A molecular pharmacological therapy for asthma based on phenotype changing in the structural cells in airways

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Sphinosine-1-phosphate (S1P) is released from mast cells by the inflammatory reaction in asthma. The inhibitory effects of β_2-adrenergic receptor agonists were markedly attenuated after exposure of airway smooth muscle to S1P. The expression of adhesion molecules (VCAM-1, ICAM-1) were enhanced after exposure of human pulmonary microvascular endothelial cells to S1P. Adherence of eosinophil to the endothelial cells was also increased under this experimental condition. When an antigen was administrated to sensitized mice, eosinophils and inflammatory cytokines were significantly elevated around airways. Moreover, respiratory resistance in response to methacholine was markedly augmented. All of the phenomena were suppressed by Rho-kinase inhibitors. Hence, RhoA/Rho-kinase pathways may be contributed to the pathophysiology of asthma (β_2-adrenerigic desensitization, eosinophil inflammation, airway hyperresponsiveness etc) implicated in phonotype changes of the structural cells the airways. Rho-kinase may be target protein for asthma therapy.