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Transcriptome Analysis of Type II-Gated Alveolar Epithelial Cells Reveals Convergent and Divergent Molecular Signatures in COPD and IPF Lung Explants
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A3835 - Transcriptome Analysis of Type II-Gated Alveolar Epithelial Cells Reveals Convergent and Divergent Molecular Signatures in COPD and IPF Lung Explants
Author Block: S. Chu1, S. Poli1, Y. Sakairi1, R. S. Kelly2, R. Chase2, X. Liang3, K. Tsoyi3, S. Y. El-Chemaly1, M. A. Perrella1, G. M. Hunninghake4, D. L. DeMeo1, E. K. Silverman1, A. M. Choi5, G. R. Washko4, B. A. Raby1, I. O. Rosas1; 1Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, United States, 2Channing Division of Network Medicine, Boston, MA, United States, 3Pulmonary and Critical Care Medicine, Boston, MA, United States, 4Brigham and Women's Hospital, Boston, MA, United States, 5Weill Cornell Medical College, New York, NY, United States.
RATIONALE: Chronic obstructive pulmonary disease (COPD) with emphysema and idiopathic pulmonary fibrosis (IPF) are smoking and age-related diseases characterized by aberrant alveolar epithelial cell (AEC) activity contributing to remodeling and destruction of lung parenchyma. High-resolution molecular phenotyping of AECs in these diseases is lacking. We analyzed the transcriptomic signatures of primary type II AECs from COPD and IPF lung explants. METHODS: AECs were isolated from biobanked human lung explants via flow cytometry and underwent RNA sequencing using a modified RNA exome capture protocol. Transcriptomes of cell populations enriched for type II AECs from COPD, IPF and control lungs (n=11 each) were characterized. We identified differentially expressed genes and performed gene ontology (GO) enrichment analysis. RESULTS: A total of 65,000 transcripts from AT2-gated cells were analyzed. We identified 57 genes that were upregulated in both COPD and IPF relative to controls, with overrepresentation of terms related to ion transport, extracellular component disassembly and hydrogen peroxide biosynthesis (e.g. CLCA4 and MMP1). 191 genes were downregulated in both conditions, including those contributing to lipid metabolism and inflammatory responses (e.g. TRIB3, HIF3A and NLRP3). 11 genes were exclusively upregulated in COPD and were associated with complement activation and B cell differentiation (e.g. ANKRD1 and IGHA1). CONCLUSIONS: RNA sequencing of type II primary AECs from COPD and IPF human lung explants has identified biologically interesting convergent and divergent gene expression signatures in the two diseases. Our work enables us to take critical steps towards gaining deeper insights into the cell type-specific pathobiology of chronic lung diseases.
Author Block: S. Chu1, S. Poli1, Y. Sakairi1, R. S. Kelly2, R. Chase2, X. Liang3, K. Tsoyi3, S. Y. El-Chemaly1, M. A. Perrella1, G. M. Hunninghake4, D. L. DeMeo1, E. K. Silverman1, A. M. Choi5, G. R. Washko4, B. A. Raby1, I. O. Rosas1; 1Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, United States, 2Channing Division of Network Medicine, Boston, MA, United States, 3Pulmonary and Critical Care Medicine, Boston, MA, United States, 4Brigham and Women's Hospital, Boston, MA, United States, 5Weill Cornell Medical College, New York, NY, United States.
RATIONALE: Chronic obstructive pulmonary disease (COPD) with emphysema and idiopathic pulmonary fibrosis (IPF) are smoking and age-related diseases characterized by aberrant alveolar epithelial cell (AEC) activity contributing to remodeling and destruction of lung parenchyma. High-resolution molecular phenotyping of AECs in these diseases is lacking. We analyzed the transcriptomic signatures of primary type II AECs from COPD and IPF lung explants. METHODS: AECs were isolated from biobanked human lung explants via flow cytometry and underwent RNA sequencing using a modified RNA exome capture protocol. Transcriptomes of cell populations enriched for type II AECs from COPD, IPF and control lungs (n=11 each) were characterized. We identified differentially expressed genes and performed gene ontology (GO) enrichment analysis. RESULTS: A total of 65,000 transcripts from AT2-gated cells were analyzed. We identified 57 genes that were upregulated in both COPD and IPF relative to controls, with overrepresentation of terms related to ion transport, extracellular component disassembly and hydrogen peroxide biosynthesis (e.g. CLCA4 and MMP1). 191 genes were downregulated in both conditions, including those contributing to lipid metabolism and inflammatory responses (e.g. TRIB3, HIF3A and NLRP3). 11 genes were exclusively upregulated in COPD and were associated with complement activation and B cell differentiation (e.g. ANKRD1 and IGHA1). CONCLUSIONS: RNA sequencing of type II primary AECs from COPD and IPF human lung explants has identified biologically interesting convergent and divergent gene expression signatures in the two diseases. Our work enables us to take critical steps towards gaining deeper insights into the cell type-specific pathobiology of chronic lung diseases.
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