Importance of p38 mitogen-activated protein kinase pathway in allergic airway remodelling and bronchial hyperresponsiveness.
p38 mitogen-activated protein kinase (MAPK) plays an important role in the activation of inflammatory cells and in the proliferation of airway structural cells. We investigated the role of p38 MAPK by using a selective inhibitor of p38 alpha and beta isoforms, SD282, in a chronic model of 15 ovalbumin exposures in sensitised mice using two doses (30 and 90 mg/kg). Allergen exposure induced bronchial hyperresponsiveness to methacholine as measured by the concentration of methacholine needed to increase pulmonary resistance by 200% (PC200), eosinophilia in bronchoalveolar lavage fluid and increase in airway smooth muscle area and goblet cell hyperplasia. In addition, p38 MAPK activity as measured by phosphorylated p38 expression on Western blots was increased after allergen challenge, which was suppressed by SD282 at both doses. SD282 inhibited bronchial hyperresponsiveness, but had no effect on eosinophils in bronchoalveolar lavage fluid. It also reduced airway smooth muscle and goblet cell hyperplasia, but had no effect on serum immunoglobulin E. p38 MAPK is involved in the pathogenesis of bronchial hyperresponsiveness but not in eosinophilic inflammation or the allergic response; however, remodelling features such as airway smooth muscle or goblet cell hyperplasia are regulated through p38 MAPK. Furthermore, bronchial hyperresponsiveness induced by chronic allergen exposure may be related to the development of airway wall remodelling.
Nath
Puneeta
P
National Heart and Lung Institute, Imperial College, Dovehouse Street, London SW3 6LY, UK.
Leung
Sum-Yee
SY
Williams
Alison
A
Noble
Alistair
A
Chakravarty
Sundeep Dugar Sarvajit
SD
Luedtke
Gregory R
GR
Medicherla
Satyanarayana
S
Higgins
Linda S
LS
Protter
Andrew
A
Chung
Kian Fan
KF
D000423:Alcian Blue / Q000494:pharmacology; D000818:Animals; D001980:Bronchi / Q000473:pathology; D016535:Bronchial Hyperreactivity / Q000473:pathology*; D004789:Enzyme Activation; D007073:Immunoglobulin E / Q000097:blood; D007211:Indoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D012137:Respiratory System / Q000378:metabolism* / Q000473:pathology; D012545:Schiff Bases / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D007211:Indoles; D012545:Schiff Bases; C514526:indole-5-carboxamide; D007073:Immunoglobulin E; D048051:p38 Mitogen-Activated Protein Kinases; D000423:Alcian Blue