Isopropyl 3-(3,4-dihydroxyphenyl)-2-hydroxypropanoate (IDHP) is one of the main bioactive metabolites of the Chinese medicinal herb Danshen, which can be absorbed into blood compounds by oral administration of Compound Danshen dripping pills (CDDPs). Previous study showed that IDHP exerted anti-inflammatory effects by abolishing the secretion of proinflammatory factors stimulated by lipopolysaccharide (LPS). However, the effects of IDHP on LPS-induced acute lung injury (ALI) are not fully understood. In the present study, we observed the effects of IDHP on mortality and lung injury in LPS-treated mice and on LPS-induced THP-1 macrophages. Pretreatment with high dose of IDHP was found to reduce the mortality of ALI mice, significantly improve LPS-induced pathological changes, and reduce protein leakage and inhibited myeloperoxidase (MPO) activity in lung tissue. IDHP also inhibited the release of inflammatory factors in bronchoalveolar lavage fluid (BALF) and lung tissue. Meanwhile, IDHP treatment significantly reduced the expression of active-caspase1, Nlrp3, Asc speck formation, Gsdmd (part of the canonical pyroptosis pathway), caspase4 (part of the non-canonical pyroptosis pathway), therefore decreasing IL-1β, IL-18, and ROS secretion in LPS-stimulated THP-1 macrophages. Moreover, after co-culturing endothelial/epithelial cells with conditioned medium (CM) from LPS-stimulated THP-1 macrophages, we found that the protein levels of occludin and Zonula occludens-1 (Zo-1) were increased in IDHP CM-treated endothelial cells compared to those that were LPS CM-treated. Lactic dehydrogenase (LDH) assay shows that IDHP also alleviated LPS-induced endothelial/epithelial cell injury. These findings indicate that the protective effect of IDHP on LPS-induced lung injury may be partly due to the inhibition of pyroptosis pathways.

3-(3,4-二羟基苯基)-2-羟基丙酸异丙酯 (IDHP) 是中草药丹参的主要生物活性代谢产物之一，口服复方丹参滴丸 (CDDPs) 后可被吸收到血液中。先前的研究表明，IDHP 通过消除脂多糖 (LPS) 刺激的促炎因子的分泌来发挥抗炎作用。然而，IDHP 对 LPS 诱导的急性肺损伤 (ALI) 的影响尚不完全清楚。在本研究中，我们观察了 IDHP 对 LPS 处理小鼠的死亡率和肺损伤以及 LPS 诱导的 THP-1 巨噬细胞的影响。发现用高剂量 IDHP 预处理可降低 ALI 小鼠的死亡率，显着改善 LPS 诱导的病理变化，并减少肺组织中的蛋白质渗漏和抑制髓过氧化物酶 (MPO) 活性。IDHP 还抑制了支气管肺泡灌洗液 (BALF) 和肺组织中炎症因子的释放。同时，IDHP 处理显着降低了 active-caspase1、Nlrp3、Asc 斑点形成、Gsdmd（典型细胞焦亡途径的一部分）、caspase4（非典型细胞焦亡途径的一部分）的表达，从而降低了 IL-1β、IL-18和 LPS 刺激的 THP-1 巨噬细胞中的 ROS 分泌。此外，在将内皮/上皮细胞与来自 LPS 刺激的 THP-1 巨噬细胞的条件培养基 (CM) 共培养后，我们发现在 IDHP CM 处理中，occludin 和 Zonula occludens-1 (Zo-1) 的蛋白质水平增加内皮细胞与经 LPS CM 处理的细胞相比。乳酸脱氢酶 (LDH) 测定显示 IDHP 还减轻了 LPS 诱导的内皮/上皮细胞损伤。这些发现表明，IDHP 对 LPS 诱导的肺损伤的保护作用可能部分是由于抑制细胞焦亡途径。