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

1-磷酸鞘氨醇（S1 P）是由哮喘的炎症反应从肥大细胞释放的。β_2-肾上腺素能受体激动剂的抑制作用在S1 P作用下明显减弱。S1 P作用于人肺微血管内皮细胞后，粘附分子VCAM-1、ICAM-1表达增强。在本实验条件下，嗜酸性粒细胞对内皮细胞的粘附也增加。当抗原被给予致敏小鼠时，气道周围的嗜酸性粒细胞和炎性细胞因子显著升高。此外，乙酰甲胆碱反应的呼吸阻力显着增强。Rho激酶抑制剂可抑制上述现象。因此，RhoA/Rho激酶通路可能参与了哮喘的病理生理过程（β_2-肾上腺素样脱敏、嗜酸性粒细胞炎症、气道高反应性等），与气道结构细胞的表型改变有关。Rho激酶可能成为哮喘治疗的靶蛋白。

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.