Pigati Patricia Angeli, Righetti Renato Fraga, Possa Samantha Souza, Romanholo Beatriz Saraiva, Rodrigues Adriana Palmeira Dias, dos Santos Anelize Sartori Alves, Xisto Débora Gonçalves, Antunes Mariana Alves, Prado Carla Máximo, Leick Edna Aparecida, Martins Milton de Arruda, Rocco Patrícia Rieken Macedo, Tibério Iolanda de Fátima Lopes Calvo
Department of Medicine, School of Medicine, University of São Paulo, São Paulo, Brazil.
Department of Medicine, Laboratory of Experimental Therapeutics, LIM-20, School of Medicine, University of São Paulo, São Paulo, Brazil.
BMC Pulm Med. 2015 Aug 12;15:85. doi: 10.1186/s12890-015-0073-4.
Previously, we showed that treatment with the Rho-kinase inhibitor Y-27632 was able to control airway responsiveness, inflammation, remodeling, and oxidative stress in an animal model of asthma, suggesting that this drug is beneficial in asthma. However, studies evaluating the effects of these inhibitors in conjunction with corticosteroids on chronic pulmonary inflammation have not been conducted. Therefore, we evaluated the effects of treatment with the Rho-kinase inhibitor Y-27632, with or without concurrent dexamethasone treatment, on airway and lung tissue mechanical responses, inflammation, extracellular matrix remodeling, and oxidative stress in guinea pigs with chronic allergic inflammation.
The guinea pigs were subjected to seven ovalbumin or saline inhalation exposures. Treatment with Y-27632 (1 mM) and dexamethasone (2 mg/kg) started at the fifth inhalation. Seventy-two hours after the seventh inhalation, the pulmonary mechanics were evaluated and exhaled nitric oxide (ENO) levels were determined. The lungs were removed and histological analysis was performed using morphometry.
The treatment of guinea pigs with the Rho-kinase inhibitor and dexamethasone (ORC group) decreased ENO, the maximal mechanical responses after antigen challenge, inflammation, extracellular matrix remodeling and oxidative stress in the lungs. This therapeutic strategy reduced the levels of collagen and IFN-γ in the airway walls, as well as IL-2, IFN-γ, 8-iso-PGF2α and NF-κB in the distal parenchyma, when compared to isolated treatment with corticosteroid or Rho-kinase inhibitor (P < 0.05) and reduced the number of TIMP-1-positive cells and eosinophils in the alveolar septa compared to corticosteroid-treated animals (P < 0.05). The combined treatment with the Rho-kinase inhibitor and the corticosteroid provided maximal control over the remodeling response and inflammation in the airways and parenchyma.
Rho-kinase inhibition, alone or in combination with corticosteroids, can be considered a future pharmacological tool for the control of asthma.
此前，我们发现，在哮喘动物模型中，用Rho激酶抑制剂Y-27632进行治疗能够控制气道反应性、炎症、重塑及氧化应激，这表明该药物对哮喘有益。然而，尚未有研究评估这些抑制剂与皮质类固醇联合使用对慢性肺部炎症的影响。因此，我们评估了在慢性过敏性炎症豚鼠中，使用或不使用地塞米松同时治疗时，Rho激酶抑制剂Y-27632治疗对气道和肺组织力学反应、炎症、细胞外基质重塑及氧化应激的影响。
对豚鼠进行7次卵清蛋白或生理盐水吸入暴露。在第5次吸入时开始用Y-27632（1 mM）和地塞米松（2 mg/kg）进行治疗。在第7次吸入72小时后，评估肺力学并测定呼出一氧化氮（ENO）水平。取出肺脏并使用形态测量法进行组织学分析。
用Rho激酶抑制剂和地塞米松治疗豚鼠（ORC组）可降低ENO、抗原激发后的最大力学反应、炎症、细胞外基质重塑及肺内氧化应激。与单独使用皮质类固醇或Rho激酶抑制剂治疗相比，这种治疗策略降低了气道壁中胶原蛋白和IFN-γ的水平，以及远端实质中IL-2、IFN-γ、8-异前列腺素F2α和NF-κB的水平（P < 0.05），并且与皮质类固醇治疗的动物相比，减少了肺泡间隔中TIMP-1阳性细胞和嗜酸性粒细胞的数量（P < 0.05）。Rho激酶抑制剂与皮质类固醇联合治疗对气道和实质中的重塑反应和炎症提供了最大程度的控制。
Rho激酶抑制，单独或与皮质类固醇联合使用，可被视为未来控制哮喘的药理学工具。
