Despite advances in Pulmonology and Intensive Care Medicine, mortality rates of patients with Acute Lung Injury (ALI) remain high, perhaps because the underlying mechanisms of this disease are poorly understood. Patients with ALI routinely require high oxygen concentrations and positive-pressure ventilation, although both therapies accentuate ongoing lung injury. While the signaling cascades activated by hyperoxia are well known, """"""""mechano-transduction"""""""" after alveolar distension is poorly understood. Recent literature suggests that 2-pore domain potassium (K2P) channels may act as mechano-sensors and mechano-transducers, and participate in stimulus-secretion coupling. However, little is known about the expression and potential functions of K2P channels in the lung. We propose a bold and novel hypothesis that K2P channels are expressed in lung epithelial cells, and that pathogenic K2P channel regulation caused by hyperoxia, mechanical stretch and TNF-a exposure, an environment similar to the one encountered in ALI, results in dysregulation of inflammatory mediator secretion from epithelial cells, and in loss of epithelial barrier function, two hallmarks of ALI. Our overarching objective is to investigate the mechanisms leading to hyperoxia- and mechanical stretch- induced lung injury, and to identify K2P channels as a new target in the search for innovative therapeutic strategies against ALI. Specifically, we will use both in vitro and in vivo approaches including K2P knockout mice to [1] investigate the effects of hyperoxia, mechanical stretch and TNF-a on K2P channel expression and function in cultured mouse and primary rat and human alveolar epithelial cells using molecular techniques, immunohistochemistry and patch clamp studies, [2] to determine the role of K2P channels in inflammatory mediator secretion from cultured and primary alveolar epithelial cells, and in broncho-alveolar lavage fluid from K2P knockout mice, and [3] to demonstrate that K2P channels regulate epithelial barrier function via Ca2+-dependent tight junction phosphorylation. We have the unique expertise and technical capabilities to study the effects of hyperoxia and mechanical stretch in both in vitro and in vivo models of ALI. In addition, Dr. Jaggar has an inimitable setup to measure global and localized intracellular Ca2+ concentrations. The academic environment at UTHSC, the outstanding mentorship, rich opportunities for collaborations, and the institutional, departmental, and divisional commitment to my research success provide the intellectual infrastructure and the financial support to guarantee my progress towards independent research funding, including an R01 award, within 5 years. These long-term goals will be achieved by targeting a minimum of 2 publications and 2 abstract presentations per year at international meetings, supplemented by formal coursework, and the close mentorship of Dr. Waters, Dr. Anand and my Career Advisory Committee.

Public Health Relevance

Acute Lung Injury remains a devastating illness posing a significant burden on our health care budget and, therefore, the development of new therapeutic strategies represents a major research interest. In this study we propose a bold and novel hypothesis that 2-Pore Domain Potassium (K2P) channels are present in lung epithelial cells, and that exposure of K2P channels to an environment similar to the one encountered in lungs of patients with Acute Lung Injury, leads to pathogenic inflammatory mediator secretion and loss of epithelial barrier function, two hallmarks of Acute Lung Injury. The overarching objective of this proposal is to advance our understanding of the mechanisms leading to oxygen-, mechanical stretch-, and inflammatory mediator-induced lung injury, and to identify K2P channels as a new target in the search for innovative therapeutic strategies against the devastating consequences associated with Acute Lung Injury.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Clinical Investigator Award (CIA) (K08)
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Special Emphasis Panel (ZHL1)
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Colombini-Hatch, Sandra
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University of Tennessee Health Science Center
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Schwingshackl, Andreas; Lopez, Benjamin; Teng, Bin et al. (2017) Hyperoxia treatment of TREK-1/TREK-2/TRAAK-deficient mice is associated with a reduction in surfactant proteins. Am J Physiol Lung Cell Mol Physiol 313:L1030-L1046
Schwingshackl, Andreas (2016) The role of stretch-activated ion channels in acute respiratory distress syndrome: finally a new target? Am J Physiol Lung Cell Mol Physiol 311:L639-52
Schwingshackl, Andreas; Kimura, Dai; Rovnaghi, Cynthia R et al. (2016) Regulation of inflammatory biomarkers by intravenous methylprednisolone in pediatric ARDS patients: Results from a double-blind, placebo-controlled randomized pilot trial. Cytokine 77:63-71
Brune, Kieran; Frank, James; Schwingshackl, Andreas et al. (2015) Pulmonary epithelial barrier function: some new players and mechanisms. Am J Physiol Lung Cell Mol Physiol 308:L731-45
Schwingshackl, Andreas; Meduri, Gianfranco Umberto; Kimura, Dai et al. (2015) Corticosteroids in pediatric ARDS: all cards on the table. Intensive Care Med 41:2036-7
Schwingshackl, Andreas; Roan, Esra; Teng, Bin et al. (2015) TREK-1 Regulates Cytokine Secretion from Cultured Human Alveolar Epithelial Cells Independently of Cytoskeletal Rearrangements. PLoS One 10:e0126781
Drago, Bonny B; Kimura, Dai; Rovnaghi, Cynthia R et al. (2015) Double-blind, placebo-controlled pilot randomized trial of methylprednisolone infusion in pediatric acute respiratory distress syndrome. Pediatr Crit Care Med 16:e74-81
Schwingshackl, Andreas; Teng, Bin; Makena, Patrudu et al. (2014) Deficiency of the two-pore-domain potassium channel TREK-1 promotes hyperoxia-induced lung injury. Crit Care Med 42:e692-701
Roan, Esra; Waters, Christopher M; Teng, Bin et al. (2014) The 2-pore domain potassium channel TREK-1 regulates stretch-induced detachment of alveolar epithelial cells. PLoS One 9:e89429
Schwingshackl, Andreas; Teng, Bin; Ghosh, Manik et al. (2013) Regulation of interleukin-6 secretion by the two-pore-domain potassium channel Trek-1 in alveolar epithelial cells. Am J Physiol Lung Cell Mol Physiol 304:L276-86

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