Grants and Contracts Details
Protease-activated receptor-2 (PAR2) is expressed in various cells in the airways and lungs including epithelial cells, airway smooth muscle, endothelial cells, fibroblasts as well as inflammatory cells such as mast cells, neurophils and macrophages. Increasing evidence has suggested that activation of PAR2 by endogenous or exogenous agonists such as mast cell tryptase, trypsin-like proteases and certain house mite allergens, contributes to airway inflammation and airway hyperresponsiveness, two prominent features of many respiratory diseases such as asthma that causes mortality and disability in millions of Americans. The mechanism of the potent actions of PAR2 in the airways and lungs remains to be explored; and an involvement of neurogenic mechanism caused by the activation of pulmonary C-fibers has been recently suggested. It has been we11 documented that hypersensitivity of these C fiber afferents plays an important role in the manifestation of airway hyperresponsiveness in various pathophysiological conditions. In addition, symptoms known to involve bronchopulmonary C· fiber activation, such as cough, bronchoconstriction and dyspnea, are commonly reported in patients suffering from airway inflammatory diseases. The primary objective of this proposed study is to uncover the mechanism involved in the interaction between PAR2 and C-fiber sensory nerves in the airways. Our central hypothesis is that activation of PAR2 increases the excitability of pulmonary C-fiber afferents by altering the function of certain ion channels in these sensory neurons. We will employ several experimental approaches including in-vivo single-fiber recording, in-vitro patch-c1amp recording and calcium imaging, as well as RT -PCR, to test this hypothesis. Our preliminary data have already demonstrated the feasibility and potential significance of the proposed study. The results obtained from this study should help to improve our understanding of the pathogenic role of the interaction between PAR2 and pulmonary sensory nerves. These results should, therefore, provide crucial information for gaining new insights into the mechanism underlying the airway hyperresponsiveness induced by PAR2 activation, which may offer new therapeutic strategies for the treatment of airway inflammatory diseases such as asthma.
|Effective start/end date||7/1/06 → 6/30/08|
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