Department of Pharmacology, Jessenius Faculty of Medicine in Martin, Comenius University Bratislava, Martin, Slovakia.
Biomedical Centre Martin, Jessenius Faculty of Medicine in Martin, Comenius University Bratislava, Martin, Slovakia.
Int J Immunopathol Pharmacol. 2024 Jan-Dec;38:3946320241282949. doi: 10.1177/03946320241282949.
Allergic asthma is a chronic inflammatory disease characterized by airway hyperresponsiveness, inflammation and remodeling. ROCK inhibitors have now been shown to have the potential to alleviate these symptoms, although the specific effects of a new ROCK inhibitor, GSK429286 A, remain underexplored.
The aim of this study was to evaluate the therapeutic effects of a novel ROCK inhibitor, GSK429286 A, which exhibits a high affinity for both ROCK1 and ROCK2 isoforms, on allergic asthma in a guinea pig model, focusing on its effects on airway hyperresponsiveness, inflammation, and remodeling.
To induce allergic asthma, guinea pigs were sensitized with ovalbumin for 28 days, and in the middle of sensitization they were treated with different doses of the RoCK inhibitor, GSK429286 A. The study evaluated the effect of the administered doses on the reduction of airway hyperresponsiveness, by measuring specific airway resistance (sRaw), and the number of coughs after citric acid inhalation. We also monitored the anti-inflammatory effect by measuring levels of inflammatory cytokines, IL-2, IL-4, IL-5, IL-13, and remodeling markers, such as collagen deposition, and goblet cell hyperplasia. In addition, we monitored the possible anti-remodeling effect of GSK429286 A by histopathological examination.
The ROCK inhibitor, GSK429286 A, showed an effect on suppressing airway hyperresponsiveness by reducing sRaw and the number of coughs in treated guinea pigs compared to controls. Our investigated drug suppressed the release of key mediators of inflammation, including IL-2, IL-4, and IL-5, thus demonstrating the effect of this ROCK inhibitor on the suppression of inflammation in the airways. Finally, GSK429286 A reduced markers of airway remodeling such as collagen deposition and goblet cell hyperplasia.
GSK429286 A, an inhibitor of the ROCK pathway, exhibits significant anti-inflammatory and antiremodeling effects in a guinea pig model of allergic asthma. Indeed, we demonstrate its effect on suppressing airway hyperreactivity and reducing cough frequency. These findings suggest that GSK429286 A may be a promising therapeutic agent for allergic asthma, although further studies are needed to investigate its long-term efficacy, underlying mechanisms, and optimal dosing strategy.
过敏性哮喘是一种以气道高反应性、炎症和重塑为特征的慢性炎症性疾病。现已表明，ROCK 抑制剂具有缓解这些症状的潜力，尽管新型 ROCK 抑制剂 GSK429286A 的具体作用仍未得到充分探索。
本研究旨在评估新型 ROCK 抑制剂 GSK429286A（对 ROCK1 和 ROCK2 同工型均具有高亲和力）在豚鼠过敏性哮喘模型中的治疗效果，重点关注其对气道高反应性、炎症和重塑的影响。
为了诱导过敏性哮喘，豚鼠用卵清蛋白致敏 28 天，在致敏中期用不同剂量的 ROCK 抑制剂 GSK429286A 进行治疗。该研究通过测量气道阻力（sRaw）和柠檬酸吸入后咳嗽次数来评估给药剂量对降低气道高反应性的影响。我们还通过测量炎症细胞因子（IL-2、IL-4、IL-5、IL-13）水平和胶原沉积、杯状细胞增生等重塑标志物来监测抗炎效果。此外，我们通过组织病理学检查监测 GSK429286A 可能的抗重塑作用。
ROCK 抑制剂 GSK429286A 可降低气道阻力（sRaw）和治疗组豚鼠咳嗽次数，从而抑制气道高反应性，与对照组相比具有统计学意义。该研究药物抑制了包括 IL-2、IL-4 和 IL-5 在内的关键炎症介质的释放，表明 ROCK 抑制剂对气道炎症的抑制作用。最后，GSK429286A 减少了胶原沉积和杯状细胞增生等气道重塑标志物。
ROCK 通路抑制剂 GSK429286A 在过敏性哮喘豚鼠模型中表现出显著的抗炎和抗重塑作用。实际上，我们证明了它对抑制气道高反应性和减少咳嗽频率的作用。这些发现表明，GSK429286A 可能是一种有前途的治疗过敏性哮喘的药物，但需要进一步研究以探讨其长期疗效、潜在机制和最佳剂量策略。
