Type VI collagen is proportionally lower around airways and blood vessels in idiopathic pulmonary fibrosis.

Abstract

Type VI collagen (COL6) is a key extracellular matrix protein that supports matrix organization and cell-matrix interactions, yet its regulation in idiopathic pulmonary fibrosis (IPF) remains poorly understood. Here, we characterize COL6 gene expression, spatial localization, remodeling, and functional effects of COL6-derived fragments. Analysis of publicly available single-cell RNA sequencing data from 30 control subjects and 32 pulmonary fibrosis patients revealed higher expression of COL6A1-A6 in fibrotic lungs, predominantly in mesenchymal cells (A1: P = 0.0002, A2: P = 0.0005, A3: P = 2.5 × 10^-5, A5: P = 0.016, A6: P = 0.007). Immunohistochemical analysis of lung tissue from never-smoker (n = 9) and ex-smoker (n = 9) control subjects and IPF patients (n = 12) showed extensive COL6 localization across parenchyma, airways, and vessels. The proportion of COL6α1 and COL6α2 was lower around IPF vessels (α1: P < 0.001, α2: P = 0.012), and COL6α2 was lower around IPF airways (P = 0.033) compared with never-smokers. Quantification of COL6 remodeling fragments in lung tissue from never-smoker (n = 3) and ex-smoker (n = 5) control subjects and IPF patients (n = 10) revealed that COL6 production (PRO-C6) localized around airways and vessels but was proportionally lower in IPF airways (never-smokers: P = 0.0075). In contrast, COL6 degradation (C6M) was widely distributed throughout the tissue, with lower levels in IPF (never-smokers: P = 0.0008). Functionally, COL6 and PRO-C6 increased fibroblast viability (COL6: P = 0.002, PRO-C6: P = 0.0021), whereas apoptosis was unaffected. Similar trends were observed in epithelial and endothelial cells. In summary, despite increased COL6 gene expression, IPF lungs exhibited lower proportions of COL6 protein and synthesis around airways and vessels, suggesting disrupted matrix organization, altered remodeling, and prosurvival effects that may contribute to fibroblast persistence and fibrosis progression.NEW & NOTEWORTHY In this study, we revealed that idiopathic pulmonary fibrosis (IPF) lungs are characterized by increased type VI collagen (COL6) gene expression but lower COL6 protein and turnover proportions around airways and blood vessels compared with controls. COL6 and a fragment associated with its production (PRO-C6) increased lung fibroblast viability. These findings highlight that pulmonary fibrotic tissue is characterized by disrupted extracellular matrix and altered tissue remodeling and suggest that COL6 may contribute to fibroblast persistence and fibrosis progression.