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Oral and inhaled p38 MAPK inhibitors: effects on inhaled LPS challenge in healthy subjects
BACKGROUND: Inhaled LPS causes neutrophilic airway inflammation in healthy subjects. We compared the effects of p38 MAPK inhibitors and fluticasone propionate on the LPS response. METHODS: Three randomised, double-blind, placebo-controlled, single dose crossover studies were performed. Active treatm...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4564450/ https://www.ncbi.nlm.nih.gov/pubmed/26265232 http://dx.doi.org/10.1007/s00228-015-1920-1 |
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author | Singh, Dave Siew, Leonard Christensen, Jared Plumb, Jonathan Clarke, Graham W. Greenaway, Steve Perros-Huguet, Christelle Clarke, Nick Kilty, Iain Tan, Lisa |
author_facet | Singh, Dave Siew, Leonard Christensen, Jared Plumb, Jonathan Clarke, Graham W. Greenaway, Steve Perros-Huguet, Christelle Clarke, Nick Kilty, Iain Tan, Lisa |
author_sort | Singh, Dave |
collection | PubMed |
description | BACKGROUND: Inhaled LPS causes neutrophilic airway inflammation in healthy subjects. We compared the effects of p38 MAPK inhibitors and fluticasone propionate on the LPS response. METHODS: Three randomised, double-blind, placebo-controlled, single dose crossover studies were performed. Active treatments were the oral p38 MAPK inhibitor PH-797804 30 mg (study 1), PH-797804 30 mg and the inhaled p38 MAPK inhibitor PF-03715455 20 mg (study 2) and inhaled fluticasone propionate 500 μg (study 3). The primary endpoint was sputum neutrophil percentage. RESULTS: Sputum neutrophil percentage post-LPS challenge was significantly inhibited (15.1 and 15.3 % reduction) by PH-797804 compared to placebo in studies 1 and 2 (p = 0.0096 and 0.0001, respectively), and by PF-03715455 (8.0 % reduction, p = 0.031); fluticasone propionate had no effect. PH-797804 significantly inhibited the increase in inflammatory mediators (IL-6, MCP-1, MIP1β and CC16) in sputum supernatant, while PF-03715455 had no effect. PH-797804 and PF-03715455 both inhibited IL-6, MCP-1, MIP1β, CC16 and CRP levels in plasma, with PH-797804 having greater effects. Fluticasone propionate had no effect on sputum supernatant or plasma biomarkers. CONCLUSIONS: PH-797804 had the greatest impact on neutrophilic airway inflammation. Oral administration of p38 MAPK inhibitors may optimise pulmonary anti-inflammatory effects. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00228-015-1920-1) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-4564450 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-45644502015-09-15 Oral and inhaled p38 MAPK inhibitors: effects on inhaled LPS challenge in healthy subjects Singh, Dave Siew, Leonard Christensen, Jared Plumb, Jonathan Clarke, Graham W. Greenaway, Steve Perros-Huguet, Christelle Clarke, Nick Kilty, Iain Tan, Lisa Eur J Clin Pharmacol Clinical Trial BACKGROUND: Inhaled LPS causes neutrophilic airway inflammation in healthy subjects. We compared the effects of p38 MAPK inhibitors and fluticasone propionate on the LPS response. METHODS: Three randomised, double-blind, placebo-controlled, single dose crossover studies were performed. Active treatments were the oral p38 MAPK inhibitor PH-797804 30 mg (study 1), PH-797804 30 mg and the inhaled p38 MAPK inhibitor PF-03715455 20 mg (study 2) and inhaled fluticasone propionate 500 μg (study 3). The primary endpoint was sputum neutrophil percentage. RESULTS: Sputum neutrophil percentage post-LPS challenge was significantly inhibited (15.1 and 15.3 % reduction) by PH-797804 compared to placebo in studies 1 and 2 (p = 0.0096 and 0.0001, respectively), and by PF-03715455 (8.0 % reduction, p = 0.031); fluticasone propionate had no effect. PH-797804 significantly inhibited the increase in inflammatory mediators (IL-6, MCP-1, MIP1β and CC16) in sputum supernatant, while PF-03715455 had no effect. PH-797804 and PF-03715455 both inhibited IL-6, MCP-1, MIP1β, CC16 and CRP levels in plasma, with PH-797804 having greater effects. Fluticasone propionate had no effect on sputum supernatant or plasma biomarkers. CONCLUSIONS: PH-797804 had the greatest impact on neutrophilic airway inflammation. Oral administration of p38 MAPK inhibitors may optimise pulmonary anti-inflammatory effects. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00228-015-1920-1) contains supplementary material, which is available to authorized users. Springer Berlin Heidelberg 2015-08-13 2015 /pmc/articles/PMC4564450/ /pubmed/26265232 http://dx.doi.org/10.1007/s00228-015-1920-1 Text en © The Author(s) 2015 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. |
spellingShingle | Clinical Trial Singh, Dave Siew, Leonard Christensen, Jared Plumb, Jonathan Clarke, Graham W. Greenaway, Steve Perros-Huguet, Christelle Clarke, Nick Kilty, Iain Tan, Lisa Oral and inhaled p38 MAPK inhibitors: effects on inhaled LPS challenge in healthy subjects |
title | Oral and inhaled p38 MAPK inhibitors: effects on inhaled LPS challenge in healthy subjects |
title_full | Oral and inhaled p38 MAPK inhibitors: effects on inhaled LPS challenge in healthy subjects |
title_fullStr | Oral and inhaled p38 MAPK inhibitors: effects on inhaled LPS challenge in healthy subjects |
title_full_unstemmed | Oral and inhaled p38 MAPK inhibitors: effects on inhaled LPS challenge in healthy subjects |
title_short | Oral and inhaled p38 MAPK inhibitors: effects on inhaled LPS challenge in healthy subjects |
title_sort | oral and inhaled p38 mapk inhibitors: effects on inhaled lps challenge in healthy subjects |
topic | Clinical Trial |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4564450/ https://www.ncbi.nlm.nih.gov/pubmed/26265232 http://dx.doi.org/10.1007/s00228-015-1920-1 |
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