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Principal Investigator: ALESSANDRO VENOSA
Organization: UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
Fiscal Year: 2024
Award: $380,122
Funding agency: National Institute of Environmental Health Sciences
Project Summary/Abstract:
Pulmonary fibrosis (PF) is a rare degenerative disease characterized by progressive lung stiffening, resulting in
death within 3-5 years of diagnosis. Compelling clinical evidence show that mutations of the epithelial cell-
specific gene encoding surfactant protein-C (SP-C), are linked to a particularly extreme lung phenotype.
Progression of PF in humans is often punctuated by inflammatory bursts, clinically termed “acute exacerbations”,
that drastically accelerate the disease and reduce life expectancy. In accord with this notion, monocyte
mobilization and the persistence of monocyte-derived macrophages in the lung are strong predictors of PF
severity. Several environmental factors have been proposed to promote and accelerate acute inflammatory
exacerbations of PF; however, the exact mechanisms have not been interrogated. The ubiquitous air pollutant
ozone (O3) represents a major, and unavoidable, environmental contributor to pulmonary disease through
oxidative stress and monocyte/macrophage rich inflammation. To closely mimic causes of human PF, we
developed a novel mouse model that develops spontaneous lesions over time, as a result of inducible ectopic
expression of the most common PF-linked SP-C mutation (SP-CI73T). This preclinical model provides a unique
platform to decipher mechanisms of PF progression and specifically the roles of acute exacerbations (induced
by O3), infiltrating monocytes, and monocyte-derived macrophages in promoting PF. Our published work showed
that SP-C mutation is accompanied by a dynamic monocyte/macrophage inflammatory response, initiated by
the epithelium. Preliminary evidence confirm that O3 exposure amplifies inflammatory cell influx and pro-
inflammatory signaling in SP-C mutant mice, worsening PF. Assessment of the proposed paradigm will provide
fundamental data to define the responses of the healthy, acutely inflamed, and fully fibrotic lung to environmental
exposure. Our hypothesis is that O3-induced acute exacerbation of PF driven by SP-C mutation enhances the
recruitment and activation of inflammatory monocytes, triggering a monocyte-derived macrophage pro-fibrotic
response. Our Specific Aims are to: 1) Define monocyte dynamics following O3-induced pulmonary inflammation
and PF. 2) Investigate the role of monocyte-derived macrophages and O3-induced exacerbation of PF; and 3) :
Establish the role of monocyte subpopulations in the PF phenotype.
Terms: <Acceleration><Acute><Air Pollutants><Bleo><Bleomycin><Blood monocyte><Body Tissues><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cessation of life><Chemical Injury><Chemokine Receptor Gene><Clinical><Data><Death><Degenerative Disorder><Dependence><Diagnosis><Disease><Disorder><Ectopic Expression><Environmental Exposure><Environmental Factor><Environmental Risk Factor><Environmental Toxin><Epidemiology><Epithelial Cells><Epithelium><Fibrosis><Fibrotic lesions in lung><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Future><Gene Transcription><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Heterogeneity><Histologic><Histologically><Histology><Human><Infiltration><Inflammation><Inflammatory><Inflammatory Response><Inhalation><Inhaling><Injury><Intracellular Communication and Signaling><Lesion><Life Expectancy><Link><Lung><Lung Diseases><Lung Grafting><Lung Inflammation><Lung Respiratory System><Lung Tissue Fibrosis><Lung Transplantation><Lung scar><Lung tissue scar><Macrophage><Marrow monocyte><Mediator><Methods><Modeling><Modern Man><Mutant Strains Mice><Mutation><Myeloid Cell Activation><Myeloid Cells><Mφ><O3><O3 exposure><Oxidative Stress><Ozone><Pathogenesis><Patients><Peripheral><Phenotype><Pneumonitis><Population><Pre-Clinical Model><Preclinical Models><Predisposition><Property><Publishing><Pulmonary Diseases><Pulmonary Disorder><Pulmonary Fibrosis><Pulmonary Graft><Pulmonary Inflammation><Pulmonary Scar><Pulmonary Surfactant Protein C><Pulmonary Surfactant-Associated Protein C><Pulmonary Surfactant-Associated Protein SP-C><Pulmonary Tissue fibrosis><Pulmonary Transplant><Pulmonary Transplantation><RNA Expression><RNA Seq><RNA sequencing><RNAseq><Role><SP-C peptide><SP-C protein><Scarring at the lung><Scarring in the lung><Severities><Signal Transduction><Signal Transduction Systems><Signaling><Sorting><Surfactant Polypeptide SP-C><Susceptibility><System><Testing><Time><Tissues><Toxic Environmental Agents><Toxic Environmental Substances><Toxic effect><Toxicities><Transcription><Vulnerable Populations><Work><biological signal transduction><chemical trauma><chemokine receptor><clinical relevance><clinically relevant><cytokine><degenerative condition><degenerative disease><disease of the lung><disorder of the lung><effective therapy><effective treatment><environmental risk><environmental toxicant><epidemiologic><epidemiological><fibrogenesis><fibrosis in the lung><fibrotic lung><flow cytophotometry><fractalkine receptor><genome mutation><improved><injured><injuries><lung disorder><lung fibrosis><lung health><lung transplant><monocyte><mouse model><mouse mutant><murine model><mutant><novel><ozone exposure><pharmacologic><pulmonary><pulmonary health><recruit><response><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><surfactant protein C><transcriptome sequencing><transcriptomic sequencing><ventilation><vulnerable group><vulnerable individual><vulnerable people>