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Global Matrisome changes in the obese lung are linked to fibroblastic stroma and premature aging

ABSTRACT: Obesity is associated with an increased risk of lung disorders, yet its effects on lung tissue structure and the microenvironment remain incompletely understood. Using a multiomics strategy combining tissue proteomics, lipidomics, solubility profiling, single-cell transcriptomics, and functional assays, we investigated how obesity affects lung composition and fibroblast behavior. Our data indicate that obesity induces remodeling of the extracellular matrix, including changes in elastic fiber-associated proteins, and is accompanied by reduced levels of protease inhibitors in lung tissue and BALF. Stromal fibroblasts accumulated lipids and exhibited increased contractility, matrisome alterations, and transcriptional hallmarks of aging. Comparison of obese and aging lungs revealed overlapping solubility changes in structural matrix proteins. These findings suggest that obesity may induce premature aging of fibroblasts and consequent remodeling of the lung microenvironment, with potential implications for tissue compliance and repair responses.

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ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Lung

SUBMITTER: Veronika Lukacs-Kornek

LAB HEAD: Veronika Lukacs-Kornek

PROVIDER: PXD064681 | Pride | 2025-08-21

REPOSITORIES: Pride

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Project description:Background: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterized by varying degrees of emphysematous lung destruction and small airway disease, each with distinct effects on clinical outcomes. There is little known about how microRNAs contribute specifically to the emphysema phenotype. We examined how microRNA expression is altered with regional emphysema severity within the lung and how these microRNAs regulate disease-associated gene-expression networks. Results: We profiled microRNAs in different regions in the lung with varying degrees of emphysema from 6 smokers with COPD and 2 controls (8 regions x 8 lungs = 64 samples). 63 microRNAs (p<0.05) were altered with regional emphysema severity as quantified by mean linear intercept (Lm). MicroRNA and gene expression data were then integrated in the same samples. A subset of microRNAs, including miR-638, miR-30c, and miR-181d, correlated with many of their predicted gene targets, suggesting a role in regulating the gene networks that underlie emphysematous lung destruction. Modulating miR-638 expression in primary human lung fibroblasts recapitulated the alterations in its targeted gene-expression network associated with emphysema progression. Pathway analysis revealed that genes involved in oxidative stress and accelerated aging were affected by miR-638 knock-down in fibroblasts. Many miR-638 gene targets in these pathways were amongst those negatively correlated with miR-638 expression in emphysematous lung tissue. Conclusions: Our findings demonstrate that microRNAs are altered with regional emphysema severity and modulate disease-associated gene expression networks. Furthermore, miR-638 may regulate gene expression associated with the oxidative stress response and aging in emphysematous lung tissue and fibroblasts. Paired samples were obtained from 8 regions at regular intervals between the apex and base of each explanted lung from six patients with severe COPD and two donors. The degree of emphysematous destruction was quantified in one sample from each region by mean linear intercept (Lm), while microRNA expression was profiled in the adjacent sample from the same region using the NCode Version 3 microRNA microarrays (Invitrogen, Carlsbad, CA). After quality control 60 samples were used for the analysis.

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Global Matrisome changes in the obese lung are linked to fibroblastic stroma and premature aging

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