Early Pulmonary Fibrosis is Defined by Niche- and Cell-Specific Molecular Programs.

Area of Science:

• Pulmonary Medicine
• Molecular Biology
• Genomics

Background:

• Preclinical familial pulmonary fibrosis (FPF) is an early stage of fibrotic lung disease.
• The molecular programs preceding fibrosis are not well understood, especially at the compartment and cell level.
• Most Idiopathic Pulmonary Fibrosis (IPF) research uses end-stage lungs, limiting insight into early disease stages.

Purpose of the Study:

• To define spatially organized molecular signatures in preclinical FPF.
• To identify circulating biomarkers linked to early fibrotic remodeling.
• To understand compartment- and cell-specific molecular changes in early pulmonary fibrosis.

Main Methods:

• Integrated multi-omic profiling of lung tissue (preclinical FPF, IPF, controls) using spatial transcriptomics and single-nucleus RNA sequencing (snRNAseq).
• Blood proteomics analysis.
• Differential gene expression and pathway enrichment analyses across spatial compartments and epithelial cell states.

Main Results:

• Preclinical FPF lung tissue shows transcriptional abnormalities (stress-response, ECM programs) despite minimal architectural changes.
• Spatial analyses reveal altered alveolar niche programs and increasing profibrotic signaling.
• Epithelial cells exhibit dysregulated states and transitional phenotypes, with signatures partially mirrored in peripheral blood.

Conclusions:

• Preclinical FPF has distinct molecular programs in specific lung compartments and cells before fibrosis is established.
• Alveolar, airway, and vascular signatures, along with epithelial remodeling states, are identified.
• Findings support a framework for early pulmonary fibrosis classification and minimally invasive stratification.