Fexofenadine protects against lipopolysaccharide-induced acute lung injury by targeting cytosolic phospholipase A2

• Published in: International immunopharmacology 2023-03, Vol.116, p.109637-109637, Article 109637
• Main Authors: Chen, Yuehong, Liu, Huan, Tian, Yunru, Luo, Zhongling, Ran, Jingjing, Miao, Zhiyong, Zhang, Qiuping, Yin, Geng, Xie, Qibing
• Format: Article
• Language: English
• Subjects: Acute lung injury; Acute Lung Injury - chemically induced; Acute Lung Injury - drug therapy; Acute Lung Injury - pathology; Animals; Cytokines; Cytosolic phospholipase A2; Fexofenadine; Lipopolysaccharide; Lipopolysaccharides; Lung - pathology; Mice; Mice, Knockout; NF-kappa B - metabolism; Phospholipases A2; Signal Transduction; Terfenadine - analogs & derivatives; Terfenadine - pharmacology
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2022.109637

•FFD reduced macrophage and neutrophil infiltration in lung tissue.•FFD inhibited the production of cytokines and chemokines.•FFD reduced downstream hydrolysis of cPLA2 arachidonic acid and leukotriene B4.•FFD inhibited LPS-induced cPLA2/ERK/P65 signaling pathway by targeting cPLA2. Acute lung injury (ALI) causes acute respiratory distress syndrome, with a high mortality rate of 40%, with currently available pharmacological treatments. Cytosolic phospholipase A2 (cPLA2) plays a critical role in the lipopolysaccharide (LPS)-induced pathology of ALI. This study assessed the therapeutic effects of fexofenadine (FFD), an on-market small-molecule drug that can target cPLA2 in LPS-induced ALI. Primary macrophages obtained from the bone marrow of wild-type and cPLA2 knockout mice and the alveolar macrophage cell line, MHS were used to test the inhibitory effect of FFD on the cPLA2/ERK/p65 signaling pathway, NF-κB p65 translocation, and cytokine and chemokine production. An LPS-induced ALI mouse model was used to assess the treatment effects of FFD. Flow cytometry detected subsets of macrophages and neutrophils. cPLA2 activity and downstream hydrolysates were detected. Treatment with a cPLA2 inhibitor or NF-κB p65 inhibitor confirmed that FFD functioned through the cPLA2/ERK/p65 signaling pathway by targeting cPLA2. FFD reduced the infiltration of macrophages and neutrophils, decreased the protein secretion in bronchoalveolar lavage fluid, and reduced the production of TNFα, IL-1β, IL-6, MCP-1, and IL-8 in the lung, bronchoalveolar lavage fluid, and sera of LPS-induced ALI mice. FFD inhibited cPLA2 activity, suppressed the cPLA2/ERK/p65 signaling pathway, inhibited translocation of p65, and decreased the production of cytokines, chemokines, and downstream hydrolysates of cPLA2, arachidonic acid, and leukotriene B4. FFD inhibits the cPLA2/ERK/p65 signaling pathway by targeting cPLA2. Therefore, FFD is promising as a therapeutic against cPLA2-involved diseases, particularly ALI.