Regulation of prostaglandin generation in carrageenan-induced pleurisy by inducible nitric oxide synthase in knockout mice (original) (raw)
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American Journal of Respiratory and Critical Care Medicine, 2000
In the present study, we investigated the role of inducible (or type 2) nitric oxide synthase (iNOS) in the development of acute inflammation by comparing the responses in wild-type mice (WT) and mice lacking (knockout [KO]). When compared with carrageenantreated iNOS-WT mice, iNOS-KO mice that had received carrageenan exhibited a reduced degree of pleural exudation and polymorphonuclear cell migration. Lung myeloperoxidase (MPO) activity and lipid peroxidation were significantly reduced in iNOS-KO mice in comparison with iNOSWT mice. Immunohistochemical analysis for nitrotyrosine revealed positive staining in lungs from carrageenantreated iNOS-WT mice. Lung tissue sections from carrageenantreated iNOS-WT mice showed positive staining for poly adenosine diphosphate (ADP)-ribose synthetase that was mainly localized in alveolar macrophages and in airway epithelial cells. The intensity and degree of staining for nitrotyrosine and poly-ADP-ribose synthetase were markedly reduced in tissue sections from carrageenan-treated iNOS-KO mice. The inflamed lungs of iNOS-KO mice also showed an improved histologic status. Furthermore, a significant reduction in the suppression of energy status, in DNA strand breakage, and in decreased cellular levels of nicotinamide adenine dinucleotide (NAD ϩ) was observed ex vivo in macrophages harvested from the pleural cavity of iNOS-KO mice subjected to carrageenan-induced pleurisy. Taken together, our results clearly show that iNOS plays an important role in the acute inflammatory response.
The protective role of endogenous glutathione in carrageenan-induced pleurisy in the rat
European Journal of Pharmacology, 1999
Peroxynitrite, a potent cytotoxic oxidant formed by the reaction of nitric oxide (NO) with the superoxide anion, was recently proposed to play a major pathogenic role in the inflammatory process. Here we have investigated the effects of endogenous melatonin, a known scavenger of peroxynitrite, in rats subjected to carrageenan-induced pleurisy. Endogenous melatonin was depleted in rats maintained on 24 h light cycle for 1 wk. In vivo depletion of endogenous melatonin enhanced the carrageenan-induced degree of pleural exudation and polymorphonuclear leukocyte migration in rats subjected to carrageenan-induced pleurisy. Lung myeloperoxidase activity and lipid peroxidation were significantly increased in melatonin-deprived rats. However, the inducible NO synthase in lung samples was unaffected by melatonin depletion. Immunohistochemical analysis for nitrotyrosine revealed a positive staining in lungs from carrageenan-treated rats that was markedly enhanced in melatonin-deprived rats. Furthermore, melatonin depletion significantly increased peroxynitrite formation as measured by the oxidation of the fluorescent dye dihydrorhodamine 123, enhanced DNA damage and the decrease in mitochondrial respiration and reduced the cellular levels of NAD؉ in macrophages harvested from the pleural cavity of rats subjected to carrageenaninduced pleurisy. In vivo treatment with exogenous melatonin (15 mg/kg intraperitoneal) significantly reversed the effects of melatonin depletion. Thus, endogenous melatonin plays an important protective role against carrageenan-induced local inflammation.-Cuzzocrea, S., Tan, D.-X., Costantino, G., Mazzon, E., Caputi, A. P., Reiter, R. J. The protective role of endogenous melatonin in carrageenan-induced pleurisy in the rat. FASEB J. 13, 1930 -1938 (1999) 1930 0892-6638/99/0013-1930/$02.25 © FASEB * P Ͻ 0.01 vs. MEL ϩ/ϩ.
Naunyn-Schmiedeberg's Archives of Pharmacology, 1999
We studied the involvement of nuclear factor-κB (NF-κB) in the regulation of inducible nitric oxide synthase expression in carrageenin-induced rat pleurisy. Injection of 0.2 ml of 1% λ-carrageenin into the pleural cavity of male Wistar rats caused after 6 h: (a) exudate formation and leukocyte migration into the pleural cavity; (b) inducible NO synthase protein expression and accumulation of NO 2plus NO 3in pleural exudate; (c) increase in p50/p65 nuclear level as well as ΝF-κB/DNA binding activity. Treatment of rats with pyrrolidine dithiocarbamate (10, 30, and 100 mg/kg) and N-α-p-tosyl-L-lysine chloromethylketone (30 mg/kg), two inhibitors of NF-κB activation, given subcutaneously concomitantly with carrageenin, caused a significant inhibition of all the parameters assayed. These results suggest that in carrageenin-induced rat pleurisy the activation of ΝF-κB plays a key role in inducible NO synthase protein expression and in the development of inflammatory response.
European Journal of Pharmacology, 1983
Effects of several anti-inflammatory drugs on the various parameters involved in the inflammatory response in rat carrageenin-inducedpleurisy, European J. Pharmacol. 95 (1983) 1-12. In rat carrageenin pleurisy, both steroidal and non-steroidal anti-inflammatory drugs (SAID and NSAID respectively) produced a dose-related reduction of exudate volume and of prostaglandin (PG)E 2 contents in the exudate at 3 h after carrageenin. However, with the exception of ketoprofen, administration of all the NSAID in low doses resulted in a significant reduction of PGE 2 contents with no significant reduction in exudate volume. NSAID reduced leucocyte number and total activities of lysosomal enzymes in the exudate at 3 h after carrageenin only at the higher doses, while SAID did so in a dose-related manner. Both SAID and NSAID reduced the arylsulfatase activity released into the exudate (free activity) dose-relatedly but not the free activity of /3-glucuronidase at 3 h after carrageenin. However, some drug treatments resulted in a lower reduction in free arylsulfatase activity than in exudate volume. These results suggest that the reduction of PGE 2 contents may be the main contribution to the anti-exudative activities of anti-inflammatory drugs in rat carrageenin pleurisy and that this effect may be complemented by the reduction of free activity of lysosomal enzymes such as arylsulfatase.
Life Sciences, 1999
The aim of the present study was to investigate the effect of two inhibitors (3-aminobenzamide and nicotinamide) of poly (ADP-ribose) synthetase on the production of the inflammatory mediator prostaglandins in a model of acute inthunmation, carrageenan-induced pleurisy, where prostaglandms are known to play a crucial role. The results show that the poly (ADP-ribose) synthetase inhibitors, 3-aminob enzamide (2.5, 5 and 10 mg/kg) and nicotinamide (12.5, 25 and 50 mgikg), inhibit the intlammatory response (pleural exudate formation, polymorphonuclear cell intiltration and prostaglandin production). The present results demonstrate that inhibition of poly (ADP-ribose) synthetase exerts potent anti-intlammatory effects. Part of these anti-inflammatory effects may be related to a reduction of prostaglandin production during the inflammatory process.
Inflammation Research, 2010
Objective We report the effects of the gastrin-releasing peptide (GRP) receptor antagonist RC-3095 in an acute inflammation model induced by carrageenan. Methods Male Wistar rats received saline or saline containing 2% λ-carrageenan into the pleural cavity, with some also receiving RC-3095 3 mg/kg subcutaneously, immediately after surgery. Four hours later, the rats were killed and pleural exudate was obtained for evaluation of total cell count, lactate dehydrogenase activity, total protein, cytokines analysis and nitrite/nitrate concentrations; myeloperoxidase (MPO) activity and oxidative stress were evaluated in the lung. Results RC-3095 exhibited pronounced anti-inflammatory actions by inhibition of leukocyte influx and blockade of MPO, nitrite/nitrate and cytokine levels. Moreover, the results showed that RC-3095 elicits action against oxidative damage in lipids and proteins, as well as increasing cell viability. Conclusion The present findings suggest that GRP plays a role in acute inflammation that can be related with the reduction of oxidative damage and that it could be effective in therapeutic applications.
Role of cyclopentenone prostaglandins in rat carrageenin pleurisy
FEBS Letters, 2001
In this study, using rat carrageenin-induced pleurisy, we found that treatment of rats with either indomethacin or NS-398 suppressed the pleurisy at 2 h but significantly exacerbated this reaction at 48 h. Exacerbated inflammation was associated with reduced prostaglandin D(2) levels, decreased heat shock factor 1 (HSF1) activation, reduced hsp72 expression and increased activation of nuclear factor kappaB (NF-kappaB). Replacement of cyclopentenone prostaglandins by treating rats with either prostaglandin J(2) or prostaglandin D(2) reversed the exacerbating effects of cyclooxygenase inhibitors leading to the resolution of the reaction. In conclusion, we demonstrate that cyclopentenone prostaglandins may act as anti-inflammatory mediators by inducing in inflammatory cells HSF1-dependent hsp72 expression and NF-kappaB inhibition, two crucial events for the remission of inflammation.
Inflammation, 2011
The aim of this study was to investigate the anti-inflammatory efficacy of rosiglitazone (ROSI) in a pleurisy model of carrageenan-induced inflammation. Efficacy was monitored in the mouse pleural cavity by evaluating leukocyte migration, exudate concentration, and myeloperoxidase (MPO) and adenosine deaminase (ADA) activities concomitantly with nitrate/nitrite (NOx), tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin-17A (IL-17A), and vascular endothelial growth factor-alpha (VEGF-α) levels 4 and 48 h after pleurisy induction. In both phases (4 and 48 h) of pleurisy, ROSI inhibited all the inflammation parameters that were tested (p<0.05). These results provide evidence that ROSI was efficacious in inhibiting pro-inflammatory mediators. These anti-inflammatory effects are assumed to mainly result from the inhibition of products released from activated leukocytes, such as MPO, ADA, NOx, TNF-α, IL-1β, IL-17A, and VEGF-α.