Anti-inflammatory properties of ebselen in a model of sephadex-induced lung inflammation

Abstract

Ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one), is a seleno-organic compound which protects tissues against oxidative stress. Furthermore, recent data has suggested that this compound possesses a range of anti-inflammatory properties.In this study the authors have investigated the effects of ebselen on Sephadexinduced lung oedema and bronchoalveolar lavage (BAL) tumour necrosis factor (TNF)-a and endothelin(ET)-1 levels in rats.Sephadex administration induced lung oedema which was accompanied by an increase in BAL TNF-a and ET-1 levels. Ebselen administration (1±30 mg . kg -1 , i.p. at 0, 4 and 12 h post Sephadex) significantly inhibited lung oedema (dose that produced 50% of the maximum inhibition of lung oedema 4.6 mg . kg -1 ) and BAL TNF-a levels in a dose-related manner with no effect on ET-1 levels.These data suggest that ebselen may be a useful therapy in lung pathologies in which bronchiolar inflammation is a feature. The Sephadex model of lung oedema in the rat is a model of acute alveolitis and bronchiolitis leading to inflammatory cell infiltration and interstitial oedema which appears to parallel many of the pathophysiological features associated with human interstitial lung diseases [1]. This model has been used previously to demonstrate the anti-inflammatory properties of compounds such as glucocorticosteroids based upon the modulation of lung oedema [2].Ebselen (2-phenyl-1,2-benzisoselenazol-3 (2H)-one) is a selenium-containing organic compound which has been found to protect tissue against oxidative attack by mimicking glutathione peroxidase and phospholipid hydroperoxide glutathione peroxidase [3]. In addition, ebselen possesses a range of anti-inflammatory activities including inhibition of the enzymes 5-lipoxygenase, inducible nitric oxide synthase, reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and inactivation of leukotriene B 4 to its biologically inactive 6-trans isomer [4]. In view of its interesting anti-inflammatory profile in a variety of animal models of inflammation [1,5], the authors investigated its effects in the Sephadex model of lung oedema. In addition, the effect of ebselen was examined on tumour necrosis factor (TNF)-a and endothelin(ET)-1 levels in the bronchoalveolar lavage (BAL) fluid from Sephadex-treated rats since these cytokines have been postulated to have a role in inflammatory lung disease [6±9]. Materials and methods AnimalsMale, Sprague-Dawley rats (350 g) were purchased from Harlan-Olac (Bicester, Oxfordshire, UK) and housed for 1 week before initiating experiments. Food and water were supplied ad libitum. Experiments were performed in accordance with the UK Home Office guidelines for animal welfare based on the Animals (Scientific Procedures) Act 1986 [10] and following approval from the Aventis Pharma Animal Care and Use Committee. MethodsRats were dosed intratracheally (i.t.) with vehicle (saline) or Sephadex beads (5 mg . kg -1 ) in a dose volume of 1 mL . kg -1 under halothane anaesthesia (4% in oxygen for 3 min). Ebselen (1...

Differential Effects of Ebselen on Neutrophil Recruitment, Chemokine, and Inflammatory Mediator Expression in a Rat Model of Lipopolysaccharide-Induced Pulmonary Inflammation

“…Furthermore, ebselen and dexamethasone were able to inhibit protein and mRNA expression for TNF-␣. These results are in agreement with data showing that ebselen inhibited, in a dose-related manner, BAL TNF-␣ induced by Sephadex particle instillation in the rat and also provided a significant protection against Sephadex-induced lung edema (62). Our data suggest that the inhibitory effect of ebselen on neutrophil influx and lung ICAM-1 expression may be achieved, at least in part, through inhibition of lung and BAL fluid TNF-␣ protein and/or mRNA expression.…”

Preclinical Profile of Ciclesonide, a Novel Corticosteroid for the Treatment of Asthma

“…24 h after Sephadex administration; body weight was recorded followed by the removal of the heart and lungs en bloc. Next, the lungs were excised, and determination of wet lung weights along with correction for 100 g of initial body weight was performed as previously described (Belvisi et al, 2000;Haddad et al, 2002).…”

Effect of the p38 kinase inhibitor, SB 203580, on sephadex induced airway inflammation in the rat

“…In fact this model appears to parallel many of the pathophysiological features associated with human interstitial lung diseases [1]. This model has been used previously to demonstrate the anti-inflammatory properties of compounds such as glucocorticosteroids and ebselen based upon their ability to modulate lung oedema [2,3]. SB 203580 (4-(4-fluorophenyl)-2-(4-methylsulphinylphenyl)-5-(4-pyridyl) imidazole) is a pyridinyl imidazole compound which inhibits interleukin (IL)-1b and tumour necrosis factor (TNF-a) production from human monocytes [4].…”

“…In fact this model appears to parallel many of the pathophysiological features associated with human interstitial lung diseases [1]. This model has been used previously to demonstrate the anti-inflammatory properties of compounds such as glucocorticosteroids and ebselen based upon their ability to modulate lung oedema [2,3].…”