Mechanisms of asthma and allergic inflammation
Proasthmatic effects and mechanisms of action of the dust mite allergen, Der p 1, in airway smooth muscle

https://doi.org/10.1016/j.jaci.2005.03.046Get rights and content

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.

Conclusion

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.

Section snippets

Animals

Thirty-four adult New Zealand White rabbits were used in this study, which was approved by the Biosafety and Animal Research Committee of the Joseph Stokes Research Institute at Children's Hospital of Philadelphia. The animals had no signs of respiratory disease for several weeks before the study, and their care and use were in accordance with the Guide for the Care and Use of Laboratory Animals prepared by the Institute of Laboratory Animal Resources, National Research Council.

Preparation and Der p 1 treatment of rabbit ASM tissues

After general

Effects of Der p 1 on rabbit ASM responsiveness

To assess the effects of Der p 1 on ASM responsiveness, agonist-mediated constrictor and relaxation responses were compared in control and Der p 1–exposed isolated rabbit ASM segments, both in the absence and presence of E-64 (1 μmol/L). As shown in Fig 1, relative to control tissues, ASM segments exposed to a maximally effective dose of Der p 1 (ie, 1 μg/mL) exhibited increased constrictor responses to exogenously administered acetylcholine. Accordingly, relative to the mean ± SE maximal

Discussion

To our knowledge, the results of the current study are the first to demonstrate that the ubiquitous aeroallergen, Der p 1, can directly exert proasthmatic-like effects on ASM function that are characterized by enhanced agonist-mediated ASM contractility and impaired β-adrenoceptor–mediated ASM relaxation. Our observed actions of purified Der p 1 on ASM function were attributed to its intrinsic cysteine protease activity, because the induced changes in ASM responsiveness were largely prevented

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    Supported by National Heart, Lung, and Blood Institute grants HL-31467 and HL-61038.

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