Topical alpha-selective p38 MAP kinase inhibition reduces acute skin inflammation in guinea pig

Satyanarayana Medicherla, Jing Ying Ma, Mamtha Reddy, Irina Esikova, Irene Kerr, Fabiola Movius, Linda S Higgins, Andrew A ProtterScios Inc, Fremont, CA , USAAbstract: Certain skin pathologies, including psoriasis, are thought to be immune-mediated inflammatory diseases. Available literature clearly...

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Autores principales:	Satyanarayana Medicherla, Jing Ying Ma, Mamtha Reddy, et al
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2010
Materias:	Pathology RB1-214 Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/a53302a6ed954f01bd30c749aa66aea5
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spelling	oai:doaj.org-article:a53302a6ed954f01bd30c749aa66aea52021-12-02T07:20:21ZTopical alpha-selective p38 MAP kinase inhibition reduces acute skin inflammation in guinea pig1178-7031https://doaj.org/article/a53302a6ed954f01bd30c749aa66aea52010-02-01T00:00:00Zhttp://www.dovepress.com/topical-alpha-selective-p38-map-kinase-inhibition-reduces-acute-skin-i-a3988https://doaj.org/toc/1178-7031Satyanarayana Medicherla, Jing Ying Ma, Mamtha Reddy, Irina Esikova, Irene Kerr, Fabiola Movius, Linda S Higgins, Andrew A ProtterScios Inc, Fremont, CA , USAAbstract: Certain skin pathologies, including psoriasis, are thought to be immune-mediated inflammatory diseases. Available literature clearly indicates the involvement of inflammatory cells (neutrophils, T cells, and macrophages), their cytokines, and the p38 mitogen-activated protein kinase (MAPK) signaling pathway in the pathophysiology of psoriasis. Neutrophils play an important role in the formation of acute inflammatory changes in psoriasis. Acute inflammation or acute flares in psoriasis remain poorly addressed in clinical medicine. In this communication, we first establish a simple and reproducible model for studying neutrophil-mediated acute skin inflammation. Using the hairless guinea pig, due to the similarity of skin architecture to that of human, acute inflammation was induced with an intradermal injection of 50 &mu;g/mL lipopolysaccharide (LPS) in 50 &mu;L solution. Myeloperoxidase (MPO) activity was measured by MPO-positive neutrophils and shown to increase for 24-hours post-injection. Simultaneously, the level of phosphorylated p38 MAPK was documented for 48-hours post-LPS injection in the skin. Next, we used this model to examine the therapeutic potential of an &alpha;-selective p38 MAPK inhibitor, SCIO-469. A comparison of topical application of SCIO-469 at 5 mg/mL or 15 mg/mL to vehicle revealed that SCIO-469 dose-dependently reduces acute skin inflammation and that this effect is statistically significant at the higher dose. Further examination of tissues that received this dose also revealed statistically significant reduction of MPO activity, phosphorylated p38 MAPK, interleukin-6, and cyclooxygenase-2. These data suggest that the &alpha;-selective p38 MAPK inhibitor, SCIO-469, acts as a topical anti-inflammatory agent via the p38 MAPK pathway to reduce neutrophil induced acute inflammation in the skin. These observations suggest that &alpha;-selective p38 MAPK inhibition may be an effective therapeutic strategy to manage acute skin inflammationKeywords: SCIO-469, skin, neutrophils, myeloperoxidase, phosphorylated p38, topical Satyanarayana MedicherlaJing Ying MaMamtha Reddyet alDove Medical PressarticlePathologyRB1-214Therapeutics. PharmacologyRM1-950ENJournal of Inflammation Research, Vol 2010, Iss default, Pp 9-16 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Pathology RB1-214 Therapeutics. Pharmacology RM1-950
spellingShingle	Pathology RB1-214 Therapeutics. Pharmacology RM1-950 Satyanarayana Medicherla Jing Ying Ma Mamtha Reddy et al Topical alpha-selective p38 MAP kinase inhibition reduces acute skin inflammation in guinea pig
description	Satyanarayana Medicherla, Jing Ying Ma, Mamtha Reddy, Irina Esikova, Irene Kerr, Fabiola Movius, Linda S Higgins, Andrew A ProtterScios Inc, Fremont, CA , USAAbstract: Certain skin pathologies, including psoriasis, are thought to be immune-mediated inflammatory diseases. Available literature clearly indicates the involvement of inflammatory cells (neutrophils, T cells, and macrophages), their cytokines, and the p38 mitogen-activated protein kinase (MAPK) signaling pathway in the pathophysiology of psoriasis. Neutrophils play an important role in the formation of acute inflammatory changes in psoriasis. Acute inflammation or acute flares in psoriasis remain poorly addressed in clinical medicine. In this communication, we first establish a simple and reproducible model for studying neutrophil-mediated acute skin inflammation. Using the hairless guinea pig, due to the similarity of skin architecture to that of human, acute inflammation was induced with an intradermal injection of 50 &mu;g/mL lipopolysaccharide (LPS) in 50 &mu;L solution. Myeloperoxidase (MPO) activity was measured by MPO-positive neutrophils and shown to increase for 24-hours post-injection. Simultaneously, the level of phosphorylated p38 MAPK was documented for 48-hours post-LPS injection in the skin. Next, we used this model to examine the therapeutic potential of an &alpha;-selective p38 MAPK inhibitor, SCIO-469. A comparison of topical application of SCIO-469 at 5 mg/mL or 15 mg/mL to vehicle revealed that SCIO-469 dose-dependently reduces acute skin inflammation and that this effect is statistically significant at the higher dose. Further examination of tissues that received this dose also revealed statistically significant reduction of MPO activity, phosphorylated p38 MAPK, interleukin-6, and cyclooxygenase-2. These data suggest that the &alpha;-selective p38 MAPK inhibitor, SCIO-469, acts as a topical anti-inflammatory agent via the p38 MAPK pathway to reduce neutrophil induced acute inflammation in the skin. These observations suggest that &alpha;-selective p38 MAPK inhibition may be an effective therapeutic strategy to manage acute skin inflammationKeywords: SCIO-469, skin, neutrophils, myeloperoxidase, phosphorylated p38, topical
format	article
author	Satyanarayana Medicherla Jing Ying Ma Mamtha Reddy et al
author_facet	Satyanarayana Medicherla Jing Ying Ma Mamtha Reddy et al
author_sort	Satyanarayana Medicherla
title	Topical alpha-selective p38 MAP kinase inhibition reduces acute skin inflammation in guinea pig
title_short	Topical alpha-selective p38 MAP kinase inhibition reduces acute skin inflammation in guinea pig
title_full	Topical alpha-selective p38 MAP kinase inhibition reduces acute skin inflammation in guinea pig
title_fullStr	Topical alpha-selective p38 MAP kinase inhibition reduces acute skin inflammation in guinea pig
title_full_unstemmed	Topical alpha-selective p38 MAP kinase inhibition reduces acute skin inflammation in guinea pig
title_sort	topical alpha-selective p38 map kinase inhibition reduces acute skin inflammation in guinea pig
publisher	Dove Medical Press
publishDate	2010
url	https://doaj.org/article/a53302a6ed954f01bd30c749aa66aea5
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Topical alpha-selective p38 MAP kinase inhibition reduces acute skin inflammation in guinea pig

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