Friday, May 9, 2025
5/9/2025
Role of Macrophage Efferocytosis in Ozone-Induced ARDS - 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.
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