The calcineurin-NFATc pathway modulates the lipid mediators in BAL fluid extracellular vesicles, thereby regulating microvascular endothelial cell barrier function.

Autor:	Karpurapu M; Division of Pulmonary, Critical Care and Sleep Medicine, Ohio State University Wexner Medical Center, Davis Heart and Lung Research Institute, Columbus, OH, United States., Nie Y; Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China., Chung S; Division of Pulmonary, Critical Care and Sleep Medicine, Ohio State University Wexner Medical Center, Davis Heart and Lung Research Institute, Columbus, OH, United States., Yan J; Department of Pharmacology, Ohio State University, Columbus, OH, United States., Dougherty P; Department of Chemistry and Biochemistry, Ohio State University, Columbus, OH, United States., Pannu S; Division of Pulmonary, Critical Care and Sleep Medicine, Ohio State University Wexner Medical Center, Davis Heart and Lung Research Institute, Columbus, OH, United States., Wisler J; Department of Surgery, Ohio State Wexner Medical Center, Columbus, OH, United States., Harkless R; Department of Surgery, Ohio State Wexner Medical Center, Columbus, OH, United States., Parinandi N; Division of Pulmonary, Critical Care and Sleep Medicine, Ohio State University Wexner Medical Center, Davis Heart and Lung Research Institute, Columbus, OH, United States., Berdyshev E; Division of Pulmonary Critical Care and Sleep Medicine, National Jewish Health, Denver, CO, United States., Pei D; Department of Chemistry and Biochemistry, Ohio State University, Columbus, OH, United States., Christman JW; Division of Pulmonary, Critical Care and Sleep Medicine, Ohio State University Wexner Medical Center, Davis Heart and Lung Research Institute, Columbus, OH, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in physiology [Front Physiol] 2024 May 15; Vol. 15, pp. 1378565. Date of Electronic Publication: 2024 May 15 (Print Publication: 2024).
DOI:	10.3389/fphys.2024.1378565
Abstrakt:	Extracellular vesicles mediate intercellular communication by transporting biologically active macromolecules. Our prior studies have demonstrated that the nuclear factor of activated T cell cytoplasmic member 3 (NFATc3) is activated in mouse pulmonary macrophages in response to lipopolysaccharide (LPS). Inhibition of NFATc3 activation by a novel cell-permeable calcineurin peptide inhibitor CNI103 mitigated the development of acute lung injury (ALI) in LPS-treated mice. Although pro-inflammatory lipid mediators are known contributors to lung inflammation and injury, it remains unclear whether the calcineurin-NFATc pathway regulates extracellular vesicle (EV) lipid content and if this content contributes to ALI pathogenesis. In this study, EVs from mouse bronchoalveolar lavage fluid (BALF) were analyzed for their lipid mediators by liquid chromatography in conjunction with mass spectrometry (LC-MS/MS). Our data demonstrate that EVs from LPS-treated mice contained significantly higher levels of arachidonic acid (AA) metabolites, which were found in low levels by prior treatment with CNI103. The catalytic activity of lung tissue cytoplasmic phospholipase A2 (cPLA2) increased during ALI, correlating with an increased amount of arachidonic acid (AA) in the EVs. Furthermore, ALI is associated with increased expression of cPLA2, cyclooxygenase 2 (COX2), and lipoxygenases (5-LOX, 12-LOX, and 15-LOX) in lung tissue, and pretreatment with CNI103 inhibited the catalytic activity of cPLA2 and the expression of cPLA2, COX, and LOX transcripts. Furthermore, co-culture of mouse pulmonary microvascular endothelial cell (PMVEC) monolayer and NFAT-luciferase reporter macrophages with BALF EVs from LPS-treated mice increased the pulmonary microvascular endothelial cell (PMVEC) monolayer barrier permeability and luciferase activity in macrophages. However, EVs from CNI103-treated mice had no negative impact on PMVEC monolayer barrier integrity. In summary, BALF EVs from LPS-treated mice carry biologically active NFATc-dependent, AA-derived lipids that play a role in regulating PMVEC monolayer barrier function. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2024 Karpurapu, Nie, Chung, Yan, Dougherty, Pannu, Wisler, Harkless, Parinandi, Berdyshev, Pei and Christman.)
Databáze:	MEDLINE
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