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Ultrastructure analysis of macrophages as a tool to shed light on Hypersensitivity Pneumonitis pathogenesis

Publication . Pacheco, Ana Sofia Nunes; Santos, Ana Rita; Bastos, Hélder Novais e

Interstitial lung diseases (ILD) are a group of more than 200 disorders that affect the pulmonary interstitium, many of which are classified as rare, making accurate diagnosis challenging. These diseases can exhibit diverse phenotypes, ranging from predominantly inflammatory and potentially reversible conditions to established, irreversible fibrosis. Interestingly, in our patient cohort, hypersensitivity pneumonitis (HP) is the most prevalent fibrotic ILD, characterized by high morbidity and mortality. Recently, the single nucleotide polymorphism rs35705950 of the MUC5B gene was associated with fibrotic HP, indicating a more severe disease progression and a reduced response to immunosuppressive therapy. Previous research from our group had shown that patients with fibrotic HP have an increased percentage of macrophages in bronchoalveolar lavage and a significant accumulation of MUC5B in lung parenchyma and in alveolar macrophages cytoplasm which led to a detailed analysis of this cell type. In this study, we analyzed the ultrastructure of alveolar macrophages in lung tissue from fibrotic HP patients, and no ILD as a control, which revealed significant differences. Macrophages from fibrotic HP patients displayed distinct dysfunctional double membrane organelles together with a decrease of preserved mitochondrias. Functional assays were conducted to understand the nature of these organelles and showed a decrease in functional mitochondria combined with the accumulation of damaged mitochondria, while no impact in the phagocytic capacity. Additionally, the stratification of macrophages from fibrotic HP patients according to the MUC5B rs35705950 genotype revealed an increase in the presence of dysfunctional double membrane organelles in patients carrying the MUC5B T-minor allele. This study of macrophages in fibrotic HP can provide key insights into disease mechanisms, facilitating future diagnosis and also guiding targeted therapies to improve patient outcomes.

2024Master thesis

Open access