Retinoic acid promotes fibrinolysis and may regulate polyp formation

Masafumi Sakashita*, Tetsuji Takabayashi, Yoshimasa Imoto, Tetsuya Homma, Kanako Yoshida, Kazuhiro Ogi, Yukihiro Kimura, Atsushi Kato, Whitney W. Stevens, Stephanie S. Smith, Kevin C. Welch, James E. Norton, Lydia A. Suh, Roderick G. Carter, Kathryn E. Hulse, Sudarshan Seshadri, Jin Young Min, Kathryn L. Pothoven, David B. Conley, Bruce K. TanKathleen E. Harris, Robert C. Kern, Shinichi Haruna, Yoshinori Matsuwaki, Ryosuke Ochiai, Shigeharu Fujieda, Robert P. Schleimer

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Patients with aspirin-exacerbated respiratory disease (AERD) regularly exhibit severe nasal polyposis. Studies suggest that chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by excessive fibrin deposition associated with a profound decrease in epithelial tissue plasminogen activator (tPA). Retinoids, including vitamin A and its active metabolite retinoic acid (RA), are necessary for maintaining epithelial function and well-known inducers of tPA in endothelial cells. Objectives: This study sought to determine whether endogenous retinoids are involved in NP pathophysiology and disease severity in patients with CRSwNP and AERD. Methods: NP tissue was collected from patients with AERD or CRSwNP, and concentrations of retinoids and fibrinolysis markers were measured using ELISA. Normal human bronchial epithelial cells were stimulated alone or in combination with RA and IL-13 for 24 hours. Results: This study observed lower retinoid levels in nasal polyps of patients with AERD than those with CRSwNP or healthy controls (P < .01). Levels of the fibrin-breakdown product d-dimer were the lowest in AERD polyps (P < .01), which is consistent with lower tPA expression (P < .01). In vitro, all-trans RA upregulated tPA levels in normal human bronchial epithelial cells by 15-fold and reversed the IL-13–induced attenuation of tPA expression in cultured cells (P < .01). Conclusions: RA, a potent inducer of epithelial tPA in vitro, is reduced in tissue from patients with AERD, a finding that may potentially contribute to decreased levels of tPA and fibrinolysis in AERD. RA can induce tPA in epithelial cells and can reverse IL-13–induced tPA suppression in vitro, suggesting the potential utility of RA in treating patients with CRSwNP and/or AERD.

Original languageEnglish (US)
Pages (from-to)1114-1124.e3
JournalJournal of Allergy and Clinical Immunology
Volume150
Issue number5
DOIs
StatePublished - Nov 2022

Keywords

  • Aspirin-exacerbated respiratory disease
  • chronic rhinosinusitis with nasal polyps
  • retinoic acid
  • tissue plasminogen activator

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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