Rovati G Enrico, Baroffio Michele, Citro Simona, Brichetto Lorenzo, Ravasi Saula, Milanese Manlio, Crimi Emanuele, Brusasco Vito
Laboratory of Molecular Pharmacology, Section of Eicosanoid Pharmacology, Dept. of Pharmacological Sciences, University of Milan, Italy.
Respir Res. 2006 Jul 28;7(1):103. doi: 10.1186/1465-9921-7-103.
The response to beta2-adrenoceptor agonists is reduced in asthmatic airways. This desensitization may be in part due to inflammatory mediators and may involve cysteinyl-leukotrienes (cysteinyl-LTs). Cysteinyl-LTs are pivotal inflammatory mediators that play important roles in the pathophysiology of asthma, allergic rhinitis, and other inflammatory conditions. We tested the hypothesis that leukotriene D4 (LTD4) and allergen challenge cause beta2-adrenoceptor desensitization through the activation of protein kinase C (PKC).
The isoproterenol-induced cAMP accumulation was evaluated in human airway smooth muscle cell cultures challenged with exogenous LTD4 or the PKC activator phorbol-12-myristate-13-acetate with or without pretreatments with the PKC inhibitor GF109203X or the CysLT1R antagonist montelukast. The relaxant response to salbutamol was studied in passively sensitized human bronchial rings challenged with allergen in physiological salt solution (PSS) alone, or in the presence of either montelukast or GF109203X.
In cell cultures, both LTD4 and phorbol-12-myristate-13-acetate caused significant reductions of maximal isoproterenol-induced cAMP accumulation, which were fully prevented by montelukast and GF109203X, respectively. More importantly, GF109203X also prevented the attenuating effect of LTD4 on isoproterenol-induced cAMP accumulation. In bronchial rings, both montelukast and GF109203X prevented the rightward displacement of the concentration-response curves to salbutamol induced by allergen challenge.
LTD4 induces beta2-adrenoceptor desensitization in human airway smooth muscle cells, which is mediated through the activation of PKC. Allergen exposure of sensitized human bronchi may also cause a beta2-adrenoceptor desensitization through the involvement of the CysLT1R-PKC pathway.
哮喘气道对β2肾上腺素能受体激动剂的反应降低。这种脱敏现象可能部分归因于炎症介质，并且可能涉及半胱氨酰白三烯（cysteinyl-LTs）。半胱氨酰白三烯是关键的炎症介质，在哮喘、过敏性鼻炎及其他炎症性疾病的病理生理学中发挥重要作用。我们检验了白三烯D4（LTD4）和变应原激发通过激活蛋白激酶C（PKC）导致β2肾上腺素能受体脱敏的假说。
在用外源性LTD4或PKC激活剂佛波醇-12-肉豆蔻酸酯-13-乙酸酯刺激的人气道平滑肌细胞培养物中，评估异丙肾上腺素诱导的环磷酸腺苷（cAMP）积累，刺激时伴有或不伴有PKC抑制剂GF109203X或半胱氨酰白三烯1型受体（CysLT1R）拮抗剂孟鲁司特的预处理。在仅用生理盐溶液（PSS）或在存在孟鲁司特或GF109203X的情况下用变应原刺激的被动致敏人支气管环中，研究对沙丁胺醇的舒张反应。
在细胞培养物中，LTD4和佛波醇-12-肉豆蔻酸酯-13-乙酸酯均导致异丙肾上腺素诱导的最大cAMP积累显著减少，孟鲁司特和GF109203X分别完全阻止了这种减少。更重要的是，GF109203X也阻止了LTD4对异丙肾上腺素诱导的cAMP积累的减弱作用。在支气管环中，孟鲁司特和GF109203X均阻止了变应原激发诱导的沙丁胺醇浓度-反应曲线的右移。
LTD4在人气道平滑肌细胞中诱导β2肾上腺素能受体脱敏，这是通过PKC的激活介导的。致敏人支气管暴露于变应原也可能通过CysLT1R-PKC途径的参与导致β2肾上腺素能受体脱敏。
