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Chronic obstructive pulmonary disease (COPD) is the 3rd leading cause of death in the US and is primarily triggered in susceptible individuals by chronic cigarette smoke (CS) exposure. Protease/antiprotease imbalances in COPD leads to destruction of lung matrix. Therapies targeting this imbalance have not yet provided a cure. Mass spectrometry (MS) has been used to analyze the proteome of healthy and COPD lungs, but extracellular matrix (ECM) and matrix bound proteins (i.e. matrisome (MAT) are difficult to detect and thus underrepresented. Decellularized lungs (DEC) have enriched MATs. We hypothesized that the proteomic profile of DEC COPD lungs is distinct from healthy and may provide new insight into COPD pathogenesis. DEC lungs from two murine COPD models (elastase, CS) were analyzed by MS using quantitative TMT-labeling and compared to healthy controls. DEC lungs from 12 normal and 4 COPD human lungs were analyzed using 3 samples from distinct regions per lung. Principal component analysis showed that the proteome of elastase model derived DEC lungs was markedly different compared to normal. Although clustering was not observed for DEC lungs from murine CS or human COPD vs controls, the MAT had detectable differences. Notably, human lung samples had high intra-lung similarity, independent of disease status. Proteome changes in DEC lungs from CS mice positively correlated with those seen in human COPD lungs (Pearson correlation r=0.17, p