Vaghasiya Jignesh, Jha Aruni, Basu Sujata, Bagan Alaina, Jengsuksavat Siwon K, Ravandi Amir, Pascoe Christopher D, Halayko Andrew J
Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB R3E 3P4, Canada.
Biology of Breathing Group, Children's Research Hospital of Manitoba, Winnipeg, MB R3E 3P4, Canada.
Biology (Basel). 2024 Aug 17;13(8):627. doi: 10.3390/biology13080627.
Oxidative stress is associated with asthma pathobiology. We reported that oxidized phosphatidylcholines (OxPCs) are mediators of oxidative stress and accumulate in the lung in response to allergen challenge. The current study begins to unravel mechanisms for OxPC accumulation in the lung, providing the first insights about how OxPCs underpin allergic airway pathophysiology, and pre-clinical testing of selective neutralization of OxPCs in a murine model of allergic asthma. We hypothesized that intranasal delivery of E06, a natural IgM antibody that neutralizes the biological activity of OxPCs, can ameliorate allergen-induced airway inflammation and airway hyperresponsiveness. Adult BALB/c mice were intranasally (i.n.) challenged with house dust mite (HDM) (25 μg/mouse, 2 weeks). Some animals also received E06 monoclonal antibody (mAb) (10 µg) i.n. 1 hr before each HDM challenge. HDM challenge reduced mRNA for anti-oxidant genes (, , , and ) in the lung by several orders of magnitude ( < 0.05). Concomitantly, total immune cell number in bronchoalveolar lavage fluid (BALF) increased significantly ( < 0.001). E06 mAb treatment prevented allergen-induced BALF immune cell number by 43% ( < 0.01). This included a significant blockade of eosinophils (by 48%, < 0.001), neutrophils (by 80%, < 0.001), macrophages (by 80%, < 0.05), and CD4 (by 30%, < 0.05) and CD8 (by 42%, < 0.01) lymphocytes. E06 effects correlated with a significant reduction in TNF (by 64%, < 0.001) and IL-1β (by 75%, < 0.05) and a trend to diminish accumulation of other cytokines (e.g., IL-4, -10, and -33, and IFN-γ). E06 mAb treatment also inhibited HDM exposure-induced increases in total respiratory resistance and small airway resistance by 24% and 26%, respectively. In conclusion, prophylactic treatment with an OxPC-neutralizing antibody significantly limits allergen-induced airway inflammation and airway hyperresponsiveness, suggesting that OxPCs are important mediators of oxidative stress-associated allergic lung pathophysiology.
氧化应激与哮喘病理生物学相关。我们曾报道，氧化型磷脂酰胆碱（OxPCs）是氧化应激的介质，在变应原激发后会在肺中蓄积。本研究开始揭示肺中OxPCs蓄积的机制，首次深入了解OxPCs如何支撑过敏性气道病理生理学，并在过敏性哮喘小鼠模型中对OxPCs的选择性中和进行临床前测试。我们假设，鼻内给予E06（一种中和OxPCs生物活性的天然IgM抗体）可改善变应原诱导的气道炎症和气道高反应性。成年BALB/c小鼠经鼻内（i.n.）给予屋尘螨（HDM）（25μg/只，共2周）激发。部分动物在每次HDM激发前1小时还经鼻内给予E06单克隆抗体（mAb）（10μg）。HDM激发使肺中抗氧化基因（、、和）的mRNA水平降低了几个数量级（<0.05）。与此同时，支气管肺泡灌洗液（BALF）中的总免疫细胞数量显著增加（<0.001）。E06 mAb治疗使变应原诱导的BALF免疫细胞数量减少了43%（<0.01）。这包括显著阻断嗜酸性粒细胞（减少48%，<0.001）、中性粒细胞（减少80%，<0.001）、巨噬细胞（减少80%，<0.05）以及CD4（减少30%，<0.05）和CD8（减少42%，<0.01）淋巴细胞。E06的作用与TNF（减少64%，<0.001）和IL-1β（减少75%，<0.05）的显著降低以及其他细胞因子（如IL-4、-10、-33和IFN-γ）蓄积的减少趋势相关。E06 mAb治疗还分别抑制了HDM暴露诱导的总呼吸阻力和小气道阻力增加24%和26%。总之，用OxPC中和抗体进行预防性治疗可显著限制变应原诱导的气道炎症和气道高反应性，提示OxPCs是氧化应激相关过敏性肺病理生理学的重要介质。
