C27-05 Dysregulated Metabolism, MAPK Activation, and Siga Deficiency in Mice With COPD Complicated by Aspergillus Infection

Abstract Background Patients with chronic obstructive pulmonary disease (COPD) exhibit heightened susceptibility to Aspergillus, yet the underlying mechanisms remain poorly defined. This study investigated the role of metabolic reprogramming and the mitogen-activated protein kinase (MAPK) signaling pathway in COPD complicated by Aspergillus infection and its relationship with mucosal immunity. Methods A murine model of COPD was established using lipopolysaccharide (LPS) and cigarette smoke exposure, followed by intranasal inoculation with Aspergillus fumigatus conidia to induce pulmonary Aspergillus infection. Expression and phosphorylation levels of MAPK pathway proteins (p38, p44/p42) were analyzed by RT-PCR, western blot, and immunohistochemistry. Cytokine levels (IL-10, IFN-γ, IL-17, IL-23, TNF-α) and secretory IgA (sIgA) in lung tissues and oral secretions were quantified by ELISA. Untargeted metabolomics was performed to characterize metabolic alterations. Results Compared to control group, COPD combined with Aspergillus infection (COPD-asp) mice displayed significantly increased p38 MAPK phosphorylation, elevated pro-inflammatory cytokines (IL-17, IL-23, TNF-α), and reduced anti-inflammatory factors (IL-10, IFN-γ). sIgA levels were markedly decreased in both lung tissues and oral secretions. Histopathological analysis revealed severe alveolar destruction in COPD-asp lungs. Metabolomic profiling identified extensive metabolic reprogramming, including disruptions in glycerophospholipid metabolism, nucleotide sugar pathways, and specific enrichment of the ferroptosis pathway. Correlation analysis linked specific metabolites, such as acylcarnitines and lysophospholipids, to MAPK hyperactivation and inflammatory cytokine levels. Conclusions Hyperactivation of the p38 MAPK pathway, driven in part by metabolic dysregulation, may promote Aspergillus susceptibility in COPD by exacerbating inflammatory responses, suppressing immune regulation, and impairing sIgA-mediated mucosal defense. Targeting MAPK signaling or restoring metabolic and mucosal immunity represents a promising therapeutic strategy for COPD-associated Aspergillus infection. This abstract is funded by: None