2. Academic Validation
  3. Fexofenadine protects against lipopolysaccharide-induced acute lung injury by targeting cytosolic phospholipase A2

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

  • Int Immunopharmacol. 2023 Feb 8;116:109637. doi: 10.1016/j.intimp.2022.109637.
Yuehong Chen 1,  Huan Liu 1,  Yunru Tian 1,  Zhongling Luo 1,  Jingjing Ran 1,  Zhiyong Miao 2,  Qiuping Zhang 1,  Geng Yin 3,  Qibing Xie 4
Affiliations

Affiliations

  • 1 Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
  • 2 Laboratory of Human Diseases and Immunotherapies, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
  • 3 Department of General Practice, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China. Electronic address: yingeng1975@163.com.
  • 4 Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China. Electronic address: xieqibing1971@163.com.
PMID: 36764283 DOI: 10.1016/j.intimp.2022.109637
Abstract

Objective: 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.

Methods: 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.

Results: 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.

Conclusion: FFD inhibits the cPLA2/ERK/p65 signaling pathway by targeting cPLA2. Therefore, FFD is promising as a therapeutic against cPLA2-involved diseases, particularly ALI.

Keywords

Acute lung injury; Cytosolic phospholipase A2; Fexofenadine; Lipopolysaccharide.

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