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

Andreas Schwingshackl, Bin Teng, Patrudu Makena, Manik Ghosh, Scott Sinclair, Charlean Luellen, Louisa Balasz, Cynthia Rovnaghi, Robert M. Bryan, Eric E. Lloyd, Elizabeth Fitzpatrick, Jordy S. Saravia, Stephania Cormier, Christopher Waters

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)e692-e701
JournalCritical care medicine
Volume42
Issue number11
DOIs
StatePublished - Jan 1 2014

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Hyperoxia
Lung Injury
Artificial Respiration
Lung
Chemokine CCL2
Bronchoalveolar Lavage Fluid
Bronchoalveolar Lavage
Cytokines
potassium channel protein TREK-1
Interleukin-6
Tumor Necrosis Factor-alpha
Cell Count
Chemokine CXCL2
Lung Compliance
Alveolar Macrophages
Laboratory Animals
Interleukin-1
Epithelial Cells
Macrophages
Air

All Science Journal Classification (ASJC) codes

  • Critical Care and Intensive Care Medicine

Cite this

Deficiency of the two-pore-domain potassium channel TREK-1 promotes hyperoxia-induced lung injury. / Schwingshackl, Andreas; Teng, Bin; Makena, Patrudu; Ghosh, Manik; Sinclair, Scott; Luellen, Charlean; Balasz, Louisa; Rovnaghi, Cynthia; Bryan, Robert M.; Lloyd, Eric E.; Fitzpatrick, Elizabeth; Saravia, Jordy S.; Cormier, Stephania; Waters, Christopher.

In: Critical care medicine, Vol. 42, No. 11, 01.01.2014, p. e692-e701.

Research output: Contribution to journalArticle

Schwingshackl, A, Teng, B, Makena, P, Ghosh, M, Sinclair, S, Luellen, C, Balasz, L, Rovnaghi, C, Bryan, RM, Lloyd, EE, Fitzpatrick, E, Saravia, JS, Cormier, S & Waters, C 2014, 'Deficiency of the two-pore-domain potassium channel TREK-1 promotes hyperoxia-induced lung injury', Critical care medicine, vol. 42, no. 11, pp. e692-e701. https://doi.org/10.1097/CCM.0000000000000603
Schwingshackl, Andreas ; Teng, Bin ; Makena, Patrudu ; Ghosh, Manik ; Sinclair, Scott ; Luellen, Charlean ; Balasz, Louisa ; Rovnaghi, Cynthia ; Bryan, Robert M. ; Lloyd, Eric E. ; Fitzpatrick, Elizabeth ; Saravia, Jordy S. ; Cormier, Stephania ; Waters, Christopher. / Deficiency of the two-pore-domain potassium channel TREK-1 promotes hyperoxia-induced lung injury. In: Critical care medicine. 2014 ; Vol. 42, No. 11. pp. e692-e701.
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abstract = "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-{\'a} 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-{\'a} 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.",
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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

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

AU - Waters, Christopher

PY - 2014/1/1

Y1 - 2014/1/1

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.

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