Role of p53-fibrinolytic system cross-talk in the regulation of quartz-induced lung injury

Yashodhar P. Bhandary, Shwetha K. Shetty, Amarnath S. Marudamuthu, Jian Fu, Barbara M. Pinson, Jeffrey Levin, Sreerama Shetty

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

Silica is the major component of airborne dust generated by wind, manufacturing and/or demolition. Chronic occupational inhalation of silica dust containing crystalline quartz is by far the predominant form of silicosis in humans. Silicosis is a progressive lung disease that typically arises after a very long latency and is a major occupational concern with no known effective treatment. The mechanism of silicosis is not clearly understood. However, silicosis is associated with increased cell death, expression of redox enzymes and pro-fibrotic cytokines and chemokines. Since alveolar epithelial cell (AEC) death and disruption of alveolar fibrinolysis is often associated with both acute and chronic lung injuries, we explored whether p53-mediated changes in the urokinase-type plasminogen activator (uPA) system contributes to silica-induced lung injury. We further sought to determine whether caveolin-1 scaffolding domain peptide (CSP), which inhibits p53 expression, mitigates lung injury associated with exposure to silica. Lung tissues and AECs isolated from wild-type (WT) mice exposed to silica exhibit increased apoptosis, p53 and PAI-1, and suppression of uPA expression. Treatment of WT mice with CSP inhibits PAI-1, restores uPA expression and prevents AEC apoptosis by suppressing p53, which is otherwise induced in mice exposed to silica. The process involves CSP-mediated inhibition of serine-15 phosphorylation of p53 by inhibition of protein phosphatase 2A-C (PP2A-C) interaction with silica-induced caveolin-1 in AECs. These observations suggest that changes in the p53-uPA fibrinolytic system cross-talk contribute to lung injury caused by inhalation of silica dust containing crystalline quartz and is protected by CSP by targeting this pathway.

Original languageEnglish
Pages (from-to)92-98
Number of pages7
JournalToxicology and Applied Pharmacology
Volume283
Issue number2
DOIs
StatePublished - Mar 1 2015

Bibliographical note

Publisher Copyright:
© 2015 Elsevier Inc.

Keywords

  • Acute lung injury
  • Alveolar type II cell apoptosis
  • Fibrinolytic system
  • Silicosis

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

Fingerprint

Dive into the research topics of 'Role of p53-fibrinolytic system cross-talk in the regulation of quartz-induced lung injury'. Together they form a unique fingerprint.

Cite this