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Principal Investigator: Andreas Schwingshackl
Organization: UNIVERSITY OF CALIFORNIA LOS ANGELES
Fiscal Year: 2024
Award: $539,686
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY:
Significance: Oxygen supplementation (hyperoxia; HO) is the most frequently applied therapy for
hospitalized patients and the cornerstone of treatment for acute hypoxic respiratory failure (ARF). It is well known,
however, that HO exposure can not only promote existing lung injury but also initiate inflammation and barrier
dysfunction in otherwise healthy lungs. The inflammatory response evoked by HO is particularly damaging to
alveolar epithelial and endothelial cells causing cellular apoptosis and alveolar barrier disruption. Clinically, the
recognition of HO-induced acute lung injury (HALI) led to an increased awareness of oxygen toxicity and
efforts to minimize oxygen exposure for ARF patients. Although clinical and experimental studies have identified
several potential mechanisms underlying HALI, currently no therapies exist to prevent or counteract HALI, and
the length of hospitalization of ARF patients has remained unchanged for two decades. These findings
underscore the urgent need for identifying molecular targets to facilitate rational drug design against HALI.
In the search for such new targets, we discovered TREK-1 potassium channels as potential new key
regulators of HALI. Our preliminary data support the novel hypothesis that HO downregulates epithelial and
endothelial TREK-1 channels, which results in cell membrane depolarization, subsequent opening of voltage-
gated Ca2+ channels, and as a consequence increased inflammatory mediator secretion, cell apoptosis and
alveolar barrier dysfunction. Furthermore, we propose that enhancement of TREK-1 activity can counteract this
injurious cascade.
We will test this hypothesis in three Specific Aims: In Aim1 we will identify the cell type(-s) predominantly
affected by HO-induced TREK-1 downregulation, using epithelial and endothelial cell-specific TREK-1 KO mouse
models and primary cells isolated from these mice. In Aim 2 we will determine the protective effects of TREK-1
enhancement against HALI using novel TREK-1 activating compounds, new cell type-specific TREK-1
overexpressing mouse models, and primary epithelial and endothelial cells isolated from these mice. In Aim 3
we will dissect the structural composition and biophysical properties of epithelial and endothelial TREK-1
channels at baseline and under HO conditions, and propose a novel signaling mechanism by which TREK-1
channels could regulate inflammation and barrier dysfunction during HALI.
This study will impact the field of acute lung injury by establishing aberrant epithelial and endothelial TREK-
1 signaling in the lung as a previously unrecognized pathway in HALI, and TREK-1 activation as the first targeted
therapeutic approach against HALI.
Terms: <AGTR2><AGTR2 gene><AT2><Acute Lung Injury><Acute Pulmonary Injury><Affect><Alveolar><Animal Model><Animal Models and Related Studies><Apoptosis><Apoptosis Pathway><Assay><Award><Awareness><Bioassay><Biochemical Markers><Biological Assay><Budgets><Cell Body><Cell Communication and Signaling><Cell Isolation><Cell Segregation><Cell Separation><Cell Separation Technology><Cell Signaling><Cell membrane><Cells><Clinical><Clinical Research><Clinical Study><Co-Immunoprecipitations><Complex><Cytoplasmic Membrane><Data><Death Rate><Development><Down-Regulation><Drug Design><Dysfunction><Endothelial Cells><Endothelium><Environment><Epithelial Cells><Epithelium><Exposure to><Fluorometry><Functional disorder><Genetic Enhancement><Healthcare><Histologic><Histologically><Hospital Admission><Hospitalization><Human><Hyperoxia><In Vitro><Individual><Inflammation><Inflammation Mediators><Inflammatory Response><Intervention><Intervention Strategies><Intracellular Communication and Signaling><K channel><K12><K12 Award><K12 Mechanism><K12 Program><KCNK2 gene product><KO mice><Knock-out Mice><Knockout Mice><Label><Length><Life><Lung><Lung Alveolar Epithelia><Lung Inflammation><Lung Respiratory System><Lung damage><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Measures><Mediating><Membrane Potentials><Mentored Clinical Scientist Development Program><Mice><Mice Mammals><Modern Man><Molecular Target><Morbidity><Morbidity - disease rate><Morphology><Murine><Mus><Null Mouse><O element><O2 element><O2 toxicity><Oxygen><Oxygen Inhalation Therapy><Oxygen Therapy Care><Pathway interactions><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Physiologic><Physiological><Physiopathology><Plasma Membrane><Pneumonitis><Potassium Channel><Potassium Ion Channels><Process><Programmed Cell Death><Pulmonary Inflammation><Resting Potentials><Role><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Structure><Supplementation><TREK gene product><TREK-1><TREK-1 gene product><TREK-1 potassium channel><TREK1 gene product><Testing><Therapeutic><Translating><Transmembrane Potentials><Warburg Therapy><acute hypoxemic respiratory failure><acute hypoxic respiratory failure><acute onset hypoxemic respiratory failure><alveolar epithelium><biological signal transduction><biophysical characteristics><biophysical characterization><biophysical measurement><biophysical parameters><biophysical properties><cell sorting><cell type><developmental><experiment><experimental research><experimental study><experiments><health care><hyperoxia associated lung injury><hyperoxia induced lung injury><hyperoxia mediated lung injury><hyperoxygenation><improved><in vivo Model><inflammatory mediator><innovate><innovation><innovative><interventional strategy><lung injury><model of animal><mortality rate><mortality ratio><mouse model><murine model><new approaches><novel><novel approaches><novel strategies><novel strategy><overexpress><overexpression><oxygen administration><oxygen poisoning><oxygen therapy><oxygen toxicity><patch clamp><pathophysiology><pathway><patient oriented outcomes><pharmacologic><plasmalemma><potassium channel protein TREK-1><prevent><preventing><protective effect><pulmonary><pulmonary damage><pulmonary injury><pulmonary tissue damage><pulmonary tissue injury><social role><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><voltage>