Deficiency of the two-pore-domain potassium channel TREK-1 promotes hyperoxia-induced lung injury.

Abstract

OBJECTIVES:

We previously reported the expression of the two-pore-domain K channel TREK-1 in lung epithelial cells and proposed a role for this channel in the regulation of alveolar epithelial cytokine secretion. In this study, we focused on investigating the role of TREK-1 in vivo in the development of hyperoxia-induced lung injury.

DESIGN:

Laboratory animal experiments.

SETTING:

University research laboratory.

SUBJECTS:

Wild-type and TREK-1-deficient mice.

INTERVENTIONS:

Mice were anesthetized and exposed to 1) room air, no mechanical ventilation, 2) 95% hyperoxia for 24 hours, and 3) 95% hyperoxia for 24 hours followed by mechanical ventilation for 4 hours.

MEASUREMENTS AND MAIN RESULTS:

Hyperoxia exposure accentuated lung injury in TREK-1-deficient mice but not controls, resulting in increase in lung injury scores, bronchoalveolar lavage fluid cell numbers, and cellular apoptosis and a decrease in quasi-static lung compliance. Exposure to a combination of hyperoxia and injurious mechanical ventilation resulted in further morphological lung damage and increased lung injury scores and bronchoalveolar lavage fluid cell numbers in control but not TREK-1-deficient mice. At baseline and after hyperoxia exposure, bronchoalveolar lavage cytokine levels were unchanged in TREK-1-deficient mice compared with controls. Exposure to hyperoxia and mechanical ventilation resulted in an increase in bronchoalveolar lavage interleukin-6, monocyte chemotactic protein-1, and tumor necrosis factor-α levels in both mouse types, but the increase in interleukin-6 and monocyte chemotactic protein-1 levels was less prominent in TREK-1-deficient mice than in controls. Lung tissue macrophage inflammatory protein-2, keratinocyte-derived cytokine, and interleukin-1β gene expression was not altered by hyperoxia in TREK-1-deficient mice compared with controls. Furthermore, we show for the first time TREK-1 expression on alveolar macrophages and unimpaired tumor necrosis factor-α secretion from TREK-1-deficient macrophages.

CONCLUSIONS:

TREK-1 deficiency resulted in increased sensitivity of lungs to hyperoxia, but this effect is less prominent if overwhelming injury is induced by the combination of hyperoxia and injurious mechanical ventilation. TREK-1 may constitute a new potential target for the development of novel treatment strategies against hyperoxia-induced lung injury.

• Authors: Andreas Schwingshackl, Bin Teng, Patrudu Makena, Manik Ghosh, Scott E Sinclair, Charlean Luellen, Louisa Balasz, Cynthia Rovnaghi, Robert M Bryan, Eric E Lloyd, Elizabeth Fitzpatrick, Jordy S Saravia, Stephania A Cormier, Christopher M Waters
• Journal: Critical care medicine (Crit Care Med) Vol. 42 Issue 11 Pg. e692-701 (Nov 2014) ISSN: 1530-0293 [Electronic] United States
• PMID: 25126877 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Potassium Channels, Tandem Pore Domain
• potassium channel protein TREK-1

Topics

• Acute Lung Injury (etiology, pathology, therapy)
• Animals
• Blotting, Western
• Bronchoalveolar Lavage Fluid (chemistry)
• Cytokines (genetics, metabolism)
• Disease Models, Animal
• Enzyme-Linked Immunosorbent Assay
• Hyperoxia (complications)
• Macrophages, Alveolar (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Microscopy, Confocal (methods)
• Potassium Channels, Tandem Pore Domain (deficiency, metabolism)
• Random Allocation
• Real-Time Polymerase Chain Reaction
• Reference Values
• Respiration, Artificial
• Risk Assessment
• Severity of Illness Index