Bukowska 2019 Eur J Pharmacol
|Bukowska A, Schild L, Bornfleth P, Peter D, Wiese-Rischke C, Gardemann A, Isermann B, Walles T, Goette A (2019) Activated clotting factor X mediates mitochondrial alterations and inflammatory responses via protease-activated receptor signaling in alveolar epithelial cells. Eur J Pharmacol 869:172875.|
Abstract: There is growing evidence for the contribution of the activated coagulation factor X (FXa) in the development of chronic inflammatory lung diseases. Therefore, we aimed to investigate effects of exogenous FXa on mitochondrial and metabolic function as well as the induction of inflammatory molecules in type II alveolar epithelial cells. Effects of FXa on epithelial cells were investigated in A549 cell line. Activation of extracellular signal-regulated kinase (ERK) and induction of inflammatory molecules were examined by immunoblot and gene expression analysis. Mitochondrial function was assessed by the measurement of oxygen consumption during maximal oxidative phosphorylation and quantitative determination of cardiolipin oxidation. Apoptosis was tested using a caspase 3 antibody. Metabolic activity and lactate dehydrogenase assay were applied for the detection of cellular viability.
FXa activated ERK1/2 and induced an increase in the expression of pro-inflammatory cytokines, which was prevented by an inhibitor of FXa, edoxaban, or an inhibitor of protease-activated receptor 1, vorapaxar. Exposure to FXa caused mitochondrial alteration with restricted capacity for ATP generation, which was effectively prevented by edoxaban, vorapaxar and GB83 (inhibitor of protease-activated receptor 2). Of note, exposure to FXa did not initiate apoptosis in epithelial cells.
FXa-dependent pro-inflammatory state and impairment of mitochondria did not reach the level of significance in lung epithelial cells. However, these effects might limit regenerative potency of lung epithelial cells, particular under clinical circumstances where lung injury causes exposure to clotting factors.
Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.
• Keywords: Activated clotting factor X, Apoptosis, Human lung epithelial cells, Inflammatory signaling, Mitochondrial dysfunction, Protease-activated receptors, “Biased” effects of GB83 • Bioblast editor: Plangger M • O2k-Network Lab: DE Magdeburg Schild L
Labels: MiParea: Respiration, Pharmacology;toxicology Pathology: Other
Organism: Human Tissue;cell: Lung;gill, Endothelial;epithelial;mesothelial cell Preparation: Intact cells
Coupling state: OXPHOS Pathway: S HRR: Oxygraph-2k