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Abnormal Surfactant Protein Expression and Activation of Anti-Apoptotic Pathways in Severe Interstitial Lung Disease (ILD) in Rubinstein-Taybi Syndrome (RTS)
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A7787 - Abnormal Surfactant Protein Expression and Activation of Anti-Apoptotic Pathways in Severe Interstitial Lung Disease (ILD) in Rubinstein-Taybi Syndrome (RTS)
Author Block: X. Li1, S. S. Wong2, J. Zhao3, A. Jegga4, K. Shayan5, J. S. Hagood2; 1Thoracic Surgery, Tianjin First Central Hospital, Tianjin, China, 2Pediatrics, University of California, La Jolla, CA, United States, 3Second-affiliated Hospital of Shandong University, Jinan, China, 4Cincinnati Childrens Hospital Medical Center, Cincinnati, OH, United States, 5University of California San Diego, San Diego, CA, United States.
Rationale: Interstitial lung disease (ILD) has been reported in patients with Rubinstein-Taybi syndrome (RTS), but has not been well-described, and the biological mechanisms underlying ILD are unknown.
Objective: To better understand the cellular and molecular alterations in ILD associated with RTS.
Methods: We performed bioinformatics analyses of the deleted region of Chr. 16 associated with severe RTS. Histopathology of ILD in severe RTS showed alveolar lipoproteinosis, cholesterol clefts, pneumocyte hyperplasia and fibrosis, with pulmonary vascular remodeling. We did Immunofluorescence (IF) staining for ATP binding cassette subfamily A member 3 (ABCA3), surfactant protein C (SFTPC), B-cell lymphoma-extra large (Bcl-xL), phosphorylated protein kinase B (pAKT), and alpha smooth muscle actin (αSMA).
Results: Bioinformatic analyses revealed that among 82 candidate genes in the deleted segment, there was enrichment of genes associated with pulmonary fibrosis, epithelial-mesenchymal transition (EMT) and tissue remodeling. Further, functional enrichment-based candidate gene prioritization using these enriched pathways and biological processes revealed five top-ranked genes (CREBBP, PDPK1, VASN, TFAP4 and ADCY9) common to all. IF staining showed marked decrease in SFTPC and ABCA3 despite apparent pneumocyte hyperplasia, increased αSMA staining in vascular smooth muscle and myofibroblasts, and increased Bcl-xL and pAkt in multiple interstitial cells in fibrotic regions.
Conclusions: In ILD associated with severe RTS with a large microdeletion on chromosome 16p13.3, there are histopathologic features similar to those seen in surfactant dysfunction mutation-associated childhood interstitial lung disease, with decreased expression of surfactant proteins in abnormal epithelial cells, together with increased myofibroblasts, microvascular remodeling, and upregulation of pAKT and BCL-xL which are anti-apoptotic, prosurvival pathways. All of these abnormalities likely contribute to the pathogenesis of interstitial lung disease in RTS.
Author Block: X. Li1, S. S. Wong2, J. Zhao3, A. Jegga4, K. Shayan5, J. S. Hagood2; 1Thoracic Surgery, Tianjin First Central Hospital, Tianjin, China, 2Pediatrics, University of California, La Jolla, CA, United States, 3Second-affiliated Hospital of Shandong University, Jinan, China, 4Cincinnati Childrens Hospital Medical Center, Cincinnati, OH, United States, 5University of California San Diego, San Diego, CA, United States.
Rationale: Interstitial lung disease (ILD) has been reported in patients with Rubinstein-Taybi syndrome (RTS), but has not been well-described, and the biological mechanisms underlying ILD are unknown.
Objective: To better understand the cellular and molecular alterations in ILD associated with RTS.
Methods: We performed bioinformatics analyses of the deleted region of Chr. 16 associated with severe RTS. Histopathology of ILD in severe RTS showed alveolar lipoproteinosis, cholesterol clefts, pneumocyte hyperplasia and fibrosis, with pulmonary vascular remodeling. We did Immunofluorescence (IF) staining for ATP binding cassette subfamily A member 3 (ABCA3), surfactant protein C (SFTPC), B-cell lymphoma-extra large (Bcl-xL), phosphorylated protein kinase B (pAKT), and alpha smooth muscle actin (αSMA).
Results: Bioinformatic analyses revealed that among 82 candidate genes in the deleted segment, there was enrichment of genes associated with pulmonary fibrosis, epithelial-mesenchymal transition (EMT) and tissue remodeling. Further, functional enrichment-based candidate gene prioritization using these enriched pathways and biological processes revealed five top-ranked genes (CREBBP, PDPK1, VASN, TFAP4 and ADCY9) common to all. IF staining showed marked decrease in SFTPC and ABCA3 despite apparent pneumocyte hyperplasia, increased αSMA staining in vascular smooth muscle and myofibroblasts, and increased Bcl-xL and pAkt in multiple interstitial cells in fibrotic regions.
Conclusions: In ILD associated with severe RTS with a large microdeletion on chromosome 16p13.3, there are histopathologic features similar to those seen in surfactant dysfunction mutation-associated childhood interstitial lung disease, with decreased expression of surfactant proteins in abnormal epithelial cells, together with increased myofibroblasts, microvascular remodeling, and upregulation of pAKT and BCL-xL which are anti-apoptotic, prosurvival pathways. All of these abnormalities likely contribute to the pathogenesis of interstitial lung disease in RTS.
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