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.
Journal Title: Pharmacological Reports - Year 2011, Vol 63, Issue 4
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 and Affiliations
Aline Brando Lima, Alexandre Machado, Patrícia Simon, Moisés Cavalcante, Daniele Rezende, Gilberto Sperandio da Silva, Paulo Nascimento, Luis Quintas, Fernando Cunha, Eliezer Barreiro, Lídia Lima, Vera Koatz
Keywords
Related Articles
- EP ID EP129722
- DOI -
- Views 76
- Downloads 0
Disparate effects of anti-TNF-α therapies on measures of disease activity and mediators of endothelial damage in ankylosing spondylitis.
Asymmetric dimethylarginine (ADMA) is associated with endothelial injury. Increased ADMA levels are found in rheumatoid arthritis (RA) and ankylosing spondylitis (AS). We set out to assess the ADMA and symmetric dimethyl...
Selenitetriglicerydes affect CYP1A1 and QR activity by involvement of reactive oxygen species and Nrf2 transcription factor.
Selenitetriglycerides are a group of compounds that contain selenium (Se) (IV). In this paper, we present the results of examinations of three structurally-related selenitetriglicerydes that contain various Se concentrat...
Role of β-adrenoceptors, cAMP phosphodiesterase and external Ca(2+) on polyamine-induced relaxation in isolated bovine tracheal strips.
Polyamines relax several smooth muscles and elicit cardiotonic effects in the rat heart via interactions with β-adrenoceptors. The aim of this work was to establish whether β(2)-adrenoceptors were involved in polyamine-r...
Purvalanol A, inhibitor of cyclin-dependent kinases attenuates proliferation of cells in the dentate gyrus of the adult rat hippocampus.
Several recent findings indicate that intensity of neurogenesis in adult brain might be regulated by enzymes involved in the cell cycle. Therefore, in the present study, we investigated whether the inhibition of cyclin-d...
Anti-diabetic effects of 1-methylnicotinamide (MNA) in streptozocin-induced diabetes in rats.
1-Methylnicotinamide (MNA), a major endogenous metabolite of nicotinamide, possesses anti-thrombotic and anti-inflammatory activity, and reverses endothelial dysfunction. In the present work, we investigated whether such...