Biomedical subjects

Salvatore Cuzzocrea

Publications and source records attributed to Salvatore Cuzzocrea.

At least 127 records · Page 7Linked to original sources

PubMed2004

EUK-134 reduces renal dysfunction and injury caused by oxidative and nitrosative stress of the kidney.

BACKGROUND/AIMS: Oxidative and nitrosative stress plays important roles in the pathogenesis of renal ischemia/reperfusion (I/R) injury. Here we investigate the effect of EUK-134, a synthetic superoxide dismutase and catalase mimetic, (i) on renal dysfunction and injury caused by I/R in vivo and (ii) on proximal tubular cell (PTC) injury and death caused by oxidative and nitrosative stress. METHODS: Rats, subjected to bilateral renal ischemia (45 min) followed by reperfusion (6 h), were administered EUK-134 (0.3 and 3 mg/kg, i.v.) prior to and during reperfusion, after which biochemical and histological indicators of renal dysfunction and injury were measured. The expression of poly(ADP-ribose) (PAR) and inducible nitric oxide (NO) synthase (iNOS) and nitrotyrosine formation were determined immunohistochemically and used as indicators of oxidative and nitrosative stress. Primary cultures of rat PTCs, isolated and cultured from the kidney cortex, were incubated with hydrogen peroxide (H2O2; 1 mM for 2 h) in the presence of increasing concentrations of EUK-134 (1-100 microM) after which PTC injury and death were measured. The effects of EUK-134 on serum levels of NO in rats subjected to renal I/R or on NO production by PTCs incubated with interferon-gamma (IFN-gamma, 100 IU/ml) and bacterial lipopolysaccharide (LPS, 10 microg/ml) in combination for 24 h were also measured. RESULTS: EUK-134 produced a significant reduction in renal dysfunction and injury caused by I/R. Specifically, serum creatinine levels, an indicator of renal dysfunction, were reduced from 227 +/- 11 (n = 12, I/R only) to 146 +/- 9 microM (n = 12, I/R +3 mg/kg EUK-134). Urinary N-acetyl-beta-D-glucosaminidase activity, an indicator of tubular damage, was reduced from 42 +/- 5 (n = 12, I/R only) to 22 +/- 3 IU/l (n = 12, I/R +3 mg/kg EUK-134). EUK-134 significantly reduced renal injury caused by oxidative stress in vivo (reduction in PAR formation), and in vitro EUK-134 reduced PTC injury and death caused by H2O2. However, EUK-134 also reduced nitrosative stress caused by I/R in vivo (reduction of iNOS expression and nitrotyrosine formation), which was reflected by a significant reduction in serum NO levels in rats subjected to renal I/R. Specifically, serum NO levels were reduced from 57 +/- 12 (n = 12, I/R only) to 23 +/- 3 mM (n = 12, I/R +3 mg/kg EUK-134). In vitro, EUK-134 significantly reduced NO production by PTCs incubated with IFN-gamma/LPS. CONCLUSION: We propose that EUK-134 reduces renal I/R injury not only via reduction of oxidative stress, but also by reducing nitrosative stress caused by renal I/R.

Animals↗

PubMed2004

Effect of methylguanidine in carrageenan-induced acute inflammation in the rats.

In vitro and in vivo studies have demonstrated that methylguanidine, an inhibitor of nitric oxide synthase (NOS), is also able to reduce tumour necrosis factor-alpha (TNF-alpha) release. In the present study, we evaluated the anti-inflammatory potential of methylguanidine treatment in two models of acute inflammation (carrageenan-induced paw edema and pleurisy) where oxyradical, nitric oxide (NO) and prostaglandins play a crucial role in the inflammatory processes. Our data show that methylguanidine, given intraperitoneally at the dose of 30 mg/kg, inhibits the inflammatory response reducing significantly (P<0.05) paw swelling, pleural exudates formation, mononuclear cell infiltration and histological injury. Furthermore, our data suggests that there is a significant (P<0.05) reduction in the activity and expression both of the inducible NOS (iNOS) and of cyclooxygenase-2 in lung tissue of pleurisy model. Methylguanidine is also able to reduce the appearance of nitrotyrosine and of the nuclear enzyme poly(adenosine diphosphate [ADP]-ribose) synthase immunoreactivity in the inflamed lung tissues. Treatment with aminoguanidine, the reference drug, significantly reduced all the evaluated pro-inflammatory parameters in carrageenan-treated rats. Taken together, the present results demonstrate that methylguanidine exerts potent anti-inflammatory effects that could be, in part, related to an inhibition of the expression/activity of the iNOS and cyclooxygenase-2 and, another part, may be related to a reduction of TNF-alpha release.

Acute Disease↗

PubMed2004

Retracted: Rosiglitazone, a ligand of the peroxisome proliferator-activated receptor-gamma, reduces acute inflammation.

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. The thiazolidinedione rosiglitazone (Avandia) is a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist, that was recently approved by the Food and Drug Administration for treatment of type II diabetes mellitus. In the present study, we have investigated the effects of rosiglitazone in animal models of acute inflammation (carrageenan-induced paw oedema and carrageenan-induced pleurisy). We report here for the first time that rosiglitazone (given at 1, 3 or 10 mg/kg i.p. concomitantly with carrageenan injection in the paw oedema model, or at 3, 10 or 30 mg/kg i.p. 15 min before carrageenan administration in the pleurisy model) exerts potent anti-inflammatory effects (e.g. inhibition of paw oedema, pleural exudate formation, mononuclear cell infiltration and histological injury) in vivo. Furthermore, rosiglitazone reduced: (1) the increase in the staining (immunohistochemistry) for nitrotyrosine and poly (ADP-ribose) polymerase (PARP), (2) the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), intercellular adhesion molecules-1 (ICAM-1) and P-selectin in the lungs of carrageenan-treated rats. In order to elucidate whether the protective effect of rosiglitazone is related to activation of the PPAR-gamma receptor, we also investigated the effect of a PPAR-gamma antagonist, bisphenol A diglycidyl ether (BADGE), on the protective effects of rosiglitazone. BADGE (30 mg/kg i.p.) administered 30 min prior to treatment with rosiglitazone significantly antagonized the effect of the PPAR-gamma agonist and thus abolished the anti-inflammatory effects of rosiglitazone. We propose that rosiglitazone and other potent PPAR-gamma agonists may be useful in the therapy of inflammation.

Animals↗

PubMed2004

Retracted: Prevention of carrageenan-induced pleurisy in mice by anti-CD30 ligand monoclonal antibody.

CD30 ligand (CD30L) and its receptor CD30 are members of the tumor necrosis factor (TNF) and TNF receptor superfamilies that play a major role in inflammation and immune regulation. To gain insight into the in vivo role of CD30L/CD30 in inflammatory diseases, we have used carrageenan (CAR)-induced pleurisy in mice, a preclinical model of airway inflammation where type 1 proinflammatory cytokines such as interleukin (IL)-1 and TNF-alpha play a key pathogenic role. The data show that prophylactic treatment with anti-CD30L mAb markedly reduces both laboratory and histological signs of CAR-induced pleurisy. These data suggest involvement of CD30-mediated signals in acute immunoinflammatory pathways induced by CAR.

Adjuvants, Immunologic↗

PubMed2004

Peroxisome proliferator-activated receptors gamma ligands and ischemia and reperfusion injury.

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 subfamily comprises of three members, PPAR-alpha, PPAR-beta and PPAR-gamma. PPAR-gamma has recently been implicated as a regulator of cellular proliferation and inflammatory responses. There is good evidence that ligands of PPAR-gamma, including certain thiazolinediones, reduce tissue injury associated with ischemia and reperfusion. The potential utility of PPAR-gamma ligands in ischemia and reperfusion will be discussed in this review.

Animals↗

PubMed2004

Role of endogenous and exogenous ligands for the peroxisome proliferators activated receptors alpha (PPAR-alpha) in the development of inflammatory bowel disease in mice.

The peroxisome proliferator-activated receptor-alpha (PPAR-alpha) is a member of the nuclear receptor superfamily of ligand-dependent transcription factors related to retinoid, steroid and thyroid hormone receptors. The aim of the present study was to examine the effects of endogenous and exogenous PPAR-alpha ligand on the development of experimental colitis. To address this question, we used an experimental model of colitis, induced by dinitrobenzene sulfonic acid (DNBS). When compared to DNBS-treated PPAR-alpha wild-type (WT) mice, DNBS-treated PPAR-alpha knockout mice (PPAR-alphaKO) mice experienced a higher rate of the extent and severity of the histological signs of colon injury. After administration of DNBS PPAR-alphaWT mice experienced hemorrhagic diarrhea, weight loss and large areas of necrosis in the mucosa of the colon were also observed. Neutrophil infiltration was associated with upregulation of ICAM-1. Immunohistochemistry for nitrotyrosine showed an intense staining in the inflamed colon. Absence of a functional PPAR-alpha gene in PPAR-alphaKO mice resulted in a significant augmentation of all the above-described parameters. On the contrary, the treatment of PPAR-alphaWT with Wy-14643 (1 mg/kg daily i.p) significantly reduced: (i) the degree of hemorrhagic diarrhea and weight loss, (ii) the degree of colon injury, (iii) the rise in MPO activity (mucosa), (iv) the increase in staining (immunohistochemistry) for nitrotyrosine, as well as (v) the upregulation of ICAM-1 caused by DNBS in the colon. In order to elucidate whether the protective effects of Wy-14643 is related to activation of the PPAR-alpha receptor, we also investigated the effect the of Wy-14643 treatment on PPAR-alpha-deficient mice. The absence of the PPAR-alpha receptor significantly abolished the protective effect of the PPAR-alpha agonist against DNBS-induced colitis. Thus, endogenous and exogenous PPAR-alpha ligands reduce the degree of colitis caused by DNBS. We propose that PPAR-alpha ligand may be useful in the treatment of inflammatory bowel disease.

Animals↗

PubMed2004

Melatonin prevents lipopolysaccharide-induced hyporeactivity in rat.

Melatonin (MT) is the principal secretory product of the pineal gland and its role as an immumo-modulator is well established. Recent evidence shows that MT exerts protective effects in septic shock, hemorrhagic shock and inflammation. Lipopolysaccharide (LPS), from Escherichia coli, administered to animals directly stimulates a number of cells and systems to produce various inflammatory mediators. LPS-induced septic shock is characterized by hypotension and vascular hyporeactivity to contracting agents. In particular, the reactive oxygen species such as superoxide and nitric oxide (NO) contribute to the pathophysiology of septic shock. In this study, we demonstrate that MT pretreatment prevents the hyporeactivity to phenylephrine in vivo and in aorta rings collected from rats treated with the endotoxin. The beneficial effect of MT seems related to its antioxidant properties and with inhibition of inducible nitric oxide synthase (iNOS) protein expression, reduction of NO production and nitrotyrosine formation, in aorta, preventing vascular, and endothelial injury. Additionally, we first demonstrate, that MT inhibited nuclear enzyme poly (ADP-ribose) synthetase activation in vascular tissue. The current study underlined the protective effect of MT on the vascular dysfunction associated with septic shock, data that could support the clinical use of MT in human endotoxemia.

Animals↗

PubMed2004

Effect of anthocyanins contained in a blackberry extract on the circulatory failure and multiple organ dysfunction caused by endotoxin in the rat.

Anthocyanins are a group of naturally occurring phenolic compounds related to the colouring of plants, flowers and fruits. These pigments are important as quality indicators, chemotaxonomic markers and for their antioxidant activities. Here we have investigated the therapeutic efficacy of anthocyanins contained in a blackberry extract on (i) circulatory failure, (ii), multiple organ dysfunction and (iii) activity of the inducible isoforms of nitric oxide (NO) synthase (iNOS) and cyclooxygenase (COX-2) in anaesthetised rats with endotoxic shock. In a model of endotoxic shock induced by lipopolysaccharide (LPS, E. coli, 10 mg/kg, i.v.) in the rat, pretreatment with anthocyanins present in the blackberry extract (5 mg/kg, i. v. 30 min before LPS) prevented the hypotension induced by LPS. Endotoxaemia also caused rises in the serum levels of (i) glutamyl oxaloacetic transaminase (GOT), glutamyl pyruvic transaminase (GPT), alkaline phosphates and bilirubin (hepatic dysfunction) (ii) creatinine (renal dysfunction), (iii) amylase and lipase (pancreatic injury), (iii) NOx and 6-keto-PGF1 alpha. Anthocyanins attenuated the hepatic and pancreatic injury, the renal dysfunction and decreased NOx and 6-keto-PGF1 alpha levels. Endotoxaemia for 6 h resulted in a substantial increase in iNOS and COX activity in rat lung, which was attenuated in rats pretreated with anthocyanins. Moreover, anthocyanins (0.02 - 0.32 mg/mL) inhibited in vitro iNOS and COX activity from lung of LPS-treated rats. Polymorphonuclear (PMN) infiltration (myeloperoxidase activity), lipid peroxidation (malondialdehyde levels), as well as tissue injury (histological examination) induced by LPS in rat lung and ileum was reduced by anthocyanins (5 mg/kg, i. v. 30 min before LPS). Furthermore, endotoxaemia induced the formation of nitrotyrosine and poly(ADP-ribose) synthetase (PARS) activation as determined by immunohistochemical analysis of lung and ileum tissues. The degree of staining was lowered by anthocyanin treatment. These results indicate that the anthocyanins contained in the blackberry extract exert multiple protective effects in endotoxic shock.

Animals↗

PubMed2004

Tempol reduces the activation of nuclear factor-kappaB in acute inflammation.

Recent studies have demonstrated that Tempol, a membrane-permeable radical scavenger, exerts protective effects in various models of inflammation and shock. Since nuclear factor-kappaB (NF-kappaB) is a transcription factor, which plays a pivotal role in the induction of genes involved in physiological processes as well as in the response to inflammation, we have investigated the effect of Tempol on NF-kappaB activation in a model of acute inflammation in mice. Injection of carrageenan into the pleural cavity of mice induced an acute inflammatory response characterized by fluid accumulation in the pleural cavity, which contained a large number of neutrophils, as well as an increased production of tumor necrosis factor-alpha, (TNF-alpha) and interleukin-1alpha (IL-1alpha). Tempol (100mg/kg i.p 30min prior to carrageenan administration) significantly attenuated the degree of pleuritis caused by carageeenan (all parameters measured). Administration of carageeenan into the chest cavity (pleuritis) was associated with the activation of NF-kappaB in the lung. In particular, the appearance of IkappaB-alpha in homogenates of lung tissue was investigated by immunoblot analysis at 4h after carrageenan administration. IkappaB-alpha levels were substantially reduced in the lung tissue from carrageenan-treated mice in comparison with sham-treated mice. Furthermore, to detect any effects of Tempol on NF-kappaB/DNA binding, lung extracts were analyzed by EMSA. The DNA binding activity significantly increased in extracts obtained from lungs of vehicle-treated mice at 4h after carrageenan administration. Treatment of mice with Tempol caused a significant inhibition of carrageenan-induced IkappaB-alpha degradation and NF-kappaB/DNA binding activity. These data confirm that Tempol exerts potent anti-inflammatory properties and clearly demonstrates for the first time that Tempol reduces the activation of NF-kappaB in vivo.

Acute Disease↗

PubMed2004

Effect of methylguanidine in a model of septic shock induced by LPS.

Septic shock, a severe form of sepsis, is characterized by cardiovascular collapse following microbial invasion of the body. The progressive hypotension, hyporeactivity to vasopressor agents and vascular leak leads to circulatory failure with multiple organ dysfunction and death. Many inflammatory mediators (e.g. TNF-alpha, IL-1 and IL-6) are involved in the pathogenesis of shock and, among them, nitric oxide (NO). The overproduction of NO during septic shock has been demonstrated to contribute to circulatory failure, myocardial dysfunction, organ injury and multiple organ failure. We have previously demonstrated with in vitro and in vivo studies that methylguanidine (MG), a guanidine compound deriving from protein catabolism, significantly inhibits iNOS activity, TNF-alpha release and carrageenan-induced acute inflammation in rats. The aim of the present study was to evaluate the possible anti-inflammatory activity of MG in a model of septic shock induced by lipopolysaccharide (LPS) in mice. MG was administered intraperitoneally (i.p.) at the dose of 30 mg/kg 1 h before and at 1 and 6 h after LPS-induced shock. LPS injection (10 mg/kg in 0.9% NaCl; 0.1 ml/mouse; i.p.) in mouse developed a shock syndrome with enhanced NO release and liver, kidney and pancreatic damage 18 h later. NOx levels, evaluated as nitrite/nitrate serum levels, was significantly reduced in MG-treated rats (78.6%, p < 0.0001; n = 10). Immunohistochemistry revealed, in the lung tissue of LPS-treated group, a positive staining for nitrotyrosine and poly(adenosine diphosphate [ADP] ribose) synthase, both of which were reduced in MG-treated mice. Furthermore, enzymatic evaluation revealed a significant reduction in liver, renal and pancreatic tissue damage and MG treatment also improved significantly the survival rate. This study provides evidence that MG attenuates the degree of inflammation and tissue damage associated with endotoxic shock in mice. The mechanisms of the anti-inflammatory effect of MG is, at least in part, dependent on the inhibition of NO formation.

Animals↗

PubMed2004

Superoxide-related signaling cascade mediates nuclear factor-kappaB activation in acute inflammation.

The nuclear factor-kappaB (NF-kappaB) is a transcription factor that plays a pivotal role in the induction of genes involved in physiological processes, as well as in the response to inflammation. In this study, we used a selective nonpeptidyl superoxide dismutase mimetic, M40403, to investigate the role of superoxide anion in NF-kappaB activation during acute inflammation in mice. Injection of carrageenan into the pleural cavity of mice induced an acute inflammatory response characterized by fluid accumulation in the pleural cavity that contained a large number of neutrophils, as well as an increased production of tumor necrosis factor-alpha and interleukin-1beta. All parameters of inflammation were attenuated by M40403 (10 mg/kg i. p., 30 min prior to carrageenan administration). These inflammatory events were associated with the activation of NF-kappaB in the lung. In particular, the appearance of inhibitory protein kappaB-alpha (IkappaB-alpha) in homogenates of lung tissues was investigated by immunoblot analysis at 4 h after carrageenan administration. IkappaB-alpha levels were substantially reduced in the lung tissue from carrageenan-treated mice in comparison with sham-treated mice. Furthermore, to detect NF-kappaB/DNA binding activity, whole extracts from lung tissue of each mouse were analyzed by electrophoretic mobility-shift assay. The DNA binding activity significantly increased in whole extracts obtained from lung tissues of vehicle-treated mice 4 h after carrageenan administration. Treatment of mice with M40403 caused a significant inhibition of carrageenan-induced IkappaB-alpha degradation and NF-kappaB/DNA binding activity. These data confirm that M40403 exerts a potent antiinflammatory activity and clearly demonstrate that the reduction of the inflammatory process is associated with modification of the activation of signal transduction pathways.

Animals↗

PubMed2004

Superoxide: a key player in hypertension.

Superoxide is increased in the vessel wall of spontaneously hypertensive rats (SHR) where, if "blocked," potentiates endothelium-dependent vasodilation. The purpose of this study was to determine the role of superoxide anion in hypertension and its interaction with nitric oxide (NO). For this purpose we used a low molecular weight synthetic superoxide dismutase mimetic (M40403), known to remove selectively superoxide anion. Baseline mean arterial pressure (MAP) was significantly elevated in the SHR compared with its normal counterpart, Wistar Kyoto (WKY). M40403 at a dose (2 mg x kg(-1) x h(-1)), which had no effect in the WKY, significantly decreased MAP in SHR rats. To determine whether superoxide anion increases MAP by inactivating NO, NO synthesis was blocked with N(G) nitro-arginine methyl ester (L-NAME, 3 mg/kg i.v.), a nonselective nitric oxide synthase inhibitor. L-NAME (3 mg/kg, i.v) blocked the anti-hypertensive effect of M40403 (2 mg/kg over 30 min). When used at a dose that yielded similar increases in MAP, norepinephrine (2.1 microg/kg) failed to alter the anti-hypertensive effects of M40403 in the SHR. To investigate whether the anti-hypertensive effect of M40403 was associated with an improvement of the alterations in vascular reactivity, a separate group of experiments was carried out ex vivo. Endothelium-dependent vasorelaxation to acetylcholine (10 nM-10 microM), an index of endothelial function, was reduced in aortic rings taken from SHR rats when compared with WKY rats. In vivo treatment with M40403 caused an improvement of the degree of the endothelial dysfunction in SHR rats. Furthermore, immunohistochemical analysis for nitrotyrosine (the product formed from the interaction of nitric oxide with superoxide) revealed a positive staining in aorta from SHR rats. The degree of staining for nitrotyrosine was markedly reduced in tissue sections obtained from SHR rats treated with M40403. Our data suggest that overt production of superoxide in SHR couples with nitric oxide, reducing its function and leading to a loss of blood vessel tone and hypertension. Another important effect appears to be at the level of endothelial cellular integrity, where by interacting with nitric oxide, superoxide anion forms peroxynitrite and subsequent endothelial cell dysfunction. By removing superoxide, M40403 restores blood pressure to near-to-normal values.

Animals↗

PubMed2004

High-density lipoproteins reduce the intestinal damage associated with ischemia/reperfusion and colitis.

High-density lipoproteins (HDLs) have been shown to reduce the organ injury and mortality in animal models of shock by reducing the expression of adhesion molecules and proinflammatory enzymes. However, there is limited evidence that HDL treatment reduces inflammation. As inflammation plays an important role in the development of colitis as well as ischemia/reperfusion (I/R) injury of the intestine, we have investigated the effects of HDL in animal models of associated with gut injury and inflammation (splanchnic artery occlusion [SAO] shock and dinitrobenzene sulfonic acid [DNBS]-induced colitis). We report here for the first time that the administration of reconstituted HDLs (recHDLs; 80 mg/kg i.v. bolus 30 min prior to ischemia in the SAO-shock model or 40 mg/kg i.v. every 24 h in the colitis model) exerts potent anti-inflammatory effects (e.g., reduced inflammatory cell infiltration and histological injury, and delayed the development of the clinical signs) in vivo. Furthermore, recHDL reduced the staining for nitrotyrosine and poly(ADP-ribose) (immunohistochemistry) and the expression of intercellular adhesion molecule-1 in the ileum of SAO-shocked rats and in the colon from DNBS-treated rats. Thus, recHDL reduces the inflammation caused by intestinal I/R and colitis. HDLs may represent a novel therapeutic approach for the therapy of inflammation of the gut.

Animals↗

PubMed2004

Protective effects of M40401, a selective superoxide dismutase mimetic, on zymosan-induced nonseptic shock.

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'-diphosphate-ribose) 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.

Animals↗

PubMed2004

Rosiglitazone, a ligand of the peroxisome proliferator-activated receptor-gamma, reduces the development of nonseptic shock induced by zymosan in mice.

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.

Animals↗

PubMed2004

Treatment with a novel poly(ADP-ribose) glycohydrolase inhibitor reduces development of septic shock-like syndrome induced by zymosan in mice.

OBJECTIVE: Poly(ADP-ribose) is synthesized from nicotinamide adenine dinucleotide by poly(ADP-ribose) polymerase (PARP) and degraded by poly(ADP-ribose) glycohydrolase (PARG). The activation of the PARP/PARG pathway has been found in a variety of animal models of diseases, including septic shock-like syndrome. We have previously demonstrated that PARP inhibition by 3-ami-nobenzamide or GPI 6150 ameliorates multiple organ dysfunctions induced by zymosan. In the present study, we investigated whether similar effect could be achieved through PARG inhibition to break the cycle of poly(ADP-ribose) turnaround. DESIGN: Experimental study. SETTING: University laboratory. SUBJECTS: Male CD mice (20-22 g). INTERVENTIONS: We tested the effects of GPI 18214 (40 mg/kg intraperitoneally bolus), a novel and potent PARG inhibitor, at 1 and 6 hr after zymosan (500 mg/kg, administered intraperitoneally as a suspension in saline) on the development of septic shock-like syndrome in mice. Organ failure and systemic inflammation in mice were assessed 18 hrs after administration of zymosan and/or GPI 18214 and monitored for 12 days (for loss of body weight and mortality). MEASUREMENTS AND MAIN RESULTS: At 18 hrs after zymosan administration, we found a significant increase of peritoneal exudates, leukocyte infiltration in peritoneal cavity as well as an infiltration of neutrophils in lung and ileum tissues and subsequent lipid peroxidation, and increased production of plasma tumor necrosis factor-alpha and interleukin-1 beta. Furthermore, zymosan administration induced significant liver, lung, pancreas, intestine, and kidney dysfunction as well as a systemic toxicity and significant loss of body weight. At the end of observation period (12 days), 90% of zymosan-treated mice were dead. GPI 18214 (40 mg/kg intraperitoneally, 1 and 6 hrs after zymosan) treatment significantly reduced peritoneal exudates, inflammatory cell infiltration, and organ injury and mortality rate in zymosan-treated mice. CONCLUSIONS: This study supports early studies that show efficacy from blocking the poly(ADP-ribose) pathway in septic shock-like syndrome model. It provides evidence that GPI 18214, a PARG inhibitor, attenuates the degree of zymosan-induced nonseptic shock in mice, suggesting that PARG may be an alternative therapeutic target for shock treatment.

Acute Disease↗

PubMed2004

Calpain inhibitor I reduces intestinal ischemia-reperfusion injury in the rat.

In this study we evaluated the effect of calpain inhibitor I on splanchnic artery occlusion (SAO) shock-mediated injury. SAO shock was induced in rats by clamping both the superior mesenteric artery and the celiac trunk for 45 min. After 1 h of reperfusion, SAO-shocked rats developed a significant fall in mean arterial blood pressure. Western blot analysis of ileum revealed a marked decrease in of IkappaB-alpha expression, and immunohistochemical examination of necrotic ileum demonstrated a marked increase in the immunoreactivity to P-selectin, intracellular adhesion molecule (ICAM-1), nitrotyrosine formation, and nuclear enzyme poly[adenosine diphosphate (ADP)-ribose] synthase (PARS) activation. An increase in myeloperoxidase activity (143 +/- 22 4.5 U/100 mg wet tissue vs. 4.5 +/- 2.5 U/100 mg wet tissue of sham-operated rats) and in malondialdehyde levels (13.12 +/- 1.2 micromol/100 mg wet tissue vs. 3.9 +/- 1.1 micromol/100 mg wet tissue of sham-operated rats) was also observed in rats subjected to ischemia-reperfusion injury. Calpain inhibitor I, given intraperitoneally 30 min before ischemia at a dose of 15 mg/kg, significantly improved mean arterial blood pressure, markedly reduced IkappaB-alpha degradation and the intensity of P-selectin and ICAM-1 in the reperfused ileum. Calpain inhibitor I also significantly prevented neutrophil infiltration (32.95 +/- 9.82 U/100 mg wet tissue), reduced malondialdehyde levels (6.76 +/- 0.98 micromol/100 mg wet tissue) and markedly improved the histological status of the reperfused tissue. In conclusion, this study demonstrates that calpain inhibitor I exerts multiple protective effects in splanchnic artery occlusion-reperfusion shock and suggests that calpain inhibitor I may be a candidate for consideration as a therapeutic intervention for ischemia-reperfusion injury.

Animals↗

PubMed2004

Reduction in the development of cerulein-induced acute pancreatitis by treatment with M40401, a new selective superoxide dismutase mimetic.

Oxidative stress plays an important role in the early stage of acute pancreatitis, as well as in the associated multiple organ injury. This study tests the hypothesis that M40401, a new superoxide dismutase mimetic, attenuates experimental acute pancreatitis. Intraperitoneal injection of cerulein in mice resulted in a severe, acute pancreatitis that was characterized by edema, neutrophil infiltration, tissue hemorrhage, and cell necrosis, as well as increases in the serum levels of amylase and/or lipase. The infiltration of the pancreatic tissue of these animals with neutrophils (measured as an increase in myeloperoxidase activity) was associated with expression of intercellular adhesion molecule-1, as well as signs of enhanced lipid peroxidation (e.g., increased tissue levels of malondialdehyde). Immunohistochemical examination demonstrated a marked increase in the staining (immunoreactivity) for nitrotyrosine and poly (ADP-ribose) polymerase in the pancreas of cerulein-treated mice. In contrast, the degree of pancreatic inflammation and tissue injury (histological score), the expression of intercellular adhesion molecule-1, the staining for nitrotyrosine and poly (ADP-ribose) polymerase, and lipid peroxidation were markedly reduced in pancreatic tissue sections obtained from cerulein-treated mice administered with M40401. These results confirm our hypothesis that superoxide anions play an important role in cerulein-mediated acute pancreatitis and support the possible clinical use of low-molecular-weight synthetic superoxide dismutase mimetics in those conditions that are associated with overproduction of superoxide.

Acute Disease↗