Laboratory of Immunopharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata 573-0101, Japan.
Department of Pharmacology, University of Virginia, Charlottesville, VA 22908-8735, USA.
Cells. 2023 Feb 11;12(4):591. doi: 10.3390/cells12040591.
Ceramides are an emerging class of anti-inflammatory lipids, and nanoscale ceramide-delivery systems are potential therapeutic strategies for inflammatory diseases. This study investigated the therapeutic effects of ceramide nanoliposomes (CNL) on type 2 inflammation-based asthma, induced by repeated ovalbumin (OVA) challenges. Asthmatic mice intratracheally treated with ceramide-free liposomes (Ghost) displayed typical airway remodeling including mucosal accumulation and subepithelial fibrosis, whereas, in CNL-treated mice, the degree of airway remodeling was significantly decreased. Compared to the Ghost group, CNL treatment unexpectedly failed to significantly influence formation of type 2 cytokines, including IL-5 and IL-13, known to facilitate pathogenic production of airway mucus predominantly comprising MUC5AC mucin. Interestingly, CNL treatment suppressed OVA-evoked hyperplasia of MUC5AC-generating goblet cells in the airways. This suggests that CNL suppressed goblet cell hyperplasia and airway mucosal accumulation independently of type 2 cytokine formation. Mechanistically, CNL treatment suppressed cell growth and EGF-induced activation of Akt, but not ERK1/2, in a human lung epithelial cell culture system recapitulating airway goblet cell hyperplasia. Taken together, CNL is suggested to have therapeutic effects on airway remodeling in allergic asthma by targeting goblet cell hyperplasia. These findings raise the potential of ceramide-based therapies for airway diseases, such as asthma.
神经酰胺是一类新兴的抗炎脂质，纳米级神经酰胺递药系统是治疗炎症性疾病的潜在策略。本研究探讨了神经酰胺纳米脂质体（CNL）对反复卵清蛋白（OVA）激发诱导的 2 型炎症型哮喘的治疗作用。用不含神经酰胺的脂质体（Ghost）经气管内处理的哮喘小鼠表现出典型的气道重塑，包括黏膜积聚和黏膜下纤维化，而 CNL 治疗组的气道重塑程度显著降低。与 Ghost 组相比，CNL 治疗出乎意料地未能显著影响包括 IL-5 和 IL-13 在内的 2 型细胞因子的形成，这些细胞因子促进气道黏液的病理性产生，主要由 MUC5AC 粘蛋白组成。有趣的是，CNL 治疗抑制了 OVA 诱发的气道中 MUC5AC 生成杯状细胞的增生。这表明 CNL 抑制杯状细胞增生和气道黏膜积聚独立于 2 型细胞因子的形成。在模拟气道杯状细胞增生的人肺上皮细胞培养系统中，CNL 治疗抑制了细胞生长和 EGF 诱导的 Akt 激活，但不抑制 ERK1/2。综上所述，CNL 通过靶向杯状细胞增生对过敏性哮喘的气道重塑具有治疗作用。这些发现为基于神经酰胺的气道疾病（如哮喘）治疗提供了潜力。
