title: 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.
abstract: 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.
authors: Laboratory of Cellular Immunopharmacology, Institute of Medical Biochemistry, Federal University of Rio de Janeiro, CCS, 21941-902, Rio de Janeiro, Brazil.
authors: Aline C
authors: AC
authors: Brando Lima
authors: Alexandre L
authors: AL
authors: Machado
authors: Patrícia
authors: P
authors: Simon
authors: Moisés M
authors: MM
authors: Cavalcante
authors: Daniele C
authors: DC
authors: Rezende
authors: Gilberto M
authors: GM
authors: Sperandio da Silva
authors: Paulo Gustavo B D
authors: PG
authors: Nascimento
authors: Luis E M
authors: LE
authors: Quintas
authors: Fernando Q
authors: FQ
authors: Cunha
authors: Eliezer J
authors: EJ
authors: Barreiro
authors: Lídia M
authors: LM
authors: Lima
authors: Vera L G
authors: VL
authors: Koatz
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001992:Bronchoalveolar Lavage Fluid; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D007249:Inflammation / Q000188:drug therapy* / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008168:Lung / Q000187:drug effects / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology*; D014508:Urea / Q000008:administration & dosage / Q000494:pharmacology* / Q000031:analogs & derivatives; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000893:Anti-Inflammatory Agents; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D011804:Quinolines; C569819:ethyl 6-cyclohexylurea-(1,3)dioxolo(5,4-g)quinoline-7-carboxylate; D014508:Urea; D048051:p38 Mitogen-Activated Protein Kinases