Received for publication June 28, 2007.
Revised November 27, 2007.
Accepted for publication November 28, 2007.

p38 Selective MAP kinase inhibitor, SD-282, reduces inflammation in a sub-chronic model of tobacco smoke-induced airway inflammation

Abstract

Chronic obstructive pulmonary disease (COPD) is characterised by pulmonary inflammation, which is relatively insensitive to inhaled corticosteroids (ICS). The extent of the pulmonary inflammation in COPD correlates with disease severity and is thought to play a significant role in disease progression. We have evaluated a selective p38 selective MAPK inhibitor, SD-282, in an 11 day model of tobacco smoke (TS) induced pulmonary inflammation in A/J mice, using dexamethasone as as a reference steroid. Two oral treatment paradigms were evaluated in this TS model: prophylactic with daily pre-treatment prior to each daily exposure, and therapeutic with daily treatment for six days commencing after 5 days of smoke exposure. Bronchoalveolar lavage and histological evaluation of lung sections taken after exposure to TS revealed an inflammatory response comprised of increased numbers of macrophages and neutrophils and enhanced mucin staining. Phospho-p38 staining in macrophages and type II epithelial cells after TS exposure was also observed. Given prophylactically or therapeutically, dexamethasone failed to inhibit any of the TS-induced inflammatory changes. By contrast, SD-282 inhibited TS-induced increases in macrophages and neutrophils. Further, SD 282 reduced TS-induced increases in COX-2 and IL-6 levels, and phospho-p38 expression in the lungs. In conclusion, SD-282 markedly reduced TS-induced inflammatory responses when given prophylactically or therapeutically whereas dexamethasone was ineffective. This is the first evidence that a p38 selective MAP kinase inhibitor can exert pulmonary anti-inflammatory activity in a TS exposure model when given in a therapeutic mode, establishing the potential of p38 MAPK inhibitors as a therapy for COPD.

Key words: COPD, Macrophages, Neutrophils, Phospho-p38, SD-282, dexamethasone

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