The anti-inflammatory activity of Ebselen but not thiols in experimental alveolitis and bronchiolitis

Abstract

This paper describes the effects of the thiol compounds glutathione and N-acetylcysteine and the seleno-organic agent Ebselen on the development of Sephadex-induced lung edema and cell infiltration in the rat. Neither thiol had any effect upon the development of the edema when administered in large, repeated doses. In contrast, when Ebselen was co-administered with the thiols, there was a dose-dependent inhibition of the development of the edema, but lung weights could not be returned to normal values. However, when the thiols were omitted and Ebselen was administered alone, the development of the edema was totally blocked. In addition, in Ebselen-only treated animals there was a selective inhibition of the infiltration of lymphocytes, basophils and eosinophils into the lung lumen without affecting the populations of macrophages and neutrophils. Again, the Ebselen-induced effect was reduced by coadministration of either thiol. These findings are discussed in terms of the potential mechanism of action of Ebselen in vivo and of the possibility of Ebselen being of therapeutic potential in cases of diffuse pulmonary inflammation in humans.

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

“…This effect was completely inhibited in a dose-dependent fashion by ebselen with an ED50 of 4.6 mg . kg -1 and confirms previous preliminary findings [1] in which COTGREAVE et al [1] demonstrated 98% inhibition of Sephadex-induced lung oedema at a single dose of 10 mg . kg -1 .…”

“…COTGREAVE et al [1] have also demonstrated that ebselen inhibits infiltration of eosinophils, lymphocytes and basophils into the airway lumen in response to Sephadex whilst leaving the macrophage and neutrophil populations largely unchanged. This profile of biological activity would appear to be ideal for a compound targeted at treating lung inflammatory diseases as ebselen possesses the required anti-inflammatory activity whilst allowing continued protection of the lung from opportunistic infections by the presence of macrophages and neutrophils.…”

“…kg -1 . The dosing regimen was determined from a previous study [1] which demonstrated preliminary data describing the inhibitory activity of a single dose of ebselen (10 mg . kg -1 , i.p.)…”

“…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].…”

“…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].…”