Lomerizine attenuates LPS-induced acute lung injury by inhibiting the macrophage activation through reducing Ca2+ influx

Yunduan Song; Yusen Gou; Jiameng Gao; Dongxin Chen; Haibo Zhang; Wenjuan Zhao; Feng Qian; Ajing Xu; Yao Shen

doi:10.3389/fphar.2023.1236469

Lomerizine attenuates LPS-induced acute lung injury by inhibiting the macrophage activation through reducing Ca²⁺ influx

Front Pharmacol. 2023 Aug 24:14:1236469. doi: 10.3389/fphar.2023.1236469. eCollection 2023.

Authors

Yunduan Song^#^{1

2}, Yusen Gou^#³, Jiameng Gao^#¹, Dongxin Chen³, Haibo Zhang³, Wenjuan Zhao³, Feng Qian³, Ajing Xu⁴, Yao Shen¹

Affiliations

¹ Department of Respiratory and Critical Care Medicine, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China.
² Department of Clinical Laboratory, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³ Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
⁴ Department of Clinical Pharmacy, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.

^# Contributed equally.

Abstract

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening lung diseases with high mortality rates, predominantly attributable to acute and severe pulmonary inflammation. Lomerizine (LMZ) is a calcium channel blocker previously used in preventing and treating migraine. Here, we found that LMZ inhibited inflammatory responses and lung pathological injury by reducing pulmonary edema, neutrophil infiltration and pro-inflammatory cytokine production in lipopolysaccharide (LPS)-induced ALI mice. In vitro experiments, upon treating with LMZ, the expression of interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α was attenuated in macrophages. The phosphorylation of p38 MAPK, ERK1/2, JNK, and NF-κB p65 was inhibited after LMZ treatment. Furthermore, LPS-induced Ca²⁺ influx was reduced by treating with LMZ, which correlated with inhibition of pro-inflammatory cytokine production. And L-type Ca²⁺ channel agonist Bay K8644 (BK) could restore cytokine generation. In conclusion, our study demonstrated that LMZ alleviates LPS-induced ALI and is a potential agent for treating ALI/ARDS.

Keywords: acute lung injury; calcium; cytokine; inflammation; lomerizine; macrophage.

Grants and funding

The present study was supported by Science and Technology Development Fund of Shanghai Pudong New Area (grant no. PKJ2021-Y35), the Science and Technology Commission of Shanghai Municipality (grant no. 20Z11901004, 20Z11901000), the National Natural Science Foundation of China (81973329, 82173821, 82072142), the Discipline Construction Promoting Project of Shanghai Pudong Hospital (grant no. Zdzk 2020-11), the Program for the Academic Leader in Health Committee of Shanghai (grant no. 21XD1403000) and the Medical discipline construction project of Pudong Health Committee of Shanghai (grant no PWYts2021-14).