Abstract Number: PB1050
Meeting: ISTH 2022 Congress
Background: Alternatively acitvated macrophages are characterized by a procoagulatory phenotype including increased expression of tissue factor (TF) and reduced activation of urokinase-type plasminogen activator (uPA) due to increased expression of plasminogen activator inhibitor 1 (PAI-1).
Aims: To identify signaling pathways required for a procoagulatory phenotype of alternatively activated macrophages.
Methods: We studied the role of K-ras in human macrophages as well as in a lung fibrosis model in mice, by inhibiting K-ras signalling pharmacologically using fendiline (key experiments confirmed with a second K-RAS inhibitor BAY-293). Lung fibrosis was induced in mice by inhalative bleomycin application
Results: Alternative activation of macrophages (AAM) by IL-4 and IL-13 led to a significant phosphorylation of ERK1/2 in vitro and in vivo. K-RAS inhibition significantly reduced the phosphorylation of ERK1/2 in macrophages leading to a significant reduction in AAM markers including TF and PAI-1. K-ras treated AAM showed significantly prolonged coagulation times as indicated by ROTEM measurements. Tissue Factor, uPA, PAI-1 as well as collagen-6 was reduced in K-RAS inhibited AAM. In bleomycin-induced lung fibrosis, mice treated with fendiline (K-RAS inhibitor) showed significantly less pulmonary fibrosis. After initial weight loss associated with pulmonary inflammation, treated mice gained weight from day 9 on, whereas untreated mice lingered at their reduced weight.
Conclusion(s): Blocking intracellular K-ras signalling in mice and human macrophages, reduced the fibrotic and coagulatory phenotype associated with pulmonary fibrosis. Mechanistically, fendiline led to a reduction of phosphorylated ERK1/2 and a downregulation of the coagulatory proteins TF, uPA, PAI-1 and collagen- 6. These cellular alterations led to a prolonged coagulation potential. Treatment of mice with fendiline reduced bleomycin-induced lung fibrosis.
To cite this abstract in AMA style:Haider P, Kral-Pointner J, Salzmann M, Podesser B, Wojta J, Hohensinner P. Blockade of K-ras signalling prevents coagulatory phenotype of alternatively activated macrophages. [abstract]. https://abstracts.isth.org/abstract/blockade-of-k-ras-signalling-prevents-coagulatory-phenotype-of-alternatively-activated-macrophages/. Accessed February 28, 2024.
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