Pneumocystis Colonization Is Associated with Enhanced Pulmonary Remodeling and Activation of Redox-Responsive Pathways in a COPD Experimental Model

Chronic Obstructive Pulmonary Disease (COPD) is characterized by persistent inflammation and structural alterations in the lung triggered mainly by oxidative stress. Colonization by the opportunistic fungus Pneumocystis has been associated with worse clinical outcomes in COPD, yet its role in airway remodeling remains unclear. To this end, an elastase-induced COPD model was established, followed by colonization with Pneumocystis. Lung tissue was analyzed histologically and molecularly to assess epithelial thickness, alveolar morphometric parameters (mean linear intercept [MLI], D0, D1, D2), inflammation, collagen deposition, and the expression of remodeling and oxidative stress markers. Emphysematous damage parameters MLI, D0, D1, and D2 were markedly elevated in co-exposed animals, indicating enhanced alveolar enlargement. Animals with COPD and Pneumocystis colonization showed a significant increase in airway inflammation compared with control, COPD, and Pneumocystis groups. Airway epithelial thickness, mucus metaplasia, and collagen deposition exhibited a summative increase in the COPD/Pneumocystis group. Redox-responsive markers, such as superoxide dismutase (SOD) and catalase, were upregulated. Moreover, protein and mRNA levels of nuclear factor erythroid 2–related factor 2 (Nrf2) and its downstream gene heme oxygenase-1 (Hmox1) were significantly increased, with the strongest activation observed in co-exposed animals. Integrative correlation analysis showed that Pneumocystis burden positively correlated with lung damage, inflammation, and epithelial remodeling. These structural alterations were accompanied by coordinated activation of the antioxidant pathway Nrf2. Taken together, Pneumocystis colonization is associated with enhanced pulmonary remodeling and modulation of antioxidant signaling in experimental COPD, promoting structural and molecular changes that may contribute to disease progression. These findings suggest that Pneumocystis acts as an amplifying factor in COPD-associated lung damage.