Change in the chondroitin/dermatan structure in distal lung tissue from COPD patients

Abstract Chronic obstructive pulmonary disease (COPD) is a progressive condition characterized by airway remodeling, including emphysema and fibrosis. Proteoglycans and their glycosaminoglycan (GAG) chains are key components of the extracellular matrix and may be altered as the disease advances. This study analyzed lung tissue from COPD patients (GOLD stages II–III and IV), non-COPD smokers, and non-smokers to assess proteoglycan and GAG changes. While LC–MS revealed no alterations in chondroitin/dermatan sulfate (CS/DS) or heparan sulfate (HS) proteoglycan core proteins, the total GAG level increased in GOLD II–IV patients. HS displayed increased N- and 2-O -sulfation in GOLD IV, while CS/DS levels and 4-O -sulfation were enhanced across GOLD II–IV. These findings were supported by transcriptomic data indicating upregulation of CHST11, the main CS/DS 4-O -sulfotransferase. In line with previous findings, TGF-β signaling was shown to be enriched in COPD patients and to regulate the CHST11 expression. These results were confirmed by TGF-β stimulation of lung fibroblasts showing increased CS/DS levels, 4-O- sulfation, and CHST11 expression. In conclusion, COPD is associated with disease-stage-specific changes in GAG sulfation, particularly enhanced CS/DS 4-O -sulfation that is likely to be driven by TGF-β. These alterations may contribute to extracellular matrix remodeling and represent potential targets for therapeutic intervention to mitigate disease progression.