Received for publication February 20, 2007.
Revised April 23, 2007.
Accepted for publication April 24, 2007.

Attenuation of ozone-induced airway inflammation and hyperresponsiveness by c-Jun NH₂ terminal kinase inhibitor, SP600125

Abstract

Ozone has potent oxidising properties and exposure to ozone causes airway hyperresponsiveness (AHR) and lung inflammation. We determined the importance of c-Jun NH₂ terminal kinase (JNK), a member of the mitogen-activated protein kinase pathway (MAPK), in ozone-induced AHR and inflammation. SP600125, a specific JNK inhibitor (30mg/kg) or vehicle, was administered by intraperitoneal injection prior to and following ozone exposure (3ppm for 3hours). SP600125 significantly reduced total cells and neutrophils in bronchoalveolar fluid recovered at 20-24h following exposure and inhibited ozone-induced AHR. Ozone exposure induced activation of JNK in the lung as measured by the expression of phosphorylated-c-Jun, an effect abolished by SP600125. Affymetrix gene-microarray revealed that ozone increased the expression of over 400 genes by more than 2-fold, including interleukin-6 (IL-6), CXCL1 (KC) and CCL2 (MCP-1). SP600125 modulated the expression of a subset 29 ozone-induced genes: IL-6 and CCL2 expression were further increased whilst metallothionein (MT-1), hemopexin and MAP3K6 expression were decreased in SP600125-treated ozone-exposed mice. Changes in mRNA for IL-6, CXCL1 and CCL2 were confirmed by real-time PCR. Ozone also decreased the expression of over 500 genes, with the most potent effect on angiopoietin-1. SP600125 modulated the expression of 15 of these genes, and in particular, SP600125 reversed ozone-induced decrease in expression of the redox sensitive transcription factor, hypoxia-induced factor-1. This study highlights an important role for JNK in response to oxidative stress through modulation of specific inflammatory and redox mediators. Inhibition of JNK with small molecule kinase inhibitors may be a means of reducing ozone-induced inflammation and AHR.

Key words: bronchial responsiveness, c-jun NH2 terminal kinase, inflammation, neutrophil, oxidative stress, ozone

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