, a soluble β-glucan, was able to significantly inhibit Zymosan uptake by macrophages in vitro, it had no effect on ZIA in vivo. These results show that ZIA is more prolonged than was originally described and involves both the innate and acquired immune pathways. C3 does not seem to have a major role in this model of joint inflammation.
John T. Berg - One of the best experts on this subject based on the ideXlab platform.
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Zymosan priming protects rats against pulmonary oxygen toxicity: characterization of the model.
Experimental biology and medicine (Maywood N.J.), 2010Co-Authors: John T. BergAbstract:This laboratory previously reported that Zymosan priming protects rats against pulmonary oxygen toxicity. That study used a standard priming protocol (3 daily intravenous injections [15 mg Zymosan/rat] with 2 days' rest) before hyperoxia. This study confirms that report and more fully characterizes the Zymosan priming model. Three studies were conducted to establish the (1) effects of dosage, (2) role of duration of rest period between injections and hyperoxia and (3) importance of injection number, on protection by Zymosan priming. Rats were exposed to >95% oxygen for 52 h or room air and acute lung injury was quantitated using standard methods. Lung injury decreased (P < 0.05 versus saline controls) in all groups of Zymosan-primed rats (3 daily intravenous injections [1-15 mg Zymosan/rat] with 2 days' rest before hyperoxia). Although the differences between Zymosan-primed groups were not statistically significant, protection (as indicated by decreasing mean values of measured parameters of lung injury) increased with dosage. A one-day rest after injections was sufficient to partially protect Zymosan-primed rats from hyperoxia (some measured parameters in the Zymosan-primed group differed significantly from comparable values in the Saline group), but full protection (all measured parameters within a group differed significantly from Saline values) was not produced until rats received two days' rest before hyperoxia. Finally, one or two Zymosan treatments produced partial protection against oxygen toxicity but three injections were needed to produce full protection. In conclusion, this study found that the standard priming protocol (3 Zymosan injections with 2 days' rest before hyperoxia) was the most effective in protecting rats against hyperoxia.
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Zymosan priming protects rats against pulmonary oxygen toxicity.
Inflammation research : official journal of the European Histamine Research Society ... [et al.], 2006Co-Authors: John T. BergAbstract:To determine whether Zymosan priming protects rats against oxygen toxicity. 37 rats were used with 6 treatment groups. 11 received Zymosan priming (3 daily i. v. injections with 15 mg Zymosan and 2 days rest) before 52 h exposure to either normobaric hyperoxia (ZP group, 5 rats) or air (ZPA group, 6 rats)]. Two other groups received saline (Saline group, 9 rats) or Zymosan by i. p. injection (Zip group, 6 rats) before hyperoxia. A fifth group received a non-priming (NP) treatment with Zymosan before hyperoxia (ZNP group, 6 rats, single i. v. injection) and a final group received no treatment (Air group, 5 rats). Pleural effusions and lung injury were then assessed. Saline, Zip or ZNP rats developed massive, proteinaceous pleural effusions indicative of oxygen toxicity while ZP rats did not (0.02 ± 0.01 ml). The ratios of effusion protein to plasma protein concentration and wet/dry lung weight were also significantly reduced in ZP rats following hyperoxia. Zymosan priming protects rats against pulmonary oxygen toxicity.
Achille P. Caputi - One of the best experts on this subject based on the ideXlab platform.
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Erythropoietin reduces the development of nonseptic shock induced by Zymosan in mice.
Critical care medicine, 2006Co-Authors: Salvatore Cuzzocrea, Rosanna Di Paola, Emanuela Mazzon, Nimesh S. A. Patel, Tiziana Genovese, Carmelo Muià, Concetta Crisafulli, Achille P. Caputi, Christoph ThiemermannAbstract:Objective: Erythropoietin is a potent stimulator of erythroid progenitor cells, and its expression is enhanced by hypoxia. In the present study, we investigated the effects of erythropoietin (1000 IU/kg subcutaneously) on the development of nonseptic shock caused by Zymosan. Design: Prospective, randomized study. Setting: University-based research laboratory. Subjects: Male CD mice. Interventions: Mice received either intraperitoneally Zymosan (500 mg/kg, administered intraperitoneally as a suspension in saline) or vehicle (0.25 mL/mouse saline). Erythropoietin was administered at the dose of 1000 IU/kg subcutaneously, 1 and 6 hrs after Zymosan administration. Organ failure and systemic inflammation in mice was assessed 18 hrs after administration of Zymosan and/or erythropoietin. Measurements and Main Results: Treatment of mice with erythropoietin (1000 IU/kg subcutaneously, 1 and 6 hrs after Zymosan administration) attenuated the peritoneal exudation and the migration of polymorphonuclear cells caused by Zymosan. Erythropoietin also attenuated the lung, liver, and pancreatic injury and renal dysfunction caused by Zymosan as well as the increase in myeloperoxidase activity caused by Zymosan in the lung and intestine. Immunohistochemical analysis for nitrotyrosine and poly(ADP-ribose) revealed positive staining in lung and intestine tissues obtained from Zymosan-treated mice. The degree of staining for nitrotyrosine and poly(ADP-ribose) was markedly reduced in tissue sections obtained from Zymosan-treated mice, which received erythropoietin. In addition, administration of Zymosan caused severe illness in the mice characterized by a systemic toxicity, significant loss of body weight, and a 70% mortality rate at the end of observation period (7 days). Treatment with erythropoietin significantly reduced the development of systemic toxicity, the loss in body weight, and the mortality caused by Zymosan. Conclusions: This study provides evidence, for the first time, that erythropoietin attenuates the degree of Zymosan-induced nonseptic shock in mice.
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Role of 5-lipoxygenase in the multiple organ failure induced by Zymosan
Intensive Care Medicine, 2004Co-Authors: Salvatore Cuzzocrea, Rosanna Di Paola, Tiziana Genovese, Ivana Serraino, Laura Dugo, Antonietta Rossi, Domenico Britti, Giuseppe Sciarra, Angelina De Sarro, Achille P. CaputiAbstract:Objective This study investigated the role of 5-lipoxygenase in the pathogenesis of multiple organ failure (MOF) induced by Zymosan. Design Male mice with a targeted disruption of the 5-lipoxygenase gene (5-LOKO) and littermate wild-type (WT) controls (5-LOWT) were used to evaluate the role of 5-lipoxygenase (5-LO) in the pathogenesis of MOF. Setting University research laboratory. Interventions and measurements MOF was induced by peritoneal injection of Zymosan (500 mg/kg i.p. as a suspension in saline) in 5-LOWT and in 5-LOKO mice. MOF was assessed 18 h after administration of Zymosan and monitored for 12 days (for loss of body weight and mortality). Results A severe inflammatory process induced by Zymosan administration in WT mice coincided with the damage of lung and small intestine, as assessed by histological examination. Myeloperoxidase activity indicative of neutrophil infiltration and lipid peroxidation were significantly increased in Zymosan-treated WT mice. Zymosan in the WT mice also induced a significant increase in the plasma level of nitrite/nitrate. Immunohistochemical examination demonstrated a marked increase in the immunoreactivity to ICAM-1 and P-selectin in the lung and intestine of Zymosan-treated WT mice. In contrast, the degree of (a) peritoneal inflammation and tissue injury, (b) upregulation/expression of P-selectin and ICAM-1, and (c) neutrophil infiltration were markedly reduced in intestine and lung tissue obtained from Zymosan-treated 5-LO deficient mice. Zymosan-treated 5-LOKO showed also a significantly decreased mortality. Conclusions These findings clearly demonstrate that 5-LO exerts a role in Zymosan-induced nonseptic shock.
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Protective effects of M40401, a selective superoxide dismutase mimetic, on Zymosan-induced nonseptic shock.
Critical care medicine, 2004Co-Authors: Salvatore Cuzzocrea, Rosanna Di Paola, Emanuela Mazzon, Tiziana Genovese, Achille P. Caputi, Ivana Serraino, Laura Dugo, Elisabetta Cuzzocrea, Francesco Fulia, Daniela SalveminiAbstract:Objective: Zymosan enhances formation of reactive oxygen species, which contributes to the pathophysiology of organ failure during nonseptic shock. Here we have investigated the effects of M40401, a new superoxide dismutase mimetic, on the organ failure associated with nonseptic shock caused by Zymosan in rats. Design: Experimental study. Setting: Laboratory. Subjects: Male Sprague-Dawley rats. Interventions: We investigated the effects of M40401 on the organ failure associated with nonseptic shock caused by Zymosan (500 mg/kg, administered intraperitoneally as a suspension in saline) in rats. Measurements and Main Results: Organ failure and systemic inflammation in rats were assessed 18 hrs after administration of Zymosan and/or M40401 and were monitored for 12 days (for loss of body weight and mortality). Treatment of rats with M40401 (10 mg/kg intraperitoneally, 1 and 6 hrs after Zymosan) attenuated the peritoneal exudation and the migration of polymorphonuclear cells caused by Zymosan. M40401 administration also attenuated the lung and intestinal injury (histology) as well as the increase in myeloperoxidase activity and malondialdehyde concentrations caused by Zymosan in lung and intestine. Immunohistochemical analysis for nitrotyrosine and for poly(adenosine 5'-diphosphateribose) revealed positive staining in lung and intestine from Zymosan-treated rats. The degree of staining for nitrotyrosine and poly(adenosine 5'-diphosphate-ribose) was markedly reduced in tissue sections obtained from Zymosan-treated rats administered with M40401. Conclusion: This study provides the first evidence that M40401 attenuates the degree of Zymosan-induced nonseptic shock in the rat.
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inducible nitric oxide synthase knockout mice exhibit resistance to the multiple organ failure induced by Zymosan
Shock, 2001Co-Authors: Salvatore Cuzzocrea, Emanuela Mazzon, Laura Dugo, Tommaso Centorrino, A. Barbera, Antonio Ciccolo, Maria Teresa Fonti, Achille P. CaputiAbstract:ABSTRACT— In the present study, by comparing the responses in wild-type mice (+/+) and mice lacking (−/−) the inducible (or type 2) nitric oxide synthase (iNOS), we investigated the role played by iNOS in the development of non-septic shock. A severe inflammatory response characterized by peritoneal exudation, high peritoneal levels of nitrate/nitrite, and leukocyte infiltration into peritoneal exudate was induced by Zymosan administration in iNOS +/+ mice. This inflammatory process coincided with the damage of lung, liver, and small intestine, as assessed by histological examination. Lung, small intestine, and liver myeloperoxidase (MPO) activity, indicative of neutrophil infiltration and lipid peroxidation, were significantly increased in Zymosan-treated iNOS +/+ mice. Peritoneal administration of Zymosan in the iNOS +/+ mice induced also a significant increase in the plasma levels of nitrite/nitrate and in the levels of peroxynitrite at 18 h after Zymosan challenge. Immunohistochemical examination demonstrated a marked increase in the immunoreactivity to nitrotyrosine and to poly ADP-ribose synthetase (PARS) in the lung, liver, and intestine of Zymosan-treated iNOS +/+ mice. The intensity and degree of nitrotyrosine and PARS were markedly reduced in tissue section from Zymosan-iNOS −/− mice. Zymosan-treated iNOS −/− mice showed a significantly decreased mortality and inhibition of the development of peritonitis. In addition, iNOS −/− mice showed a significant protection on the development of organ failure since tissue injury and MPO were reduced in lung, small intestine, and liver. Furthermore, a significant reduction of suppression of mitochondrial respiration, DNA strand breakage, and reduction of cellular levels of NAD† was observed in ex vivo macrophages harvested from the peritoneal cavity of iNOS −/− mice subjected to Zymosan-induced non-septic shock. In vivo treatment with aminoguanidine (300 mg/kg 1 and 6 h after Zymosan administration) significantly prevents the inflammatory process. Taken together, our results clearly demonstrate that iNOS plays an important role in Zymosaninduced non-septic shock.
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Role of melatonin in reduction of lipid peroxidation and peroxynitrite formation in non-septic shock induced by Zymosan
Shock (Augusta Ga.), 1999Co-Authors: Gamal H. El-sokkary, Achille P. Caputi, Russel J. Reiter, Salvator Cuzzocrea, Abdel Fattah M.m. Hassanein, Dun Xian TanAbstract:Zymosan, a non-bacterial agent, causes inflammation by inducing the production of a variety of cytokines and pro-inflammatory mediators, wherein reactive oxygen species including nitric oxide and peroxynitrite are known to play a crucial role in the inflammatory process. The current study was designed to investigate the protective effect of melatonin, a radical scavenger and antioxidant, on non-septic shock induced by Zymosan in the rat. Four groups of rats (controls, melatonin-injected [5 mg/kg x 6], Zymosan-injected [500 mg/kg], and Zymosan + melatonin) were used in this experiment. Thiobarbituric acid reactive substances (malondialdehyde [MDA] + 4-hydroxyalkenals [4-HDA]), as an index of lipid peroxidation, were measured in the liver, lung, small intestine (ileum), kidney and pancreas. Twenty-four hours after Zymosan administration, MDA + 4-HDA levels were significantly increased in the liver, lung, small intestine, and kidney while the increase in the pancreas was not statistically significant compared to levels in control rats. The percentage increases in lipid peroxidation products were 34.3%, 39.2%, 48.5%, 32.5%, and 17.4% for the liver, lung, small intestine, kidney, and pancreas, respectively. In animals given melatonin 30 minutes before Zymosan, and 5 more times after Zymosan (i.e., every 4 hours), the increase in MDA + 4-HDA levels was reduced in all organs studied. There was also a significant increase in the volume of peritoneal exudate in Zymosan-treated rats that was reduced when the Zymosan-shocked rats received melatonin. After Zymosan administration, immunohistochemical and histological examination demonstrated a marked increase in the immunoreactivity to nitrotyrosine, a specific "footprint" of peroxynitrite, and tissue damage in the liver, lung, and small intestine of Zymosan-shocked rats. Again, melatonin treatment reduced both nitrotyrosine immunoreactivity and tissue damage associated with Zymosan administration.
Rosanna Di Paola - One of the best experts on this subject based on the ideXlab platform.
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Effect of NADPH-oxidase inhibitors in the experimental model of Zymosan-induced shock in mice
Free radical research, 2011Co-Authors: Daniela Impellizzeri, Rosanna Di Paola, Emanuela Mazzon, Placido Bramanti, Irene Paterniti, Salvatore CuzzocreaAbstract:AbstractThe aim of this study was to investigate the effects of NADPH-oxidase inhibitors, in a mouse model of Zymosan. Zymosan-induced shock was induced in mice by administration of Zymosan (500 mg/kg, i.p.). The pharmacological treatment was the administration of apocynin (5 mg/kg 10% DMSO i.p.) and diphenylene iodonium chloride (DPI) (1 mg/kg i.v.) 1 h and 6 h after Zymosan administration. MOF and systemic inflammation in mice was assessed 18 h after administration of Zymosan. NADPH-oxidase inhibitors caused a significant reduction of the (1) peritoneal exudate formation, (2) neutrophil infiltration, (3) multiple organ dysfunction syndrome, (4) nitrotyrosine, (5) poly (ADP-ribose) (PAR), (6) cytokine formation, (7) adhesion molecule expression, (8) nuclear factor (NF-κB) expression and (9) apoptosis induced by Zymosan. Moreover, NADPH-oxidase inhibitors treatment significantly reduced the systemic toxicity, the loss in body weight and the mortality caused by Zymosan. This study has shown that NADPH-oxid...
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Fumonisin b1 reduces the development of multiple organ failure induced by Zymosan in mice.
Shock (Augusta Ga.), 2009Co-Authors: Salvatore Cuzzocrea, Rosanna Di Paola, Emanuela Mazzon, Tiziana Genovese, Concetta Crisafulli, Emanuela Esposito, Placido Bramanti, Daniela SalveminiAbstract:Ceramide is a major proapoptotic mediator released in response to numerous stimuli, including oxidative stress and cytokines. The role of ceramide in the pathophysiology of inflammation is just emerging, and the potential relevance of this pathway in nonseptic shock is not known. The aim of this study was to investigate the effects of fumonisin B1 (FB1), a specific inhibitor of ceramide synthase, on the development of nonseptic shock in mice caused by Zymosan. CD1 mice received either Zymosan (500 mg/kg, administered i.p. as a suspension in saline) or vehicle (0.25 mL per mouse saline). Fumonisin B1 (3 mg/kg, i.p.) was administered 1 and 6 h after Zymosan administration. Organ failure and systemic inflammation in mice were assessed 18 h after administration of Zymosan and/or FB1. Treatment of mice with FB1 attenuated peritoneal exudate formation and the migration of polymorphonuclear cells caused by Zymosan. Fumonisin B1 also attenuated plasma markers of lung, liver and pancreatic injury, and renal dysfunction caused by Zymosan and the increase in myeloperoxidase activity in the intestine caused by Zymosan. Immunohistochemical analyses for the presence of ceramide and nitrotyrosine revealed positive staining in intestinal tissue obtained from Zymosan-injected mice. The degree of staining for ceramide and nitrotyrosine was markedly reduced in tissue sections obtained from Zymosan-injected mice that had received FB1. In addition, administration of Zymosan caused a severe illness in the mice characterized by a systemic toxicity, significant loss of body weight, and 80% mortality within 12 days. Treatment with FB1 significantly reduced systemic toxicity, weight loss, and mortality caused by Zymosan. This study provides evidence that FB1 attenuates the degree of Zymosan-induced nonseptic shock in mice.
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Erythropoietin reduces the development of nonseptic shock induced by Zymosan in mice.
Critical care medicine, 2006Co-Authors: Salvatore Cuzzocrea, Rosanna Di Paola, Emanuela Mazzon, Nimesh S. A. Patel, Tiziana Genovese, Carmelo Muià, Concetta Crisafulli, Achille P. Caputi, Christoph ThiemermannAbstract:Objective: Erythropoietin is a potent stimulator of erythroid progenitor cells, and its expression is enhanced by hypoxia. In the present study, we investigated the effects of erythropoietin (1000 IU/kg subcutaneously) on the development of nonseptic shock caused by Zymosan. Design: Prospective, randomized study. Setting: University-based research laboratory. Subjects: Male CD mice. Interventions: Mice received either intraperitoneally Zymosan (500 mg/kg, administered intraperitoneally as a suspension in saline) or vehicle (0.25 mL/mouse saline). Erythropoietin was administered at the dose of 1000 IU/kg subcutaneously, 1 and 6 hrs after Zymosan administration. Organ failure and systemic inflammation in mice was assessed 18 hrs after administration of Zymosan and/or erythropoietin. Measurements and Main Results: Treatment of mice with erythropoietin (1000 IU/kg subcutaneously, 1 and 6 hrs after Zymosan administration) attenuated the peritoneal exudation and the migration of polymorphonuclear cells caused by Zymosan. Erythropoietin also attenuated the lung, liver, and pancreatic injury and renal dysfunction caused by Zymosan as well as the increase in myeloperoxidase activity caused by Zymosan in the lung and intestine. Immunohistochemical analysis for nitrotyrosine and poly(ADP-ribose) revealed positive staining in lung and intestine tissues obtained from Zymosan-treated mice. The degree of staining for nitrotyrosine and poly(ADP-ribose) was markedly reduced in tissue sections obtained from Zymosan-treated mice, which received erythropoietin. In addition, administration of Zymosan caused severe illness in the mice characterized by a systemic toxicity, significant loss of body weight, and a 70% mortality rate at the end of observation period (7 days). Treatment with erythropoietin significantly reduced the development of systemic toxicity, the loss in body weight, and the mortality caused by Zymosan. Conclusions: This study provides evidence, for the first time, that erythropoietin attenuates the degree of Zymosan-induced nonseptic shock in mice.
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GREEN TEA POLYPHENOL EXTRACT ATTENUATES Zymosan-INDUCED NON SEPTIC SHOCK IN MICE.
Shock (Augusta Ga.), 2006Co-Authors: Rosanna Di Paola, Emanuela Mazzon, Tiziana Genovese, Carmelo Muià, Concetta Crisafulli, Emanuela Esposito, Paolo Di Bella, Marta Menegazzi, Rosaria Meli, Hisanori SuzukiAbstract:Multiple-organ failure (MOF) is defined as the progressive deterioration in function which occurs in several organs or systems in patients with septic shock, multiple trauma, severe burns, or pancreatitis. In the present study, we have investigated the effects of Green Tea extract (GTE) on the development of general inflammation caused by Zymosan (500 mg/kg, administered i.p. as a suspension in saline) in mice. Organ failure and systemic inflammation in mice was assessed 18 hours after administration of Zymosan and/or GTE and monitored for 12 days (for loss of body weight and mortality). Treatment of mice with GTE (25 mg/kg i.p., 1 and 6 hours after Zymosan) attenuated the peritoneal exudation and the migration of polymorphonuclear cells (PMNs) caused by Zymosan, GTE also attenuated the lung, liver and pancreatic injury and renal dysfunction caused by Zymosan as well as the increase in myeloperoxidase (MPO) activity caused by Zymosan in the lung and intestine. Immunohistochemical analysis for inducible nitric oxide synthase (iNOS), nitrotyrosine and poly(ADP-ribose) (PAR) revealed positive staining in lung and intestine tissues obtained from Zymosan-treated mice. The degree of staining for nitrotyrosine, iNOS and PAR were markedly reduced in tissue sections obtained from Zymosan-treated mice, which received GTE. In conclusion this study provides evidence, for the first time, that GTE attenuates the degree of Zymosan induced generalized inflammation in mice.
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Role of 5-lipoxygenase in the multiple organ failure induced by Zymosan
Intensive Care Medicine, 2004Co-Authors: Salvatore Cuzzocrea, Rosanna Di Paola, Tiziana Genovese, Ivana Serraino, Laura Dugo, Antonietta Rossi, Domenico Britti, Giuseppe Sciarra, Angelina De Sarro, Achille P. CaputiAbstract:Objective This study investigated the role of 5-lipoxygenase in the pathogenesis of multiple organ failure (MOF) induced by Zymosan. Design Male mice with a targeted disruption of the 5-lipoxygenase gene (5-LOKO) and littermate wild-type (WT) controls (5-LOWT) were used to evaluate the role of 5-lipoxygenase (5-LO) in the pathogenesis of MOF. Setting University research laboratory. Interventions and measurements MOF was induced by peritoneal injection of Zymosan (500 mg/kg i.p. as a suspension in saline) in 5-LOWT and in 5-LOKO mice. MOF was assessed 18 h after administration of Zymosan and monitored for 12 days (for loss of body weight and mortality). Results A severe inflammatory process induced by Zymosan administration in WT mice coincided with the damage of lung and small intestine, as assessed by histological examination. Myeloperoxidase activity indicative of neutrophil infiltration and lipid peroxidation were significantly increased in Zymosan-treated WT mice. Zymosan in the WT mice also induced a significant increase in the plasma level of nitrite/nitrate. Immunohistochemical examination demonstrated a marked increase in the immunoreactivity to ICAM-1 and P-selectin in the lung and intestine of Zymosan-treated WT mice. In contrast, the degree of (a) peritoneal inflammation and tissue injury, (b) upregulation/expression of P-selectin and ICAM-1, and (c) neutrophil infiltration were markedly reduced in intestine and lung tissue obtained from Zymosan-treated 5-LO deficient mice. Zymosan-treated 5-LOKO showed also a significantly decreased mortality. Conclusions These findings clearly demonstrate that 5-LO exerts a role in Zymosan-induced nonseptic shock.
