Anti-inflammatory effects of LASSBio-998,a new drug candidate designed to be a p38 MAPK inhibitor,in an experimental model of acute lung inflammation

We investigated the effects of lassbio-998 (l-998),a compound designed to be a p38 mapk (mitogen-activated protein kinase) inhibitor,on lipopolysaccharide (lps)-induced acute lung inflammation in vivo. balb/c mice were challenged with aerosolized lps inhalation (0.5 mg/ml) 4 h after oral administration of l-998. three hours after lps inhalation,bronchoalveolar lavage fluid was obtained to measure the levels of the proinflammatory cytokines tnf-α (tumor necrosis factor-α) and il-1 (interleukin-1) and the chemokines mcp-1 (monocyte chemoattractant protein-1) and kc (keratinocyte chemoattractant). in addition,neutrophil infiltration and p38 mapk phosphorylation was measured. l-998 inhibited lps-induced production of tnf-α and il-1β,and did not alter kc and mcp-1 levels. furthermore,l-998 also significantly decreased neutrophil accumulation in lung tissues. as expected,l-998 diminished p38 mapk phosphorylation and reduced acute lung inflammation. inhibition of p38 mapk phosphorylation by l-998 was also demonstrated in lps-challenged murine c57bl/6 peritoneal macrophages in vitro,with concentration-dependent effects. l-998 suppressed lps-induced lung inflammation,most likely by inhibition of the cytokine-p38 mapk pathway,and we postulate that l-998 could be a clinically relevant anti-inflammatory drug candidate. copyright © 2011 by institute of pharmacology polish academy of sciences.