Spatial characterization of instructive tissue niches in distal human lung

Chronic lung diseases (CLDs) such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) represent a growing public health burden, yet their early pathogenesis and progressing mechanisms remain poorly understood. While late-stage disease iswell characterized histopathologically, there is a critical gap in our knowledge of the molecular and cellular events that precede visible tissue remodeling—particularly within microenvironments of the distal human lung. Conventional bulk tissue omics approaches fail to resolve the heterogeneity of these microdomains, while single-cell transcriptomic techniques often fail to capture the extracellular matrix (ECM) dynamics that are instrumental to disease progression. To address this, I utilized a spatial proteomics technique based on laser-capture microdissection coupled mass spectrometry (LCM-MS) to generate (patho)physiological region-specific proteomic profiles of the distal human lung. Usingwell-preserved formalin-fixed, paraffin-embedded (FFPE) human lung specimens, I systematically profiled 135 histopathologically defined regions from healthy controls, patients with mild COPD (GOLD II), and severe COPD (GOLD IV). This was complemented by donor-matched single-nucleus RNA sequencing (snRNA-seq) to assess transcriptional shifts across cell types and transitional cell states. A total number of 6,700 proteins, including 418 matrisome components, was identified across anatomically and pathologically distinct regions. In the healthy lung, proteomic gradients along the airway tree were uncovered and novel molecular markers of understudied compartments were established, such as the respiratory bronchioles (RB), which were enriched in surfactant protein B (SFTPB), CXCL13, and non-fibrillar collagen COL10A1. In mild COPD, I observed a loss of basal and secretory epithelial cell markers at the RB, a disruption of COL10A1 deposition, and mislocalization of CD47 — all suggestive of early niche destabilization. Thyroid hormone response and metabolic reprogramming were spatially upregulated in the distal airway and alveoli in GOLD II patents, indicating early tissue adaptation to stress. In an additional CLD study employing the same methodology, cellular shifts associated with metaplasia and fibroblastic foci were captured in IPF, revealing proteomic transitions that precede morphological changes.