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

作者：Brando Lima Aline C; Machado Alexandre L; Simon Patricia; Cavalcante Moises M; Rezende Daniele C; Sperandio da Silva Gilberto M; Nascimento Paulo Gustavo B D; Quintas Luis E M^*; Cunha Fernando Q; Barreiro Eliezer J; Lima Lidia M; Koatz Vera L G

来源：Pharmacological Reports, 2011, 63(4): 1029-1039.

• LASSBio-998
• INF-alpha
• lung inflammation
• p38 mitogen-activated protein kinase
• anti-inflammatory drug candidate

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-alpha (tumor necrosis factor-alpha) 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-alpha and IL-I beta, 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.

• 出版日期2011-8
• 单位河北医科大学