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Crystalline silica particles induce DNA damage in respiratory epithelium by ATX secretion and Rac1 activation

Rongrong Wu1, Johan Högberg1, Mikael Adner1

  • 1Institute of Environmental Medicine, Karolinska Institutet, Box 210, SE-17177, Stockholm, Sweden.

Biochemical and Biophysical Research Communications
|February 26, 2021
PubMed

Insights

Carcinogenic crystalline silica particles rapidly activate the autotaxin (ATX) and lysophosphatidic acid (LPA) pathway, causing DNA damage in lung cells within minutes. ATX inhibition prevents this genotoxic effect, highlighting its role in particle-induced lung injury.

Area of Science:

  • Toxicology
  • Cell Biology
  • Molecular Biology

Background:

  • Autotaxin (ATX) and lysophosphatidic acid (LPA) are linked to lung fibrosis and cancer.
  • Previous research indicated ATX amplifies DNA damage from crystalline silica (CSi) in bronchial epithelia over hours.
  • CSi exposure rapidly induces mitochondrial dysfunction and DNA double-strand breaks (DSBs) within minutes.

Purpose of the Study:

  • To investigate the role of the ATX-LPA axis in the rapid DNA damage response to CSi exposure.
  • To determine if ATX activation occurs rapidly after CSi inhalation and contributes to genotoxicity.

Main Methods:

  • Utilized 16HBE human bronchial epithelial cells and mouse models.
  • Measured ATX secretion, mitochondrial depolarization, and DNA damage (γH2AX, Comet assay, 53BP1).
  • Employed ATX inhibitors (HA130, PF8380), LPA administration, and a Rac1 inhibitor (NSC23766).

Main Results:

  • CSi exposure triggered rapid ATX secretion (3 min) and activation of the ATX-LPA axis.
  • ATX inhibitors and Rac1 inhibition prevented CSi-induced mitochondrial depolarization and DNA damage.
  • Inhaled CSi rapidly induced ATX activation and DSBs in mouse bronchial epithelia.

Conclusions:

  • CSi rapidly activates the ATX-LPA axis, leading to genotoxicity in bronchial epithelial cells within minutes.
  • The ATX-LPA pathway is a critical mediator of the rapid DNA damaging effects of inhaled particles like CSi.
  • Targeting the ATX-LPA axis may offer a therapeutic strategy for particle-induced lung damage.
Keywords:
Autotaxin (ATX)Crystalline silica particles (CSi)DNA damageLysophosphatidic acid (LPA)Ras-related C3 botulinum toxin substrate 1 (Rac1)

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