Chronic obstructive pulmonary disease (
COPD) is characterized by
pulmonary inflammation, which is relatively insensitive to inhaled
corticosteroids. The extent of the
pulmonary inflammation in
COPD correlates with disease severity, and it is thought to play a significant role in
disease progression. We have evaluated a selective p38alpha-selective
mitogen-activated protein kinase (MAPK) inhibitor,
indole-5-carboxamide (
ATP-competitive inhibitor of p38
kinase) (SD-282), in an 11-day model of tobacco
smoke (TS)-induced
pulmonary inflammation in A/J mice, by using
dexamethasone as a reference
steroid. Two oral treatment paradigms were evaluated in this TS model: prophylactic with daily pretreatment before each daily exposure, and therapeutic with daily treatment for 6 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 composed 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. Furthermore,
SD 282 reduced TS-induced increases in
cyclooxygenase-2 and
interleukin-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 p38alpha-selective MAPK 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.