Biomedical subjects

Salvatore Cuzzocrea

Publications and source records attributed to Salvatore Cuzzocrea.

At least 109 records · Page 6Linked to original sources

PubMed2004

Differential effects of caspase inhibitors on the renal dysfunction and injury caused by ischemia-reperfusion of the rat kidney.

Caspase activation has been implicated in the development of ischemia-reperfusion injury. Here, we investigate the effects of different caspase inhibitors on the renal dysfunction and injury caused by ischemia-reperfusion of the rat kidney. Bilateral clamping of renal pedicles (45 min) followed by reperfusion (6 h) caused significant renal dysfunction and marked renal injury. Caspase-1 inhibitor II (N-acetyl-L-tyrosyl-L-valyl-N-[(1S)-1-(carboxymethyl)-3-chloro-2-oxo-propyl]-L-alaninamide, Ac-YVAD-CMK, 3 mg/kg, administered i.p.) significantly reduced biochemical and histological evidence of renal dysfunction and injury. However, although caspase-3 inhibitor I (N-acetyl-L-aspartyl-L-glutamyl-N-(2-carboxyl-1-formylethyl]-L-valinamide, Ac-DEVD-CHO, 3 mg/kg, administered i.p.) produced a significant improvement of renal (glomerular) dysfunction (reduction of serum creatinine levels), it was not able to reduce tubular dysfunction and injury. Furthermore, the pan-caspase inhibitor caspase inhibitor III (N-tert-butoxycarbonyl-aspartyl(OMe)-fluoromethylketone, Boc-D-FMK, 3 mg/kg, administered i.p.) did not reduce renal dysfunction and injury. Both caspase-1 and -3 inhibitors markedly reduced the evidence of oxidative and nitrosative stress in rat kidneys subjected to ischemia-reperfusion. Overall, these results demonstrate that inhibition of caspase-1 reduces renal ischemia-reperfusion injury to a greater extent than caspase-3 inhibition, supporting the notion that the mode of acute cell death in our model of renal ischemia-reperfusion is primarily via necrosis. Furthermore, our finding that a pan-caspase inhibitor did not reduce the renal dysfunction and injury suggests that activation of some caspases during ischemia-reperfusion could provide protection against acute ischemic renal injury. Overall, these results demonstrate that inhibition of caspase-1 activity reduces renal ischemia-reperfusion injury and that this therapeutic strategy may be of benefit against ischemic acute renal failure.

Animals↗

PubMed2004

Inhibitors of poly(ADP-ribose) polymerase modulate signal transduction pathways and secondary damage in experimental spinal cord trauma.

Poly(ADP-ribose) polymerase (PARP), a nuclear enzyme activated by strand breaks in DNA, plays an important role in the tissue injury associated with stroke and neurotrauma. The aim of our study was to evaluate the therapeutic efficacy of in vivo inhibition of PARP in an experimental model of spinal cord trauma, which was induced by the application of vascular clips (force of 24g) to the dura via a four-level T5-T8 laminectomy. Spinal cord injury in mice resulted in severe trauma characterized by edema, neutrophil infiltration (measured as an increase in myeloperoxidase activity), and apoptosis (measured by terminal deoxynucleotidyltransferase-mediated UTP end labeling coloration). Infiltration of spinal cord tissue with neutrophils was associated with a marked increase in immunoreactivity for poly(ADP-ribose) (PAR), index of PARP activation, in the spinal cord tissue. These inflammatory events were associated with the activation of nuclear factor-kappaB (NF-kappaB) at 4 h after spinal cord damage. Treatment of the mice with the PARP inhibitors 3-aminobenzamide (3-AB) or 5-aminoisoquinolinone (5-AIQ) significantly reduced the degree of 1) spinal cord inflammation and tissue injury (histological score), 2) PAR formation, 3) neutrophil infiltration, and 4) apoptosis. Treatment with these PARP inhibitors also reduced DNA binding of NF-kappaB and inhibitory kappaB degradation. In a separate set of experiments, we have also demonstrated that PARP inhibitors significantly ameliorated the recovery of limb function (evaluated by motor recovery score). Taken together, our results clearly demonstrate that treatment with PARP inhibitors reduces the development of inflammation and tissue injury events associated with spinal cord trauma.

Animals↗

PubMed2004

15d-prostaglandin J2 reduces multiple organ failure caused by wall-fragment of Gram-positive and Gram-negative bacteria.

Septic shock is still the major cause of death in surgical intensive care units. Both gram-positive (G+) and gram-negative (G-) bacteria have been isolated in the blood of a large portion of septic patients, and these polymicrobial infections often have a higher mortality than infections due to a single organism. Cell wall fragments from G+ and G- bacteria synergise to cause shock and multiple organ dysfunction in vivo (G+/G- shock). Male Wistar rats were anaesthetised and received a coadministration of wall fragments from G+ and G- bacteria, Staphilococcus aureus (S. aureus) peptidoglycan [0.3 mg/kg, intravenously (i.v.)] and Escherichia coli (E. coli) lipopolysaccharide (1 mg/kg, i.v.) or vehicle (saline, 1 ml/kg, i.v.). G+/G- shock for 6 h resulted in an increase in serum levels of creatinine (indicator of renal dysfunction), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (gamma-GT), bilirubin (markers for hepatic injury and dysfunction) and creatine kinase (CK, an indicator of neuromuscular, skeletal muscle or cardiac injury). Pretreatment of rats with the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist 15d-prostaglandin J2 (0.3 mg/kg, i.v., 30 min prior to G+/G-) reduced the multiple organ injury/dysfunction caused by coadministration of peptidoglycan+lipopolysaccharide. The selective PPAR-gamma antagonist GW9662 (2-Chloro-5-nitrobenzanilide) (1 mg/kg, i.v., given 45 min prior to G+/G-) abolished the protective effects of 15d-prostaglandin J2. 15d- prostaglandin J2 did not affect the biphasic fall in blood pressure or the increase in heart rate caused by administration of peptidoglycan+lipopolysaccharide. The mechanism(s) of the protective effect of this cyclopentenone prostaglandin are-at least in part-PPAR-gamma dependent, as the protection afforded by 15d-prostaglandin J2 was reduced by the PPAR-gamma antagonist GW9662. We propose that 15d-prostaglandin J2 or other ligands for PPAR-gamma may be useful in the therapy of the organ injury associated with septic shock.

Alanine Transaminase↗

PubMed2004

Reduction of the multiple organ injury and dysfunction caused by endotoxemia in 5-lipoxygenase knockout mice and by the 5-lipoxygenase inhibitor zileuton.

The role of 5-lipoxygenase (5-LOX) in the pathophysiology of the organ injury/dysfunction caused by endotoxin is not known. Here, we investigate the effects of treatment with 5-LOX inhibitor zileuton in rats and targeted disruption of the 5-LOX gene in mice (5-LOX(-/-)) on multiple organ injury/dysfunction caused by severe endotoxemia. We also investigate the expression of beta2-integrins CD11a/CD18 and CD11b/CD18 on rat leukocytes by flow cytometry. Zileuton [3 mg/kg intravenously (i.v.)] or vehicle (10% dimethyl sulfoxide) was administered to rats 15 min prior to lipopolysaccharide (LPS; Escherichia coli, 6 mg/kg i.v.) or vehicle (saline). 5-LOX(-/-) mice and wild-type littermate controls were treated with LPS (E. coli, 20 mg/kg intraperitoneally) or vehicle (saline). Endotoxemia for 6 h in rats or 16 h in mice resulted in liver injury/dysfunction (increase in the serum levels of aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, alkaline phosphatase, bilirubin), renal dysfunction (creatinine), and pancreatic injury (lipase, amylase). Absence of functional 5-LOX (zileuton treatment or targeted disruption of the 5-LOX gene) reduced the multiple organ injury/dysfunction caused by endotoxemia. Polymorphonuclear leukocyte infiltration (myeloperoxidase activity) in the lung and ileum as well as pulmonary injury (histology) were markedly reduced in 5-LOX(-/-) mice. Zileuton also reduced the LPS-induced expression of CD11b/CD18 on rat leukocytes. We propose that endogenous 5-LOX metabolites enhance the degree of multiple organ injury/dysfunction caused by severe endotoxemia by promoting the expression of the adhesion molecule CD11b/CD18 and that inhibitors of 5-LOX may be useful in the therapy of the organ injury/dysfunction associated with endotoxic shock.

Animals↗

PubMed2004

Glucocorticoid-induced TNF receptor family gene (GITR) knockout mice exhibit a resistance to splanchnic artery occlusion (SAO) shock.

In the present study, we used glucocorticoid-induced tumor necrosis factor (TNF) receptor family gene knockout (GITR-KO) mice to evaluate a possible role of GITR on the pathogenesis of splanchnic artery occlusion (SAO) shock, which was induced in mice by clamping the superior mesenteric artery and the celiac artery for 30 min, followed thereafter by release of the clamp (reperfusion). At 60 min after reperfusion, animals were killed for histological examination and biochemical studies. There was a marked increase in the lipid peroxidation in the ileum of the SAO-shocked, GITR wild-type (WT) mice after reperfusion. The absence of GITR significantly reduced the lipid peroxidation in the intestine. SAO-shocked WT mice developed a significant increase of ileum tissue, TNF-alpha, and myeloperoxidase activity and marked histological injury. SAO shock was also associated with a significant mortality (5% survival at 24 h after reperfusion). Reperfused ileum tissue sections from SAO-shocked WT mice showed positive staining for P-selectin, intercellular adhesion molecule 1 (ICAM-1), and E-selectin. The intensity and degree of P-selectin, E-selectin, and ICAM-1 were markedly reduced in tissue section from SAO-shocked, GITR-KO mice. SAO-shocked, GITR-KO mice also showed a significant reduction of the TNF-alpha production and neutrophil infiltration into the reperfused intestine, an improved histological status of the reperfused tissues, and an improved survival. Taken together, our results clearly demonstrate that GITR plays an important role in the ischemia and reperfusion injury and put forward the hypothesis that modulation of GITR expression may represent a novel and possible strategy.

Animals↗

PubMed2004

M40403 prevents myocardial injury induced by acute hyperglycaemia in perfused rat heart.

M40403 is a low-molecular-weight, synthetic manganese-containing biscyclohexylpyridine superoxide dismutase mimetic (SODm) that removes superoxide anions (O(2)(-)) without interfering with other reactive species known to be involved in cardiovascular alterations (e.g. nitric oxide [NO] and peroxynitrite [ONOO(-)]). As such, M40403 represents an important pharmacological tool to dissect the roles of O(2)(-) in functional and biochemical cardiovascular alterations induced by perfusion of high glucose concentrations into the heart. Perfusion of a high glucose concentration of glucose into the heart elicited important cardiovascular alterations characterized by QT interval prolongation, increase in coronary perfusion pressure (CPP), lipid peroxidation, decrease in MnSOD activity and DNA damage. All parameters of cardiovascular alteration were attenuated by M40403 (1-10 mg/l). Furthermore, perfusion of a high of glucose concentration induced a significant formation of nitrotyrosine as well as an activation of poly(adenosine diphosphate [ADP]-ribose) synthetase (PARS), as determined by immunohistochemical analysis of heart tissue. The extent of staining for nitrotyrosine and PARS was reduced by M40403. These results clearly indicate that O(2)(-) plays a critical role in the development of the functional and biochemical cardiovascular alterations induced by perfusion of a high concentration of glucose into the heart. Therefore, synthetic enzymes of SOD, such as M40403, offer a novel therapeutic approach for the management of various cardiovascular diseases where these radicals have been postulated to play a role.

Animals↗

PubMed2004

Erythropoietin reduces the development of experimental inflammatory bowel disease.

Inflammatory bowel disease is characterized by oxidative and nitrosative stress, leukocyte infiltration, and up-regulation of the expression of intercellular adhesion molecule-1 (ICAM-1) in the colon. Erythropoietin (EPO) is a potent stimulator of erythroid progenitor cells, and its expression is enhanced by hypoxia. Here we investigate the effects EPO has 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 with DNBS-treated mice, EPO (1000 IU/kg day s.c.)-treated mice subjected to DNBS-induced colitis experienced significantly lower rates in the extent and severity of the histological signs of colon injury. DNBS-treated mice experienced diarrhea and weight loss. At 4 days after administration of DNBS, the mucosa of the colon exhibited large areas of necrosis. Neutrophil infiltration (determined by histology as well as an increase in myeloperoxidase activity in the mucosa) was associated with up-regulation of ICAM-1. Immunohistochemistry for nitrotyrosine and poly(ADP-ribose) showed an intense staining in the inflamed colon. On the contrary, the treatment of DNBS-treated mice with EPO significantly reduced the degree of diarrhea and weight loss caused by administration of DNBS. EPO also caused a substantial reduction of the degree of colon injury, the rise in myeloperoxidase activity (mucosa), and the increase in staining (immunohistochemistry) for nitrotyrosine as well as the up-regulation of ICAM-1 caused by DNBS in the colon. Thus, treatment of rat with EPO reduces the degree of colitis caused by DNBS. We propose that EPO may be useful in the treatment of inflammatory bowel disease.

Animals↗

PubMed2004

Methylguanidine reduces the development of non septic shock induced by zymosan in mice.

In the present study we evaluate the effect of methylguanidine (MG), a product of protein catabolism, in a model of acute inflammation (zymosan induced inflammation) in mice where oxyradical and nitric oxide (NO) play a crucial role. Our data show that MG, given intraperitoneally at the dose of 30 mg/Kg, inhibits the inflammatory response reducing significantly (P < 0.05) peritoneal exudates formation, mononuclear cell infiltration and histological injury in mice. Furthermore, our data suggests that there is a significant (P < 0.05) reduction in kidney, liver and pancreas injury as demonstrated by the reduction in amylase, lipase, creatinine, AST, ALT, bilirubine and alkaline phosfatase levels. MG is also able to reduce the appearance of nitrotyrosine and of the nuclear enzyme poly (adenosine diphosphate [ADP]-ribose) synthase (PARS) immunoreactivity in the inflamed intestinal and lung tissues. The histological examination revealed a significant reduction in zymosan-induced intestinal and lung damage in MG-treated mice. Taken together, the present results demonstrate that MG exerts potent anti-inflammatory effects on zymosan-induced shock.

Analysis of Variance↗

PubMed2004

Inhibition of poly(ADP-ribose) polymerase prevents allergen-induced asthma-like reaction in sensitized Guinea pigs.

Poly(ADP-ribose) polymerase (PARP) plays an important role in tissue injury in conditions associated with oxidative stress and inflammation. Because asthma is a chronic inflammatory disorder of the airways, we designed the present experimental study to evaluate the effects of PARP inhibition on allergen-induced asthma-like reaction in ovalbumin-sensitized guinea pigs. Cough and dyspnea in response to ovalbumin aerosol were absent in naive guinea pigs, whereas they became severe in the sensitized animals. In the latter ones, ovalbumin aerosol also induced a rapid increase in PARP activity, bronchiolar constriction, pulmonary air space inflation, mast cell degranulation, poly(ADP-ribose) and nitrotyrosine immunostaining, myeloperoxidase activity, and malondialdehyde in lung tissue, as well as a rise in the amounts of nitrites and tumor necrosis factor-alpha in bronchoalveolar lavage fluid. Pretreatment with the PARP inhibitors 3-aminobenzamide (10 mg/kg b.wt.) or 5-aminoisoquinolinone (0.5 mg/kg b.wt.) given i.p. 3 h before ovalbumin challenge significantly reduced the severity of cough and the occurrence of dyspnea and delayed the onset of respiratory abnormalities. Both PARP inhibitors were also able to prevent the above morphological and biochemical changes of lung tissue or bronchoalveolar lavage fluid induced by ovalbumin challenge. Conversely, p-aminobenzoic acid, the inactive analog of 3-aminobenzamide, had no effects.

Allergens↗

PubMed2004

Role of 5-lipoxygenase in the multiple organ failure induced by zymosan.

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.

Animals↗

PubMed2004

Calpain I inhibitor ameliorates the indices of disease severity in a murine model of cerulein-induced acute pancreatitis.

OBJECTIVE: Nuclear factor-kappaB (NF-kappaB) is a transcription factor which plays a pivotal role in the induction of genes involved in the response to injury and inflammation. Calpain I inhibitor is a potent antioxidant which is an effective inhibitor of NF-kappaB. This study examined whether the postulate that calpain I inhibitor attenuates experimental acute pancreatitis. DESIGN AND SETTING: In a murine model we measured NF-kappaB activation, expression of intercellular adhesion molecule (ICAM) 1, nitrotyrosine, inducible nitric oxide synthase (iNOS), nuclear enzyme poly(ADP-ribose) synthetase (PARS), myeloperoxidase, malondialdehyde, amylase and lipase and determined histological evidence of lung and pancreas injury in four groups: control (saline only), cerulein, calpain I inhibitor plus cerulein and calpain I inhibitor plus saline. MEASUREMENTS AND RESULTS: Intraperitoneal injection of cerulein in mice resulted in severe, acute pancreatitis characterised by oedema, neutrophil infiltration, tissue haemorrhage and necrosis and elevated serum levels of amylase and lipase. Infiltration of pancreatic and lung tissue with neutrophils (measured as increase in myeloperoxidase activity) was associated with enhanced lipid peroxidation (increased tissue levels of malondialdehyde). Immunohistochemical examination demonstrated a marked increase in immunoreactivity for nitrotyrosine, iNOS and PARS in the pancreas and lung of cerulein-treated mice. In contrast, pre-treatment with calpain I inhibitor markedly reduced: the degree of pancreas and lung injury; upregulation/expression of ICAM-1; staining for iNOS, nitrotyrosine and PARS; and lipid peroxidation. Additionally, calpain I inhibitor treatment significantly prevented the activation of NF-kappaB as suggested by the inhibition of IkappaB-alpha; degradation in the pancreas tissues after cerulein administration. CONCLUSIONS: Taken together, our results clearly demonstrate that prevention of the activation of NF-kappaB by calpain I inhibitor ameliorates experimental murine acute pancreatitis.

Acute Disease↗

PubMed2004

Beneficial effects of 5-aminoisoquinolinone, a novel, potent, water-soluble, inhibitor of poly (ADP-ribose) polymerase, in a rat model of splanchnic artery occlusion and reperfusion.

Poly(ADP-ribose) polymerase (PARP), a nuclear enzyme activated by strand breaks in DNA, plays an important role in the tissue injury associated with ischemia-reperfusion and inflammation. Splanchnic artery occlusion and reperfusion causes an enhanced formation of reactive oxygen species which contribute to the pathophysiology of shock. The aim of the present study was to investigate the effects of 5-aminoisoquinolinone (5-AIQ), a potent water-soluble inhibitor of poly(ADP-ribose) polymerase (PARP), in the pathogenesis of splanchnic artery occlusion shock. Splanchnic artery occlusion shock was induced in rats by clamping both the superior mesenteric artery and the celiac artery for 45 min, followed thereafter by release of the clamp (reperfusion). At 60 min after reperfusion, all animals were sacrificed for histological examination and biochemical studies. Treatment of rats with 5-AIQ (3 mg/kg i.v.), attenuated the fall of mean arterial blood pressure caused by splanchnic artery occlusion shock. 5-AIQ also attenuated the ileum injury as well as the increase in the tissue levels of myeloperoxidase and malondialdehyde caused by splanchnic artery occlusion shock in the ileum. The immunohistochemical examination also demonstrated a marked increase in the immunoreactivity to PAR, nitrotyrosine, and intercellular adhesion molecule (ICAM-1) in the necrotic ileum from splanchnic artery occlusion-shocked rats. 5-AIQ treatment significantly reduced the increase of positive staining for PAR, nitrotyrosine and ICAM-I. In conclusion, these results show that 5-AIQ, a new water-soluble potent inhibitor of poly(ADP-ribose) polymerase, exerts multiple protective effects in splanchnic artery occlusion/reperfusion shock.

Animals↗

PubMed2004

A protective effect of the synthetic coumarine derivative Cloricromene against DNB-colitis in the rat.

Biologic therapies, namely antibodies against tumor necrosis factor-alpha (TNF- alpha) or its receptors, have been recently introduced for the treatment of patients with inflammatory bowel disease (IBD). In the present study the effects of cloricromene, an agent with known antithrombotic actions and with demonstrated anti-TNF- alpha activity were investigated in a rat model of experimental colitis induced with dinitrobenzenesulphonic acid (DNB)/ethanol. We investigated three experimental groups: (i) sham-colitis with vehicle-treatment (controls, n = 6), (ii) colitis with vehicle-treatment (saline, 0.1 ml s.c., daily) (DNB-V, n = 7), (iii) colitis with cloricromene-treatment (10 mg/kg/day s.c.; DNB-C, n = 8). After 7 days, the weight gain, colon wet weight, macroscopic damage score, coagulation parameters, colon mucosal myeloperoxidase activity (MPO), and tissue concentrations of TNF- alpha and of macrophage inhibitory peptide-2 (MIP-2) were assessed. The macroscopic damage scores, colon wet weights, and tissue MIP-2 levels were significantly increased in untreated and in cloricromene-treated rats compared with controls. Cloricromene treatment was associated with a minor body weight loss (p < 0.025) and significantly reduced tissue concentrations of MPO and TNF-alpha (p < 0.02, both). Blood coagulation parameters were not affected by treatment. In the DNB-model treatment with cloricromene effectively reduces tissue levels of TNF- alpha and of myeloperoxidase, whereas MIP-2 concentrations were not influenced. Blood coagulation parameters remained unchanged indicating safety of treatment. Since biological therapies frequently fail to improve disease course of IBD, other therapies with similar targets should be further investigated.

Animals↗

PubMed2004

A newly identified role for superoxide in inflammatory pain.

Novel classes of pain-relieving molecules are needed to fill the void between nonsteroidal anti-inflammatory agents and narcotics. Our studies have identified superoxide as a novel mediator of hyperalgesia (clinically defined as an augmented sensitivity to painful stimuli) and have exposed potential pathways through which this radical modulates the hyperalgesic response. The role of superoxide in pain was elucidated using a superoxide dismutase mimetic, M40403 [a manganese(II) complex with a bis(cyclo-hexylpyridine-substituted) macrocyclic ligand]. Intraplantar injection of carrageenan in rats led to time-dependent development of peripheral inflammation [measured parameters of inflammation included paw edema, cytokine release in the paw exudates, nitrotyrosine formation (a marker of peroxynitrite formation and oxidative stress), and poly-ADP-ribose-polymerase activation (the nuclear enzyme activated by superoxide/peroxynitrite)] and hyperalgesia. M40403 blocked all measured parameters of inflammation and hyperalgesia. Furthermore, when given therapeutically (2 h after the induction of hyperalgesia) either by intravenous or intrathecal administration, M40403 but not its inactive congener M40404 inhibited hyperalgesia with a rapid onset of action. Our results also show that, at the level of the spinal cord and time of peak hyperalgesia, endogenous manganese superoxide dismutase was nitrated and subsequently deactivated, losing its capacity to remove superoxide. The antihyperalgesic effects of M40403 were not reversed by naloxone excluding the potential involvement of an opiate pathway. Collectively, these studies have unraveled a critical role for superoxide in the nociceptive signaling cascade both peripherally and centrally. The discovery of this pathway opens a new therapeutic strategy for the development of novel nonnarcotic antihyperalgesic agents.

Animals↗

PubMed2004

Rosiglitazone, a ligand of the peroxisome proliferator-activated receptor-gamma, reduces acute pancreatitis induced by cerulein.

OBJECTIVE: In the present study, we investigated the effects of rosiglitazone (10 mg/kg, i.p.), a PPAR-gamma agonist, on the development of acute pancreatitis. DESIGN: Intraperitoneal injection of cerulein in mice induced an acute pancreatitis characterized by edema, neutrophil infiltration elevated serum levels of amylase and lipase. This experimental model was performed to test the anti-inflammatory activity of rosiglitazone. SETTING. University research laboratory. INTERVENTIONS: Male CD mice (20-22 g) were allocated into four groups (n=10 for each group): (a) Cerulein+vehicle group. Mice were treated hourly (x 5) with cerulein (50 microg/kg, in saline solution, i.p.); (b) Rosiglitazone group (same as the Cerulein+vehicle group but were administered rosiglitazone, 10 mg/kg bolus, 30 min prior to cerulein); (c) Sham+saline group. Mice were treated with saline instead of cerulein; (d) Sham+Rosiglitazone. Identical to Rosiglitazone group except that the saline was administered instead of cerulein. Mice were killed at 6 h after the induction of pancreatitis. Blood samples, pancreas, and lungs were collected. MEASUREMENTS AND RESULTS: Infiltration of pancreatic and lung tissue with neutrophils was associated with enhanced lipid peroxidation. Immunohistochemical examination demonstrated a marked increase in immunoreactivity for nitrotyrosine and for ICAM-1 in the pancreas of cerulein-treated mice. In contrast, the degree of (a) pancreatic inflammation and tissue injury, (b) upregulation/formation of ICAM-1 and nitrotyrosine, and (c) neutrophils infiltration was markedly reduced in pancreatic tissue obtained from rosiglitazone-treated mice. CONCLUSION: These findings support the view that rosiglitazone and other potent PPAR-gamma agonists may be useful in the therapy of acute pancreatitis.

Acute Disease↗

PubMed2004

The cyclopentenone prostaglandin 15-deoxy-Delta(12,14)-prostaglandin J2 ameliorates ischemic acute renal failure.

OBJECTIVE: Here we investigate the effects of the endogenous prostaglandin D2 metabolite 15-deoxy-Delta(12,14)-prostaglandin J2, on the renal dysfunction and injury caused by ischemia/reperfusion of the kidney. METHODS: Male Wistar rats, subjected to bilateral renal ischemia for 45 min followed by reperfusion for up to 48 h, were administered 15-deoxy-Delta(12,14)-prostaglandin J2 (1 mg/kg, intravenously) 5 min prior to and again after 3 or 12 h reperfusion. RESULTS: 15-deoxy-Delta(12,14)-prostaglandin J2 significantly reduced (i) renal and tubular dysfunction (serum urea and creatinine levels, creatinine clearance, fractional excretion of Na+ (FENA)), (ii) tubular and reperfusion-injury (urinary N-acetyl-beta-D-glucosaminidase, aspartate aminotransferase (ASP) and gamma-glutamyltransferase (gamma-GT)) and (iii) histological evidence of renal injury. 15-deoxy-Delta(12,14)-prostaglandin J2 also improved renal function (plasma creatinine levels) and reduced the histological signs of renal injury (after 48 h reperfusion). Administration of 15-deoxy-Delta(12,14)-prostaglandin J2 markedly reduced the expression of inducible nitric oxide synthase (iNOS) and intercellular adhesion molecule-1 during reperfusion (determined using immunohistochemistry). Immunohistochemical analysis of p65 translocation and Western blot analysis of IkappaB-alpha degradation revealed that 15-deoxy-Delta(12,14)-prostaglandin J2 inhibited the activation of nuclear factor (NF)-kappaB in renal cells. Subsequently, 15d-PGJ2 was able to significantly reduce nitric oxide production during renal ischemia/reperfusion and by primary cultures of rat proximal tubular (PT) cells incubated with interferon-gamma and bacterial lipopolysaccharide (LPS) in combination. CONCLUSIONS: We demonstrate here, for the first time, that 15-deoxy-Delta(12,14)-prostaglandin J2 significantly reduces renal ischemia/reperfusion-injury via reduction of pro-inflammatory gene expression during reperfusion subsequent to the inhibition of the activation of NF-kappaB.

Animals↗

PubMed2004

Hyperbaric oxygen therapy prevents vascular derangement during zymosan-induced multiple-organ-failure syndrome.

OBJECTIVE: This study investigated the effects of hyperbaric oxygen (HBO) therapy on the cardiovascular alteration (e.g. mean arterial pressure, vascular reactivity of thoracic aorta rings changes) caused by zymosan in rats. DESIGN: Rats. SETTING: University research laboratory. INTERVENTION AND MEASUREMENTS: We investigated the effects of HBO therapy (2 ATA at the fourth and eleventh hours after study onset) on the cardiovascular alteration caused by zymosan (500 mg/kg, administered i.p. as a suspension in saline) in rats. Cardiovascular alterations were assessed 18 h after administration of zymosan and/or HBO therapy. RESULTS: Treatment of rats with HBO therapy attenuated the vasoplegic response to zymosan. In fact, the analysis of arterial pressure curves revealed no signs of vasoplegic shock. The aorta rings of animals treated with zymosan and HBO had a significantly increased contraction to norepinephrine (NE) and endothelin-1 (ET-1) and dilation to acetylcholine (ACh) compared with the zymosan group. The HBO therapy also attenuated the increase of malondialdehyde (MDA) levels caused by zymosan in the aorta. Immunohistochemical analysis for nitrotyrosine and for iNOS revealed positive staining in the aorta from zymosan-treated rats. The degree of staining for nitrotyrosine and iNOS was markedly reduced in tissue sections obtained from zymosan-rats treated with HBO therapy. CONCLUSION: This study provides the first evidence that HBO therapy attenuates the degree of zymosan-induced cardiovascular derangement in the rat.

Analysis of Variance↗

PubMed2004

Effects of GW274150, a novel and selective inhibitor of iNOS activity, in acute lung inflammation.

1. The aim of this study was to investigate the effect of GW274150, a novel, potent and selective inhibitor of inducible nitric oxide synthase (iNOS) activity in a model of lung injury induced by carrageenan administration in the rats. 2. Injection of carrageenan into the pleural cavity of rats elicited an acute inflammatory response characterized by: fluid accumulation in the pleural cavity which contained a large number of polymorphonuclear cells (PMNs) as well as an infiltration of PMNs in lung tissues and subsequent lipid peroxidation, and increased production of nitrite/nitrate (NO(x)), tumour necrosis factor alpha (TNF-alpha) and interleukin-1beta (IL-1beta). 3. All parameters of inflammation were attenuated in a dose-dependent manner by GW274150 (2.5, 5 and 10 mg x kg(-1) injected i.p. 5 min before carrageenan). 4. Carrageenan induced an upregulation of the intracellular adhesion molecules-1 (ICAM-1), as well as nitrotyrosine and poly (ADP-ribose) (PAR) as determined by immunohistochemical analysis of lung tissues. 5. The degree of staining for the ICAM-1, nitrotyrosine and PAR was reduced by GW274150. These results clearly confirm that NO from iNOS plays a role in the development of the inflammatory response by altering key components of the inflammatory cascade. 6. GW274150 may offer a novel therapeutic approach for the management of various inflammatory diseases where NO and related radicals have been postulated to play a role.

Animals↗