Proasthmatic effects and mechanisms of action of the dust mite allergen, Der p 1, in airway smooth muscle.
BACKGROUND
House dust mite allergen exposure is a key risk factor for the development of allergic asthma. Beyond provoking immune cell-mediated allergic responses, house dust mite allergens were recently shown to exert direct effects on airway structural cells secondary to their intrinsic protease activities.


OBJECTIVE
This study tested the hypothesis that house dust mite allergen exposure can produce changes in airway responsiveness through a direct effect on airway smooth muscle (ASM).


METHODS
Isolated rabbit ASM tissues were exposed to the house dust mite allergen, Der p 1, and induced changes in ASM responsiveness and activation of mitogen-activated protein kinase (MAPK) signaling pathways were examined under different experimental conditions.


RESULTS
The observations demonstrated the following: (1) Der p 1 exposure elicited enhanced constrictor responses and impaired relaxation responses in the ASM tissues, (2) these proasthmatic-like effects of Der p 1 were attributed to its intrinsic cysteine protease activity, and (3) the induced changes in ASM responsiveness were associated with activation of both the extracellular signal-regulated kinase (ERK) 1/2 and the p38 MAPK signaling pathways. Additionally, specific blockade of ERK1/2 signaling was found to prevent the Der p 1-induced changes in ASM responsiveness, whereas inhibition of p38 MAPK signaling enhanced the proasthmatic-like action of Der p 1, with the latter effect a result of augmented activation of ERK1/2.


CONCLUSIONS
These findings are the first to demonstrate that the dust mite allergen, Der p 1, can directly elicit changes in ASM responsiveness that are associated with activation of MAPK signaling, wherein proasthmatic effects induced by Der p 1 are attributed to activation of ERK1/2, whereas coactivation of p38 MAPK exerts a homeostatic action by negatively regulating ERK1/2 signaling.
Division of Pulmonary Medicine, Joseph Stokes Jr Research Institute, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. grunstein@email.chop.edu
Michael M
MM
Grunstein
Haviva
H
Veler
Xiaoyin
X
Shan
Joshua
J
Larson
Judith S
JS
Grunstein
Sing
S
Chuang
D000818:Animals; D039741:Antigens, Dermatophagoides / Q000276:immunology / Q000494:pharmacology*; D060829:Arthropod Proteins; D016535:Bronchial Hyperreactivity / Q000276:immunology*; D003546:Cysteine Endopeptidases; D004789:Enzyme Activation / Q000187:drug effects; D015151:Immunoblotting; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000276:immunology; D009924:Organ Culture Techniques; D011817:Rabbits; D014132:Trachea / Q000187:drug effects* / Q000276:immunology
D039741:Antigens, Dermatophagoides; D060829:Arthropod Proteins; D003546:Cysteine Endopeptidases; C451162:Dermatophagoides pteronyssinus antigen p 1