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Principal Investigator: JARED M. RADBEL
Organization: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
Fiscal Year: 2024
Award: $222,505
Funding agency: National Institute of Environmental Health Sciences
Project Summary/Abstract
Acute respiratory distress syndrome (ARDS) develops in some individuals as a sequela to indirect stress
on the lung from systemic infection (sepsis/endotoxemia). However, it is unclear why only some patients with
sepsis develop ARDS. One possible risk factor leading to ARDS in patients with sepsis is exposure to air
pollutants such as ozone. Recently, FDA acceptable environmental levels of ozone exposure have been
directly linked to the development of ARDS. Our overall goal is to elucidate the mechanisms underlying the
increased risk of developing ARDS following exposure to oxidants such as ozone. ARDS develops, in part,
due to an accumulation of dead and dying neutrophils and neutrophil-derived proinflammatory apoptotic bodies
in the lung. Under homeostatic conditions, these are removed by macrophages via a process known as
efferocytosis. We hypothesize that the increased risk of ARDS following ozone exposure is due impaired
efferocytosis. Moreover, this is exacerbated in individuals with genetic deficits in the pulmonary collectin,
surfactant protein D (SPD), which controls macrophage efferocytosis. To test this, we developed a novel
experimental model in which mice are exposed to inhaled ozone followed by intravenous (i.v.)
lipopolysaccharide (LPS), a bacterial-derived toxin released into the blood during sepsis (endotoxemia). Our
aims are to (1) Determine if ozone exposure and decreased SPD activity exacerbate inflammation and acute
lung injury (ALI) by impairing macrophage efferocytosis and (2) Determine if decreased SPD activity
exacerbates ozone-induced impairment of macrophage efferocytosis in humans. Wild type and lung-specific
conditional SPD knock out mice will be treated with ozone followed by LPS. Macrophage efferocytosis will be
measured by flow cytometry. The mechanistic pathways associated with oxidative stress, which is important in
ozone toxicity, will be identified using RNA sequencing (RNAseq). We will analyze lung inflammation and
macrophage efferocytosis in human subjects, stratified according to single nucleotide polymorphisms within the
SPD gene, following controlled ozone exposure. The results of these experiments will provide novel
mechanistic insights into the relationship between ozone exposure, macrophage function, SPD variation, and
susceptibility to ARDS. These studies are significant, as oxidants such as ozone have been implicated as a
risk factor the development of ARDS. The experiments, coursework, and structured mentorship proposed in
this application will provide the basis for an NIH R01 grant and initiate the PI's career in independent
translational research.
Terms: <ARDS><Acute Lung Injury><Acute Pulmonary Injury><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Adult ARDS><Adult RDS><Adult Respiratory Distress Syndrome><Affect><Air Pollutants><Animals><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Apoptotic><Blood><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Blood Reticuloendothelial System><Clinical><Cohort Studies><Collagenous Lectins><Collectins><Concurrent Studies><Da Nang Lung><Development><Disease><Disorder><Endotoxemia><Environmental Protection Agency><Epidemiologic Research><Epidemiologic Studies><Epidemiological Studies><Epidemiology Research><Experimental Models><Exposure to><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Genes><Genetic><Goals><Grant><Human><Human Pathology><Impairment><Individual><Inflammation><Inflammatory><Inhalation><Inhaling><Intravenous><KO mice><Knock-out Mice><Knockout Mice><Link><Lipopolysaccharides><Lung><Lung Inflammation><Lung Protein D><Lung Respiratory System><Lung damage><Macrophage><Marrow Neutrophil><Measures><Mentorship><Mice><Mice Mammals><Modeling><Modern Man><Murine><Mus><Mφ><NIH><National Institutes of Health><Neutrophilia><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Null Mouse><O3><O3 exposure><Oxidants><Oxidative Stress><Oxidative Stress Induction><Oxidizing Agents><Ozone><Pathway interactions><Patients><Pneumonitis><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Predisposition><Process><Production><Pulmonary Inflammation><Pulmonary Surfactant Protein D><Pulmonary Surfactant-Associated Protein D><RNA Seq><RNA sequencing><RNAseq><Reporting><Resolution><Risk><Risk Factors><Role><SP-D><Sepsis><Shock Lung><Single Base Polymorphism><Single Nucleotide Polymorphism><Stiff lung><Stress><Structure><Surfactant Protein D><Surfactant-Associated Glycoprotein D><Susceptibility><Systemic infection><Testing><Toxic effect><Toxicities><Toxin><Translational Research><Translational Science><United States Environmental Protection Agency><United States National Institutes of Health><Variant><Variation><blood infection><bloodstream infection><career><developmental><electron acceptor><epidemiologic investigation><epidemiology study><experiment><experimental research><experimental study><experiments><flow cytophotometry><human subject><insight><lung injury><mortality><neutrophil><novel><ozone exposure><pathway><prevent><preventing><pulmonary><pulmonary damage><pulmonary injury><pulmonary tissue damage><pulmonary tissue injury><resolutions><role model><single nucleotide variant><social role><transcriptome sequencing><transcriptomic sequencing><translation research><translational investigation><wet lung>