Rotundic acid reduces LPS‐induced acute lung injury in vitro and in vivo through regulating TLR4 dimer

• Published in: Phytotherapy research Vol. 35; no. 8; pp. 4485 - 4498
• Main Authors: Li, Xin‐Xing, Yuan, Renyikun, Wang, Qin‐Qin, Han, Shan, Liu, Zhenjie, Xu, Qiongming, Yang, Shilin, Gao, Hongwei
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01-08-2021; Wiley Subscription Services, Inc
• Subjects: 1-Phosphatidylinositol 3-kinase; acute lung injury; anti‐inflammation; Calcium influx; Dimerization; Dimers; Edema; Endotoxins; Inflammation; Injury prevention; Interleukins; Lipopolysaccharides; Lungs; MAP kinase; Nitric oxide; Nitric-oxide synthase; Prostaglandin endoperoxide synthase; rotundic acid; TLR4 dimerization; TLR4 protein; Toll-like receptors; Tumor necrosis factor; Tumor necrosis factor-TNF; Xylene; rotundic acid; anti-inflammation; TLR4 dimerization; acute lung injury
• ISSN: 0951-418X; 1099-1573
• DOI: 10.1002/ptr.7152

Acute lung injury (ALI) is a serious clinical disease. Rotundic acid (RA), a natural ingredient isolated from Ilex rotunda Thunb, exhibits multiple pharmacological activities. However, RA's therapeutic effect and mechanism on ALI remain to be elucidated. The present study aimed to further clarify its regulating effects on inflammation in vitro and in vivo. Our results indicated that RA significantly inhibited the overproduction of interleukin‐6 (IL‐6), tumor necrosis factor‐α (TNF‐α), cyclooxygenase‐2 (COX‐2), and inducible nitric oxide synthase (iNOS). RA decreased ROS production and calcium influx. In addition, RA inhibited the activation of PI3K, MAPK, and NF‐κB pathways and enhanced the activity of nuclear factor E2‐related factor 2 (Nrf2) signaling. The cellular thermal shift assay and docking results indicated that RA bind to TLR4 to block TLR4 dimerization. Furthermore, RA pretreatment effectively inhibited ear edema induced by xylene and LPS‐induced endotoxin death and had a protective effect on LPS‐induced ALI. Our findings collectively indicated that RA has anti‐inflammatory effects, which may serve as a potential therapeutic option for pulmonary inflammation.