Jagiellonian University Medical College, Faculty of Pharmacy, Department of Pharmaceutical Biochemistry, Medyczna 9, 30-688 Kraków, Poland.
Jagiellonian University Medical College, Faculty of Pharmacy, Department of Pharmacokinetics and Physical Pharmacy, Medyczna 9, 30-688 Kraków, Poland.
Int Immunopharmacol. 2023 Jun;119:110264. doi: 10.1016/j.intimp.2023.110264. Epub 2023 May 7.
Asthma is a heterogeneous, chronic respiratory disease characterized by airway inflammation and remodeling. Phosphodiesterase (PDE) inhibitors represent one of the intensively studied groups of potential anti-asthmatic agents due to their affecting both airway inflammation and remodeling. However, the effect of inhaled pan-PDE inhibitors on allergen induced asthma has not been reported to date. In this study we investigated the impact of two, representative strong pan-PDE inhibitors from the group of 7,8-disubstituted derivatives of 1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione: compound 38 and 145, on airway inflammation and remodeling in murine model of ovalbumin (OVA)-challenged allergic asthma. Female Balb/c mice were sensitized and challenged with OVA, 38 and 145 were administrated by inhalation, before each OVA challenge. The inhaled pan-PDE inhibitors markedly reduced the OVA-induced airway inflammatory cell infiltration, eosinophil recruitment, Th2 cytokine level in bronchoalveolar lavage fluid, as well as both, total and OVA-specific IgE levels in plasma. In addition, inhaled 38 and 145 decreased many typical features of airway remodeling, including goblet cell metaplasia, mucus hypersecretion, collagen overproduction and deposition, as well as Tgfb1, VEGF, and α-SMA expression in airways of allergen challenged mice. We also demonstrated that both 38 and 145 alleviate airway inflammation and remodelling by inhibition of the TGF-β/Smad signaling pathway activated in OVA-challenged mice. Taken together, these results suggest that the investigated pan-PDE inhibitors administered by inhalation are dual acting agents targeting both airway inflammation and remodeling in OVA-challenged allergic asthma and may represent promising, anti-asthmatic drug candidates.
哮喘是一种异质性的慢性呼吸道疾病，其特征为气道炎症和重塑。磷酸二酯酶（PDE）抑制剂是研究最为深入的潜在抗哮喘药物之一，因为它们既能影响气道炎症，也能影响气道重塑。然而，迄今为止，尚未有关于吸入性泛 PDE 抑制剂对变应原诱导性哮喘的影响的报道。在这项研究中，我们研究了两组 7,8-二取代衍生物 1,3-二甲基-3,7-二氢-1H-嘌呤-2,6-二酮中的两种代表性强泛 PDE 抑制剂对卵清蛋白（OVA）诱导的变应性哮喘小鼠模型中气道炎症和重塑的影响：化合物 38 和 145。雌性 Balb/c 小鼠用 OVA 致敏和激发，在每次 OVA 激发前通过吸入给予 38 和 145。吸入性泛 PDE 抑制剂显著减少了 OVA 诱导的气道炎症细胞浸润、嗜酸性粒细胞募集、支气管肺泡灌洗液中 Th2 细胞因子水平，以及血浆中的总 IgE 和 OVA 特异性 IgE 水平。此外，吸入 38 和 145 减少了气道重塑的许多典型特征，包括杯状细胞化生、粘液过度分泌、胶原过度产生和沉积，以及 TGF-β/Smad 信号通路激活导致的气道中 Tgfb1、VEGF 和 α-SMA 的表达。我们还证明，38 和 145 均通过抑制 OVA 激发小鼠中激活的 TGF-β/Smad 信号通路，缓解气道炎症和重塑。总之，这些结果表明，研究中的吸入性泛 PDE 抑制剂是通过双重作用机制，靶向 OVA 激发的变应性哮喘中的气道炎症和重塑，可能代表有前途的抗哮喘药物候选物。
