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May 20, 2026

A22-21 Comprehensive Lipidomic Profiling of Bronchoalveolar Lavage Fluid (BALF) in Alpha-1 Antitrypsin Deficiency (AATD)

Key Points

Characterize the lipidomic profile of bronchoalveolar lavage fluid (BALF) in alpha-1 antitrypsin deficiency (AATD) to identify metabolic dysregulation.
BALF collected from AATD patients and healthy controls incorporating various COPD statuses.
Lipid extraction and analysis performed using UPLC and mass spectrometry.
PCA used to evaluate lipid expression differences across groups.
442 lipid features were analyzed with 194 being differentially expressed across groups.
PCA indicated distinct clustering of MM-COPD, while ZZ-aug patients resembled healthy ZZ individuals.
Preliminary results suggest triglycerides and ceramides are significantly impacted.

Abstract

Abstract Rationale Inflammation and metabolic dysfunction of the alveolar space - particularly lipid species - has been linked to Chronic Obstructive Pulmonary Disease (COPD) pathogenesis. Similar metabolic disruption has been reported in Alpha-1 Antitrypsin Deficiency (AATD), however little is known about defective cellular metabolism in the lung. Given the disturbed lipid metabolism reported in the AATD liver, detailed lipidomic profiling of the lung is warranted. Here we aim to characterize the lipidomic profile of AATD bronchoalveolar lavage fluid (BALF) to define the pathogenic changes in lipid metabolism specific to AATD. Methods BALF was collected from the right upper lobe of AATD patients (ZZ and ZZ with augmentation ZZ-aug) and healthy controls (MM) with and without COPD using an optimized protocol (Herron et al., Thorax, 2025). Lipids were extracted in isopropanol, dried and reconstituted with 0.5μg/mL EquiSPLASH® LIPIDOMIX®. Samples were analyzed on a Waters ACQUITY™ Premier UPLC System with an ACQUITY™ Premier CSH C18 column (1.7µm, 2.1x100mm) and Xevo™ G3 QToF mass spectrometer. Pooled QC samples and blanks were included, and results were analyzed using MetaboAnalyst, ProgenesisQI, and Lipostar2. Results Fifty-one samples were included in the positive mode (ESI+) analysis; 7 MM, 14 MM-COPD, 8 ZZ, 15 ZZ-COPD, and 7 ZZ-aug. Initial analyses detected 17,005 chromatographic peaks, and after QC and blank removal 442 lipid features were included in the analysis. Of these, 194 were differentially expressed between the five groups. PCA analysis showed that the MM-COPD group clustered separately from all others, suggesting ZZ-COPD lungs are not as strongly affected by lipid dysregulation. Interestingly, ZZ-aug patients clustered closer to healthy ZZ patients than ZZ-COPD, suggesting that augmentation therapy corrects this minor lipid metabolism dysregulation. Preliminary, in-silico identification suggests that triglycerides and ceramides are the most affected lipid classes, and further characterization is underway. Different normalization strategies are also being trialed to improve intergroup variability. Conclusions Lipidomic differences can be seen in MM-COPD and AATD BALF, with minimal differences between the different AATD phenotypes. Additional experiments (Oil-Red O staining, flow cytometry, Seahorse mitochondrial profiling) are underway to further probe the role of lipid metabolism in AATD. This abstract is funded by: Alpha-1 Foundation

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