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

Abstract

SB 203580 is a pyridinyl imidazole compound which inhibits the release of pro-inflammatory cytokines, such as tumour necrosis factor-a (TNF-a) and interleukin-1b (IL-1b), in vitro and in vivo by inhibiting p38 mitogen-activated protein kinase (MAPK).The present study investigated the effects of SB 203580 in a model of airway inflammation induced by the topical administration of Sephadex into the rat airways. This inflammatory response is characterized by the development of lung oedema, airway tissue inflammatory cell recruitment and an increase in lung TNF-a and IL-1b levels.Sephadex-induced lung oedema was accompanied by a significant increase in lung tissue TNF-a but not IL-1b levels. There was also a significant increase in lung tissue macrophages and an increase in eosinophils which did not reach significance. SB 203580 administration significantly inhibited lung oedema (ED50=18 mg . kg -1 ) in a dose-related manner but was without significant effect on lung tissue cell recruitment or cytokine levels.These data suggest that the increase in tumour necrosis factor-a and lung oedema are separate processes which both contribute to Sephadex pathology. Furthermore, the inhibitory effect of SB 203580 on Sephadex-induced lung oedema suggests that p38 kinase inhibitors may be of use in pulmonary pathologies in which lung oedema is a feature. The Sephadex model of lung oedema in the rat is a model characterized by acute alveolitis and bronchiolitis, leading to inflammatory cell infiltration and interstitial oedema. 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]. The molecular target of this and related compounds has been identified as p38 mitogen-activated protein kinase (MAPK) [4]. In addition to in vitro data, p38 kinase inhibitors, such as SB 203580, have been shown to inhibit LPS-induced systemic TNF-a release in rats [5,6] and has been shown to be efficacious in in vivo models of arthritis [5] and inflammatory angiogenesis [7]. Furthermore, it has recently been demonstrated that in the airways SB 203580 inhibits bronchoalveolar (BAL) IL-1b levels and the associated neutrophilia in an LPS-induced model of airway inflammation in the rat [6] and BAL TNF-a levels following allergen challenge in sensitized Brown Norway rats [8].Increased levels of TNF-a in the airways following Sephadex treatment have been suggested to play a causative role in Sephadex-induced lung pathology [9]. In this study the effect of SB 203580 on Sephadex-induced airway inflammation in the rat was examined. Materials and methods AnimalsMale,...

Inflammation-promoting activity of HMGB1 on human microvascular endothelial cells

“…lung tissue TNF levels, suggesting these are distinct cellular processes. 56 Because neither SB203580 nor PD98059 affect JNK MAP kinase activation, this pathway may assume greater prominence when the p38 pathway is inhibited. Thus, TNF secretion and its effects on microvascular endothelial cells following HMGB1 stimulation may not be solely controlled by the p38 MAP kinase signaling pathway and may result from activation of other intracellular signals.…”

Selective Suppression of Neutrophil Accumulation in Ongoing Pulmonary Inflammation by Systemic Inhibition of p38 Mitogen-Activated Protein Kinase

“…Initial studies established the ability of p38 MAPK inhibitors to reduce neutrophil influx and cytokine release in models of peritonitis and arthritis in the absence of generalized immunosuppression (37)(38)(39)(40)(41)(42)(43)(44). Early studies predominately used first generation p38 MAPK inhibitors such as the pyridinyl imadazoles SK&F86002 and SB203580 (39,(45)(46)(47)(48). SB203580 has considerable inhibitory effects toward c-Raf and JNK2␣1.…”

Modulation of inflammation and pathology during dengue virus infection by p38 MAPK inhibitor SB203580

“…69 Although inhibition of these inflammatory mediators has been 70 studied in chronic inflammatory syndromes for decades, it is only 71 recently that such approach has been developed for treatment of 72 patients with acute inflammation (Schieven, 2009). Along this line, 73 SB203580, a p38 MAPK inhibitor, suppresses in vitro production of 74 TNF-a and reduces pro-inflammatory cytokines in mice and rats 75 (Birrell et al, 2000;Yong et al, 2009;Escott et al, 2000). 76 Two MAPKs, p38 and ERK1/2, were recently found to be acti- .…”