Department of Basic Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02446, Korea.
Int J Mol Sci. 2022 Aug 28;23(17):9745. doi: 10.3390/ijms23179745.
Lysophosphatidic acid (LPA), an intercellular lipid mediator, is increased in the bronchoalveolar fluids of patients with asthma after allergen exposure. LPA administration exaggerates allergic responses, and the type 2 LPA receptor (LPA) has been reported as a therapeutic target for asthma. However, results with LPA agonist and antagonist along with LPA gene deficient mice have been controversial and contradictory. We compared the effects of LPA antagonist (H2L5186303) and agonist (GRI977143) in a single experimental protocol of ovalbumin (OVA)-induced allergic asthma by treating drugs before antigen sensitization or challenge. H2L5186303 showed strong suppressive efficacy when administered before OVA sensitization and challenge, such as suppression of airway hyper responsiveness, inflammatory cytokine levels, mucin production, and eosinophil numbers. However, GRI977143 showed significant suppression when administered before an OVA challenge. Increases in eosinophil and lymphocyte counts in the bronchoalveolar lavage fluid, Th2 cytokine levels, inflammatory scores, and mucin production were differentially ameliorated by the two drugs. The results demonstrate the multiple roles of LPA in asthmatic responses. We suggest that the development of LPA antagonists would achieve better therapeutic efficacy against asthma than agonists.
溶血磷脂酸（LPA）是一种细胞间脂质介质，在变应原暴露后哮喘患者的支气管肺泡液中增加。LPA 给药可夸大过敏反应，并且已报道 2 型 LPA 受体（LPA）是哮喘的治疗靶标。然而，LPA 激动剂和拮抗剂以及 LPA 基因缺陷小鼠的结果一直存在争议和矛盾。我们通过在卵清蛋白（OVA）诱导的变应性哮喘的单一实验方案中比较 LPA 拮抗剂（H2L5186303）和激动剂（GRI977143）的作用，在抗原致敏或挑战之前用药物治疗。H2L5186303 在 OVA 致敏和挑战之前给药时显示出很强的抑制作用，例如抑制气道高反应性、炎症细胞因子水平、粘蛋白产生和嗜酸性粒细胞数量。然而，GRI977143 在 OVA 挑战之前给药时表现出显著的抑制作用。两种药物均不同程度地改善了支气管肺泡灌洗液中嗜酸性粒细胞和淋巴细胞计数、Th2 细胞因子水平、炎症评分和粘蛋白产生的增加。结果表明 LPA 在哮喘反应中具有多种作用。我们建议开发 LPA 拮抗剂将比激动剂对哮喘具有更好的治疗效果。
