Hdac inhibitor abrogates lta−induced pai-1 expression in pleural mesothelial cells and attenuates experimental pleural fibrosis

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Abstract

Lipoteichoic acid (LTA) stimulates pleural mesothelial cell (PMC) to overproduce plasmino-gen activator inhibitor-1 (PAI-1), and thus may promote pleural fibrosis in Gram-positive bacteria (GPB) parapneumonic effusion (PPE). Histone deacetylase inhibitor (HDACi) was found to possess anti-fibrotic properties. However, the effects of HDACi on pleural fibrosis remain unclear. The effusion PAI-1 was measured among 64 patients with GPB PPE. Pleural fibrosis was measured as radiographical residual pleural thickening (RPT) and opacity at a 12-month follow-up. The LTA−stimulated human PMCs and intrapleural doxycycline−injected rats were pretreated with or without the pan-HDACi, m-carboxycinnamic acid bis-hydroxamide (CBHA), then PAI-1 and collagen expression and activated signalings in PMCs, and morphologic pleural changes in rats were mea-sured. Effusion PAI-1 levels were significantly higher in GPB PPE patients with RPT > 10 mm (n = 26) than those without (n = 38), and had positive correlation with pleural fibrosis shadowing. CBHA significantly reduced LTA−induced PAI-1 and collagen expression via inhibition of JNK, and decreased PAI-1 promoter activity and mRNA levels in PMCs. Furthermore, in doxycycline−treated rats, CBHA substantially repressed PAI-1 and collagen synthesis in pleural mesothelium and minimized pleural fibrosis. Conclusively, CBHA abrogates LTA−induced PAI-1 and collagen expression in PMCs and attenuates experimental pleural fibrosis. PAI-1 inhibition by HDACi may confer potential therapy for pleural fibrosis.

Original languageEnglish
Article number585
JournalPharmaceuticals
Volume14
Issue number6
DOIs
Publication statusPublished - Jun 2021

Keywords

  • Histone deacetylase inhibitor
  • Lipoteichoic acid
  • Plasminogen activator inhibitor-1
  • Pleural fibrosis
  • Pleural mesothelial cell
  • Residual pleural thickening

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

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