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Identification of Bronchial Epithelial Genes Associated with Type-2 Eosinophilic Inflammation in Asthma

ABSTRACT: Airway inflammation has a critical role in asthma pathogenesis and pathophysiology. Yet, the molecular pathways contributing to airway inflammation are not fully known, particularly Type-2 (T2) inflammation characterized by both eosinophilia and FeNO levels. Here, we seek to identify genes whose level of expression in epithelial brushing samples is associated with both bronchoalveolar lavage (BAL) eosinophilia and generation of FeNO. We used a segmental allergen bronchoprovocation (SBP-Ag) procedure in asthma subjects, and RNA-sequencing (RNA-seq) analyses of BAL cells and brushing samples before and 48 h after SBP-Ag. Allergen bronchoprovocation increased FeNO levels which correlated with eosinophilia but not neutrophilia. Thirteen genes were identified in brushing samples, whose expression changed in response to SBP-Ag and correlated with both airway eosinophilia and FeNO levels after SBP-Ag. Among these 13 genes, the epithelial cell product, CDH26 was a candidate to contribute to the amplification of T2 inflammation as reflected by eosinophilia and FeNO, and causal mediation analyses with pro-T2 and pro-eosinophilic cytokine mediators in BAL fluids. Among the genes associated with reduced eosinophila and FeNO, HEY2 is known to enhance cell proliferation, migration, invasion, and EMT, as well as to reduce apoptosis. This unbiased RNA-seq analysis in subjects with allergic asthma has revealed several epithelial cell genes that may be critical for the development or augmentation of T2 inflammation in asthma, particularly CDH26.

ORGANISM(S): Homo sapiens

PROVIDER: GSE264325 | GEO | 2025/01/06

REPOSITORIES: GEO

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Project description:Murine Pulmonary Responses to Ambient Baltimore Particulate Matter: Genomic Analysis and Contribution to Airway Hyperresponsiveness; Asthma is a complex disease characterized by airway hyperresponsiveness (AHR) and chronic airway inflammation. Environmental factors such as ambient particulate matter (PM), a major air pollutant, has been demonstrated in epidemiological studies to contribute to asthma exacerbation and increased asthma prevalence. OBJECTIVE: We investigated the genomic and pathophysiological effects of Baltimore PM (median diameter 1.78 Âµm) in a murine model of asthma to identify potential biomarkers. METHODS: A/J mice with ovalbumin (OVA) âinduced AHR were exposed to PM (20 mg/kg, intratracheal), and both AHR and bronchoalveolar lavage (BAL) were assayed on days 1, 4, and 7 post exposure. Lung gene expression profiling (Affymetrix Mouse430_ 2.0) by PM (20 mg/kg, intratracheal) were assayed on OVA- and / or PM--challenged mice. RESULTS: Significant increases of airway responsiveness in OVA-treated mice were observed, indicating an asthmatic phenotype. Ambient PM exposure induced significant changes in AHR in both naive mice and OVA-induced asthmatic mice. In both naive and OVA challenged asthmatic mice, PM induced eosinophil and neutrophil infiltration into airways, elevated BAL protein content, and stimulated secretion of TH1 cytokines (IFN-g, IL-6, and TNF-a) and TH2 cytokines (IL-4, IL-5, and eotaxin) into BAL. Consistent with these results, PM induced expression of genes of innate immune response, chemotaxis and complementary system. CONCLUSION: These studies, consistent with epidemiological data, indicate that PM increases AHR and lung inflammation in naÃ¯ve mice and exacerbates the asthma phenotype of increased AHR and gene expression pattern changes correlated with acute lung inflammation and airway damage. We used microarrays to detail the global programme of gene expression induced by rhPBEF treatment and VALI. Experiment Overall Design: animals were treated by PBS, Oval albumin, PM, or both OVA/PM

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Identification of Bronchial Epithelial Genes Associated with Type-2 Eosinophilic Inflammation in Asthma

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