Hyperoxia treatment of TREK-1/TREK-2/TRAAK-deficient mice is associated with a reduction in surfactant proteins

Andreas Schwingshackl, Benjamin Lopez, Bin Teng, Charlean Luellen, Florian Lesage, John Belperio, Riccardo Olcese, Christopher M. Waters

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

We previously proposed a role for the twopore domain potassium (K2P) channel TREK-1 in hyperoxia (HO)-induced lung injury. To determine whether redundancy among the three TREK isoforms (TREK-1, TREK-2, and TRAAK) could protect from HO-induced injury, we now examined the effect of deletion of all three TREK isoforms in a clinically relevant scenario of prolonged HO exposure and mechanical ventilation (MV). We exposed WT and TREK-1/TREK-2/TRAAK-deficient [triple knockout (KO)] mice to either room air, 72-h HO, MV [high and low tidal volume (TV)], or a combination of HO + MV and measured quasistatic lung compliance, bronchoalveolar lavage (BAL) protein concentration, histologic lung injury scores (LIS), cellular apoptosis, and cytokine levels. We determined surfactant gene and protein expression and attempted to prevent HO-induced lung injury by prophylactically administering an exogenous surfactant (Curosurf). HO treatment increased lung injury in triple KO but not WT mice, including an elevated LIS, BAL protein concentration, and markers of apoptosis, decreased lung compliance, and a more proinflammatory cytokine phenotype. MV alone had no effect on lung injury markers. Exposure to HO + MV (low TV) further decreased lung compliance in triple KO but not WT mice, and HO + MV (high TV) was lethal for triple KO mice. In triple KO mice, the HO-induced lung injury was associated with decreased surfactant protein (SP) A and SPC but not SPB and SPD expression. However, these changes could not be explained by alterations in the transcription factors nuclear factor-1 (NF-1), NKX2.1/thyroid transcription factor-1 (TTF-1) or c-jun, or lamellar body levels. Prophylactic Curosurf administration did not improve lung injury scores or compliance in triple KO mice.

Original languageEnglish
Pages (from-to)L1030-L1046
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume313
Issue number6
DOIs
StatePublished - Dec 2017

Bibliographical note

Publisher Copyright:
© 2017 the American Physiological Society.

Keywords

  • ALI
  • ARDS
  • Acute lung injury
  • Acute respiratory distress syndrome
  • Lung
  • Lung injury
  • Mechanical stretch
  • Surfactant hyperoxia
  • TRAAK
  • TREK
  • Ventilator-associated injury

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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