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Distinct molecular profiles underpin mild to moderate equine asthma cytological profiles

ABSTRACT: This project used a state-of-the-art, multi-omics approach to improve our understanding of the aetiopathogenesis of a highly prevalent, performance-limiting disorder of racehorses; mild to moderate equine asthma (MMEA). This advanced knowledge is a prerequisite to improving prophylactic, management and therapeutic options for this condition. Although a number of risk factors for MMEA have been identified, incomplete understanding of the precise aetiopathogenesis of this syndrome means that options for intervention are currently limited. This study aimed to apply a multi-omic approach, reveal key inflammatory pathways involved in inflammatory cell recruitment to the lower airways and highlight pathways specific to different MMEA inflammatory cell profiles (MMEA endotypes). Thus, we compared BALF cell gene and protein expression data from horses with normal bronchoalveolar lavage fluid (BALF) cytology (n = 8) with those isolated from horses with neutrophilic (n = 4), mastocytic (n = 8), mixed neutrophilic/mastocytic (n=4) and mixed eosinophilic/mastocytic (n=3) inflammation. Analyses on transcriptomic and proteomic data derived from BALF cells from horses with neutrophilic cytology showed enrichment in classical inflammatory pathways, while horses with mastocytic cytology showed enrichment in pathways involved in hypersensitivity reactions related to non-classical inflammation that could mimic a Th2 immune response. The mixed eosinophilic/mastocytic group also presented with a non-classical inflammatory profile while, the mixed neutrophilic/mastocytic group revealed profiles consistent with both neutrophilic inflammation and hypersensitivity. Our adopted multi-omics approach (both gene and protein expression) has enabled a more holistic assessment of the immunological status of the lower airways associated with the different cytological profiles of equine asthma.

ORGANISM(S): Equus caballus

PROVIDER: GSE277308 | GEO | 2024/12/05

REPOSITORIES: GEO

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Project description:Asthma is a complex, chronic respiratory disease with marked clinical and pathophysiological heterogeneity. Distinct inflammatory phenotypes of eosinophilic, mixed, neutrophilic and paucigranulocytic asthma are identified in patients, but most in vivo mouse models, studying asthma mechanisms, mimic only eosinophilic phenotype in humans. The detailed unbiased in vivo studies on molecular responses among different kinds of inflammation in asthma models are lacking. Therefore, we developed mouse models representing three different inflammatory phenotypes of airway inflammation, namely eosinophilic, mixed, and neutrophilic asthma via different methods of house dust mite sensitisation. We used microarrays to determine the global gene expression in the lungs of mice with eosinophilic, mixed and neutrophilic inflammatory phenotypes to uncover underlying differences in clinical presentation and to find novel molecular targets and pathways, which might reflect different molecular mechanisms of the disease. By whole genome transcriptome profiling, we found that airway tight junction (TJ) molecules, mucins and inflammasome-related genes are differentially expressed in distinct phenotypes of allergic airway inflammation. Next, detailed analysis of several molecules from these families by quantitative RT-PCR, western blot and confocal microscopy revealed that (i) Zo-1 and Cldn18 were downregulated in all phenotypes, while Cldn4 upregulation was characteristic for neutrophilic airway inflammation; (ii) mucins Clca1 (Gob5) and Muc5ac were upregulated in eosinophilic and even more in neutrophilic asthma, and (iii) upregulation of inflammasome-related molecules such as Nlrp3, Nlrc4, Casp-1 and IL-1b was characteristic for neutrophilic asthma. Finally, we showed that inflammasome/Th-17/neutrophilic axis cytokines, namely IL-1b and IL-17 impaired epithelial barrier function and increased mucins expressions in primary human bronchial epithelial cells from normal and asthmatic donors. Our findings suggest that differential expression of TJs, mucins and inflammasome-related molecules in distinct asthma phenotypes could be mechanistically linked and might further reflect the differences observed in the clinic.

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Distinct molecular profiles underpin mild to moderate equine asthma cytological profiles

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