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 μg/mL
lipopolysaccharide (LPS) in 50 μL
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 α-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 α-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 α-selective
p38 MAPK inhibition may be an effective therapeutic strategy to manage acute skin
inflammation.