Mitochondrial respiratory dysfunctions of alveolar macrophages in interstitial lung disease: an exploratory study of bioenergetic and clinical links

Background Intracellular metabolism is essential for macrophage function. However, the association between the metabolic profile of alveolar macrophages (AMs), which are responsible for pulmonary innate immune responses, and the progression of pulmonary fibrosis in humans remains unclear. Methods This exploratory study investigated whether mitochondrial bioenergetics in bronchoalveolar lavage (BAL)-derived AMs can distinguish interstitial lung disease (ILD) from non-ILD conditions. A total of 12 patients undergoing diagnostic BAL were analyzed (ILD, n = 7; non-ILD, n = 5). CD11c + AMs were isolated and analyzed using an extracellular flux analyzer to quantify metabolic parameters. Principal component analysis (PCA) and penalized logistic regression were used for multivariate discrimination. Results The AMs in ILD showed reduced ATP-linked respiration (3.55 vs. 10.67 pmol/min/10 5 cells, p = 0.003) and coupling efficiency (10.55% vs. 25.81%, p = 0.018) compared with non-ILD AMs. PCA using all four metrics distinguished ILD from non-ILD AMs. Logistic regression classified subjects with 83% cross-validated accuracy. ATP-linked respiration and coupling efficiency were independent predictors under Firth correction. Collectively, AMs from ILD cases exhibited mitochondrial dysfunction, particularly reduced ATP-linked respiration. Conclusion This bioenergetic profile may offer preliminary insights into mitochondrial bioenergetic alterations in AMs from ILDs and their potential relevance to disease characterization. Larger longitudinal studies are warranted to validate these findings and their clinical utility.