TY - JOUR
T1 - Deficiency of the two-pore-domain potassium channel TREK-1 promotes hyperoxia-induced lung injury
AU - Schwingshackl, Andreas
AU - Teng, Bin
AU - Makena, Patrudu
AU - Ghosh, Manik
AU - Sinclair, Scott E.
AU - Luellen, Charlean
AU - Balasz, Louisa
AU - Rovnaghi, Cynthia
AU - Bryan, Robert M.
AU - Lloyd, Eric E.
AU - Fitzpatrick, Elizabeth
AU - Saravia, Jordy S.
AU - Cormier, Stephania A.
AU - Waters, Christopher M.
N1 - Publisher Copyright:
Copyright © 2014 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins.
PY - 2014
Y1 - 2014
N2 - Objectives: We previously reported the expression of the twoporedomain 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-á 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, keratinocytederived 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-á 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 hyperoxiainduced lung injury.
AB - Objectives: We previously reported the expression of the twoporedomain 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-á 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, keratinocytederived 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-á 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 hyperoxiainduced lung injury.
KW - Acute respiratory distress syndrome
KW - Lung
KW - Lung injury
KW - TREK
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U2 - 10.1097/CCM.0000000000000603
DO - 10.1097/CCM.0000000000000603
M3 - Article
C2 - 25126877
AN - SCOPUS:84922011572
SN - 0090-3493
VL - 42
SP - e692-e701
JO - Critical Care Medicine
JF - Critical Care Medicine
IS - 11
ER -