4.6 Article

HDAC Inhibitor Abrogates LTA-Induced PAI-1 Expression in Pleural Mesothelial Cells and Attenuates Experimental Pleural Fibrosis

期刊

PHARMACEUTICALS
卷 14, 期 6, 页码 -

出版社

MDPI
DOI: 10.3390/ph14060585

关键词

histone deacetylase inhibitor; lipoteichoic acid; plasminogen activator inhibitor-1; pleural fibrosis; pleural mesothelial cell; residual pleural thickening

资金

  1. Ministry of Science and Technology of Taiwan [MOST 107-2314-B-038-089, 109-2314-B-038-095-MY3]
  2. Ministry of Education of Taiwan [DP2-10721121-T-01]
  3. Taipei Medical University Hospital [107IIT06]
  4. MacKay Junior College of Medicine, Nursing, and Management [MKC108R02]

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The study found that HDACi can reduce the overproduction of PAI-1 and collagen induced by LTA, thereby alleviating pleural fibrosis by inhibiting JNK. This treatment may offer potential therapy for pleural fibrosis caused by GPB PPE.
Lipoteichoic acid (LTA) stimulates pleural mesothelial cell (PMC) to overproduce plasminogen 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 measured. 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.

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