Document text
Principal Investigator: CHRISTOPHER M WATERS
Organization: UNIVERSITY OF KENTUCKY
Fiscal Year: 2023
Award: $232,586
Funding agency: National Heart Lung and Blood Institute
Acute lung injury and its more severe form, acute respiratory distress syndrome
(ARDS), are devastating illnesses with high rates of incidence and mortality. Patients
with acute lung injury are typically provided supplemental oxygen using positive
pressure mechanical ventilation, but this can lead to additional injury, termed ventilator-
induced lung injury (VILI). The long term objective of this proposal is to improve
understanding of the mechanisms by which the combination of exposure to high levels
of oxygen (hyperoxia) and overdistention (or stretch) of lung cells contributes to
ventilator-induced lung injury. The central hypothesis of this application is that
hyperoxia induces structural changes in alveolar epithelial and endothelial cells, as well
as macrophages, that alter their mechanical properties making them more susceptible
to injury caused by mechanical stretch. Mechanisms of the initiation of cell injury will be
investigated using primary cultures of mouse alveolar type II (AT2) epithelial cells,
primary human lung endothelial cells, mouse alveolar and bone marrow-derived
macrophages, cultures of mouse lung slices, and a mouse model of combined
hyperoxia and VILI. In Aim 1 we will test the hypothesis that exposure of cells or lung
slices causes changes in cell structural elements that increase the elastic modulus of
the cells through activation of RhoA. We will measure the Young’s modulus, an
indication of an object’s ability to deform, using atomic force microscopy in the
indentation mode, and we will determine how hyperoxia changes cytoskeletal structures
including f-actin, microtubules, and focal adhesions. In Aim 2 we will investigate how
hyperoxia increases stretch-induced cell detachment and injury. In Aim 3 we will test
the hypothesis that RhoA-mediated changes in structure and mechanical properties
increases lung injury in mice in a combined model of hyperoxia and VILI. The proposed
studies will investigate the biophysical mechanisms that contribute to lung injury during
mechanical ventilation and provide new insights into mechanotransduction, the process
of converting mechanical signals to biological signals.
Terms: <ARDS><Acceleration><Actin-Activated ATPase><Actins><Acute Lung Injury><Acute Pulmonary Injury><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Adhesion Plaques><Adult ARDS><Adult RDS><Adult Respiratory Distress Syndrome><Alveolar><Animal Model><Animal Models and Related Studies><Antioxidants><Apoptosis><Apoptosis Pathway><Atomic Force Microscopy><Bacterial Pneumonia><Basement membrane><Biological><Biophysical Process><Biophysics><Bone Marrow><Bone Marrow Reticuloendothelial System><Calponin Phosphatase><Cell Adhesion><Cell Body><Cell Communication and Signaling><Cell Death><Cell Signaling><Cell membrane><Cell-Matrix Adherens Junctions><Cells><Cellular Adhesion><Cellular Matrix><Cellular Mechanotransduction><Cellular injury><Clinical><Cultured Cells><Cytoplasmic Membrane><Cytoskeletal System><Cytoskeleton><Da Nang Lung><Disease><Disorder><Elasticity><Elements><Endothelial Cells><Endothelium><Epithelial Cells><Epithelium><Exposure to><F-Actin><FGF-7><FLJ12216><Fibroblast Growth Factor 7><Filamentous Actin><Focal Adhesions><Focal Contacts><Force Microscopy><GTP Phosphohydrolases><GTPases><Gelsolin><Grippe><Guanosine Triphosphate Phosphohydrolases><Guanosinetriphosphatases><Human><Hyperoxia><Incidence><Inflammasome><Inflammation><Inflammatory><Influenza><Injury><Intensive Care Units><Intracellular Communication and Signaling><Investigation><Kinases><Knock-out><Knockout><Light><Lung><Lung Alveolar Epithelia><Lung Parenchyma><Lung Respiratory System><Lung Tissue><Lung damage><MLCK><MLCK108><MLCK210><MYLK><MYLK gene><Macrophage><Masks><Measures><Mechanical Signal Transduction><Mechanical ventilation><Mechanics><Mechanosensory Transduction><Mediating><Mice><Mice Mammals><Micro-tubule><Microtubules><Modeling><Modern Man><Modulus><Murine><Mus><Myosin ATPase><Myosin Adenosine Triphosphatase><Myosin Adenosinetriphosphatase><Myosin Light Chains><Myosin-Light-Chain Phosphatase><Myosins><Mφ><Necrosis><Necrotic><O element><O2 element><Oxygen><Pathway interactions><Patients><Phosphorylation><Phosphotransferase Gene><Phosphotransferases><Photoradiation><Plasma Membrane><Predisposition><Preparation><Process><Programmed Cell Death><Protein Phosphorylation><Proteins><Resistance><Rho-associated kinase><Rho-kinase><Rupture><SDGF-3><Scanning Force Microscopy><Severities><Shock Lung><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Slice><Stiff lung><Stretching><Structure><Structure of parenchyma of lung><Susceptibility><Testing><Therapeutic Intervention><Tidal Volume><Transphosphorylases><Ventilator-induced lung injury><Work><alveolar epithelium><anti-oxidant><bacteria pneumonia><biologic><biological signal transduction><biophysical characteristics><biophysical characterization><biophysical foundation><biophysical measurement><biophysical mechanism><biophysical parameters><biophysical principles><biophysical properties><biophysical sciences><cell damage><cell injury><cellular damage><damage to cells><ezrin><guanosinetriphosphatase><hyperoxia associated lung injury><hyperoxia induced lung injury><hyperoxia mediated lung injury><hyperoxygenation><improved><injured><injuries><injury to cells><insight><intervention therapy><intracellular skeleton><keratinocyte growth factor><lung injury><mechanic><mechanical><mechanical cue><mechanical pressure><mechanical properties><mechanical respiratory assist><mechanical signal><mechanically ventilated><mechanosensing><mechanotransduction><membrane-organizing extension spike protein><model of animal><moesin><mortality><mouse model><murine model><myosin phosphatase><necrocytosis><palifermin><pathway><phosphoprotein p81><plasmalemma><preparations><prevent><preventing><pulmonary><pulmonary damage><pulmonary injury><pulmonary tissue damage><pulmonary tissue injury><radixin><radixin protein><resistant><respiratory airway volume><response><supplemental oxygen><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><ventilation induced lung injury><ventilator associated lung injury><wet lung>