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

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 fex-ofenadine (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-kappa B 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-kappa B p65 inhibitor confirmed that FFD functioned through the cPLA2/ERK/p65 signaling pathway by tar-geting cPLA2. Results: FFD reduced the infiltration of macrophages and neutrophils, decreased the protein secretion in bron-choalveolar lavage fluid, and reduced the production of TNF alpha, IL-1 beta, IL-6, MCP-1, and IL-8 in the lung, bron-choalveolar 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, che-mokines, 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.

Automated summary

This study evaluated the therapeutic effects of FFD, a small-molecule drug that targets cPLA2, on LPS-induced ALI. FFD inhibited cPLA2 activity and the cPLA2/ERK/p65 signaling pathway, suppressed p65 translocation, and reduced the production of cytokines, chemokines, and downstream hydrolysates. These findings suggest that FFD holds promise as a therapeutic option for cPLA2-involved diseases, particularly ALI.