Schaafsma Dedmer, Bos I Sophie T, Zuidhof Annet B, Zaagsma Johan, Meurs Herman
Department of Molecular Pharmacology, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
Respir Res. 2006 Sep 26;7(1):121. doi: 10.1186/1465-9921-7-121.
In guinea pigs, we have previously demonstrated that the contribution of Rho-kinase to airway responsiveness in vivo and ex vivo is enhanced after active sensitization with ovalbumin (OA). Using conscious, unrestrained OA-sensitized guina pigs, we now investigated the role of Rho-kinase in the development of airway hyperresponsiveness (AHR) after the allergen-induced early (EAR) and late asthmatic reaction (LAR) in vivo.
Histamine and PGF2alpha PC100-values (provocation concentrations causing 100% increase in pleural pressure) were assessed before OA-challenge (basal airway responsiveness) and after the OA-induced EAR (5 h after challenge) and LAR (23 h after challenge). Thirty minutes later, saline or the specific Rho-kinase inhibitor Y-27632 (5 mM, nebulizer concentration) were nebulized, after which PC100-values were reassessed.
In contrast to saline, Y-27632 inhalation significantly decreased the basal responsiveness toward histamine and PGF2alpha before OA-challenge, as indicated by increased PC100 -values. Both after the allergen-induced EAR and LAR, AHR to histamine and PGF2alpha was present, which was reversed by Y-27632 inhalation. Moreover, there was an increased effectiveness of Y-27632 to reduce airway responsiveness to histamine and PGF2alpha after the EAR and LAR as compared to pre-challenge conditions. Saline inhalations did not affect histamine or PGF2alpha PC100-values at all. Interestingly, under all conditions Y-27632 was significantly more effective in reducing airway responsiveness to PGF2alpha as compared to histamine. Also, there was a clear tendency (P = 0.08) to a more pronounced degree of AHR after the EAR for PGF2alpha than for histamine.
The results indicate that inhalation of the Rho-kinase inhibitor Y-27632 causes a considerable bronchoprotection to both histamine and PGF2alpha. Moreover, the results are indicative of a differential involvement of Rho-kinase in the agonist-induced airway obstruction in vivo. Increased Rho-kinase activity contributes to the allergen-induced AHR to histamine and PGF2alpha after both the EAR and the LAR, which is effectively reversed by inhalation of Y-27632. Therefore, Rho-kinase can be considered as a potential pharmacotherapeutical target in allergic asthma.
在豚鼠中，我们之前已经证明，在用卵清蛋白（OA）进行主动致敏后，Rho激酶在体内和体外对气道反应性的作用会增强。现在，我们使用清醒、未束缚的OA致敏豚鼠，研究了Rho激酶在变应原诱导的体内早期哮喘反应（EAR）和晚期哮喘反应（LAR）后气道高反应性（AHR）发展中的作用。
在OA激发前（基础气道反应性）以及OA诱导的EAR（激发后5小时）和LAR（激发后23小时）后，评估组胺和PGF2α的PC100值（引起胸膜压力增加100%的激发浓度）。30分钟后，雾化吸入生理盐水或特异性Rho激酶抑制剂Y-27632（5 mM，雾化器浓度），之后重新评估PC100值。
与生理盐水相比，吸入Y-27632可显著降低OA激发前对组胺和PGF2α的基础反应性，表现为PC100值升高。在变应原诱导的EAR和LAR后，均出现了对组胺和PGF2α的AHR，吸入Y-27632可使其逆转。此外，与激发前相比，EAR和LAR后Y-27632降低气道对组胺和PGF2α反应性的效果增强。吸入生理盐水对组胺或PGF2α的PC100值完全没有影响。有趣的是，在所有条件下，与组胺相比，Y-27632在降低气道对PGF2α的反应性方面显著更有效。此外，EAR后PGF2α的AHR程度比组胺更明显，有明显的趋势（P = 0.08）。
结果表明，吸入Rho激酶抑制剂Y-27632对组胺和PGF2α均有显著的支气管保护作用。此外，结果表明Rho激酶在体内激动剂诱导的气道阻塞中存在不同程度的参与。Rho激酶活性增加导致EAR和LAR后变应原诱导的对组胺和PGF2α的AHR，吸入Y-27632可有效逆转。因此，Rho激酶可被视为过敏性哮喘潜在的药物治疗靶点。
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