Rajesh K Kasam1, Prathibha R Gajjala1, Anil G Jegga2, Jennifer A Courtney3, Scott H Randell4, Elizabeth L Kramer1, John P Clancy5, Satish K Madala6. 1. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH; Divisions of Pulmonary Medicine. 2. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH; Bioinformatics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, 45229 USA. 3. Molecular and Developmental Biology Graduate Program, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, 45229. 4. Department of Cell Biology & Physiology, The University of North Carolina at Chapel Hill, North Carolina, 27599 USA. 5. Cystic Fibrosis Foundataion, Bethesda, Maryland, 20814 USA. 6. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH; Divisions of Pulmonary Medicine. Electronic address: satish.madala@cchmc.org.
Abstract
BACKGROUND: Cystic fibrosis (CF) patients develop severe lung disease including chronic airway infections, neutrophilic inflammation, and progressive fibrotic remodeling in airways. However, cellular and molecular processes that regulate excessive collagen deposition in airways in these patients remain unclear. Fibrocytes are bone marrow (BM)-derived mesenchymal cells that express the hematopoietic cell marker CD45, and mesenchymal cell markers and implicated in collagen deposition in several fibrotic diseases. It is unknown whether fibrocytes accumulate in the lungs of CF patients, so the current study evaluates the presence of fibrocytes in the fibrotic lesions of airways in explanted CF lungs compared to non-CF unused donor lungs (control). METHODS: We used immunofluorescence staining to determine if fibrocytes accumulate in explanted CF lungs compared to healthy donor lungs. Simultaneously, we evaluated cells collected by bronchoalveolar lavage (BAL) in CF patients using multi-color flow cytometry. Finally, we analyzed transcripts differentially expressed in fibrocytes isolated from the explanted CF lungs compared to control to assess fibrocyte-specific pro-fibrotic gene networks. RESULTS: Our findings demonstrate fibrocyte accumulation in CF lungs compared to non-CF lungs. Additionally, fibrocytes were detected in the BAL of all CF children. Transcriptomic analysis of fibrocytes identified dysregulated genes associated with fibrotic remodeling in CF lungs. CONCLUSIONS: With significantly increased fibrocytes that show increased expression of pro-fibrotic gene transcripts compared to control, our findings suggest an intervention for fibrotic remodeling as a potential therapeutic target in CF.
BACKGROUND:Cystic fibrosis (CF) patients develop severe lung disease including chronic airway infections, neutrophilic inflammation, and progressive fibrotic remodeling in airways. However, cellular and molecular processes that regulate excessive collagen deposition in airways in these patients remain unclear. Fibrocytes are bone marrow (BM)-derived mesenchymal cells that express the hematopoietic cell marker CD45, and mesenchymal cell markers and implicated in collagen deposition in several fibrotic diseases. It is unknown whether fibrocytes accumulate in the lungs of CF patients, so the current study evaluates the presence of fibrocytes in the fibrotic lesions of airways in explanted CF lungs compared to non-CF unused donor lungs (control). METHODS: We used immunofluorescence staining to determine if fibrocytes accumulate in explanted CF lungs compared to healthy donor lungs. Simultaneously, we evaluated cells collected by bronchoalveolar lavage (BAL) in CF patients using multi-color flow cytometry. Finally, we analyzed transcripts differentially expressed in fibrocytes isolated from the explanted CF lungs compared to control to assess fibrocyte-specific pro-fibrotic gene networks. RESULTS: Our findings demonstrate fibrocyte accumulation in CF lungs compared to non-CF lungs. Additionally, fibrocytes were detected in the BAL of all CF children. Transcriptomic analysis of fibrocytes identified dysregulated genes associated with fibrotic remodeling in CF lungs. CONCLUSIONS: With significantly increased fibrocytes that show increased expression of pro-fibrotic gene transcripts compared to control, our findings suggest an intervention for fibrotic remodeling as a potential therapeutic target in CF.
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