Division of Pulmonary and Critical Care Medicine, Department of Medicine, and.
Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, Maryland.
Am J Respir Cell Mol Biol. 2024 Jan;70(1):11-25. doi: 10.1165/rcmb.2023-0127OC.
The generation of bioactive truncated oxidized phospholipids (Tr-OxPLs) from oxidation of cell-membrane or circulating lipoproteins is a common feature of various pathological states. Scavenger receptor CD36 is involved in lipid transport and acts as a receptor for Tr-OxPLs. Interestingly, Tr-OxPLs and CD36 are involved in endothelial dysfunction-derived acute lung injury, but the precise mechanistic connections remain unexplored. In the present study, we investigated the role of CD36 in mediating pulmonary endothelial cell (EC) dysfunction caused by Tr-OxPLs. Our results demonstrated that the Tr-OxPLs KOdia-PC, Paz-PC, PGPC, PON-PC, POV-PC, and lysophosphocholine caused an acute EC barrier disruption as revealed by measurements of transendothelial electrical resistance and VE-cadherin immunostaining. More importantly, a synthetic amphipathic helical peptide, L37pA, targeting human CD36 strongly attenuated Tr-OxPL-induced EC permeability. L37pA also suppressed Tr-OxPL-induced endothelial inflammatory activation monitored by mRNA expression of inflammatory cytokines/chemokines and adhesion molecules. In addition, L37pA blocked Tr-OxPL-induced NF-κB activation and tyrosine phosphorylation of Src kinase and VE-cadherin. The Src inhibitor SU6656 attenuated KOdia-PC-induced EC permeability and inflammation, but inhibition of the Toll-like receptors (TLRs) TLR1, TLR2, TLR4, and TLR6 had no such protective effects. CD36-knockout mice were more resistant to Tr-OxPL-induced lung injury. Treatment with L37pA was equally effective in ameliorating Tr-OxPL-induced vascular leak and lung inflammation as determined by an Evans blue extravasation assay and total cell and protein content in BAL fluid. Altogether, these results demonstrate an essential role of CD36 in mediating Tr-OxPL-induced EC dysfunction and suggest a strong therapeutic potential of CD36 inhibitory peptides in mitigating lung injury and inflammation.
氧化型磷脂（Tr-OxPLs）是细胞膜或循环脂蛋白氧化的产物，在各种病理状态下普遍存在。清道夫受体 CD36 参与脂质转运，并作为 Tr-OxPLs 的受体。有趣的是，Tr-OxPLs 和 CD36 参与了内皮功能障碍导致的急性肺损伤，但确切的机制联系仍未被探索。在本研究中，我们研究了 CD36 在介导 Tr-OxPLs 引起的肺内皮细胞（EC）功能障碍中的作用。我们的结果表明，Tr-OxPLs KOdia-PC、Paz-PC、PGPC、PON-PC、POV-PC 和溶血磷脂酰胆碱导致跨内皮电阻和 VE-钙粘蛋白免疫染色测量的 EC 屏障急性破坏。更重要的是，一种针对人 CD36 的合成两亲性螺旋肽 L37pA 强烈减弱了 Tr-OxPL 诱导的 EC 通透性。L37pA 还抑制了 Tr-OxPL 诱导的内皮炎症激活，通过炎症细胞因子/趋化因子和粘附分子的 mRNA 表达来监测。此外，L37pA 阻断了 Tr-OxPL 诱导的 NF-κB 激活和 Src 激酶及 VE-钙粘蛋白的酪氨酸磷酸化。Src 抑制剂 SU6656 减弱了 KOdia-PC 诱导的 EC 通透性和炎症，但 Toll 样受体（TLRs）TLR1、TLR2、TLR4 和 TLR6 的抑制没有这种保护作用。CD36 敲除小鼠对 Tr-OxPL 诱导的肺损伤更有抵抗力。L37pA 治疗同样有效，通过 Evans 蓝渗出测定和 BAL 液中的总细胞和蛋白含量来改善 Tr-OxPL 诱导的血管渗漏和肺炎症。总之，这些结果表明 CD36 在介导 Tr-OxPLs 诱导的 EC 功能障碍中起关键作用，并提示 CD36 抑制肽在减轻肺损伤和炎症方面具有很强的治疗潜力。
