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A2311 - Lung Macrophage Function in Cystic Fibrosis - Regional Differences Correlating with Severity of Lung Damage
Author Block: D. Seidler1, A. Nymon2, J. Czum3, D. Dorman3, J. Dessaint3, A. Ashare3; 1Pulmonary/Critical Care, Dartmouth Hitchcock, Lebanon, NH, United States, 2Geisel School of Medicine, Hanover, NH, United States, 3Dartmouth Hitchcock, Lebanon, NH, United States.
Background: Lung function decline in CF can be largely attributed to irreversible destruction of the muscle and elastic tissue of the airways, a process referred to as bronchiectasis. Bronchiectasis develops in localized regions of the lung with an upper lobe predilection and worsens over time. We have previously shown that there is stability of the microbiome in different regions of the lung despite clear differences in regional lung damage. These findings suggest that local host factors promote lung damage, but the actual mechanism underlying regional heterogeneity of disease remains unclear.
Methods: Fifteen CF subjects underwent CT scan and bronchoscopy. A CT scan was obtained with calculation of lobar Brody Scores. Bronchoscopy was done to obtain regional bronchoalveolar lavage (BAL) samples from the lobes with the highest, lowest, and median Brody scores and primary alveolar macrophages (AMs) were isolated from each region. Regional inflammatory cytokines were measured by ELISA.
Results: We found that the majority of patients had the highest Brody Scores in the RUL and that inflammatory cytokine levels correlated significantly with Brody Score. The regional differences in Brody score were due in large part to regional differences in bronchiectasis and peribronchial wall thickening. AMs from the region with the highest Brody Score demonstrated a more robust inflammatory response to hypoxia compared to AMs from regions with the lowest Brody score. There was no regional difference in the inflammatory response of AMs to Pseudomonas. RNASeq analyses of regional AMs demonstrated upregulation of genes regulating glycolysis in AMs isolated from regions with the highest Brody scores (RUL). Using a Seahorse XF, we confirmed that AMs from the RUL are more glycolytic compared to AMs from the RLL. In addition, treating AMs from the RUL with a glycolysis blocker resulted in decreased inflammation following hypoxia.
Conclusions: Our study is the first to demonstrate that there are metabolic differences between AMs isolated from different regions of the CF lung. These data suggest that glycolysis/OX PHOS balance may be an important regulator of hypoxia-induced inflammation by AMs. This balance alters the pool of reducing equivalents, which directly affects the epigenetic landscape of the cells, thereby altering their potential metabolic responses.
Clinical Implications: Understanding regional differences in AM mediated inflammatory response and development of bronchiectasis could lead to novel approaches to therapy in CF.