Lung microenvironments and disease progression in fibrotic hypersensitivity pneumonitis

ABSTRACT: Rationale: Fibrotic hypersensitivity pneumonitis (fHP) is an interstitial lung disease caused by sensitization to an inhaled allergen. Objectives: We aimed to identify the molecular determinants associated with progression of fibrosis. Methods: Nine fHP explant lungs and six unused donor lungs (as controls) were systematically sampled (4 samples/lung). According to microCT measures, fHP cores were clustered into a mild, moderate and severe fibrosis group. Gene expression profiles were assessed using Weighted Gene Co-expression Network Analysis (WGCNA), xCell, gene ontology and structure enrichment analysis. Gene expression of the prevailing molecular traits was also compared with IPF. The explant lung findings were evaluated in separate clinical fHP cohorts using tissue, bronchoalveolar lavage samples and computed tomography scans. Results: We found six molecular traits that associated with differential lung involvement. In fHP, extracellular matrix and antigen presentation/sensitization transcriptomic signatures characterized lung zones with only mild structural and histological changes, whereas signatures involved in honeycombing and B-cells dominated the transcriptome in the most severely affected lung zones. With increasing disease severity, endothelial function was progressively lost and progressive disruption in normal cellular homeostatic processes emerged. All six were also found in IPF, with largely similar associations with disease microenvironments. The molecular traits correlated with in vivo disease behaviour in a separate clinical fHP cohort. Conclusion: We identified six molecular traits which characterise the morphological progression of fHP and associate with in vivo clinical behaviour. Comparing IPF with fHP, the transcriptome landscape was determined considerably by local disease extent, rather than by diagnosis alone.

ORGANISM(S): Homo sapiens

PROVIDER: GSE184316 | GEO | 2022/01/01

REPOSITORIES: GEO