Abstract
9: AN IN VIVO MODEL OF HUMAN AIRWAYS FOR INVESTIGATING FIBROSIS
Journal of investigative medicine, Vol.64(3), pp.802-803
03/2016
DOI: 10.1136/jim-2016-000080.9
Abstract
Purpose of StudyLimited models exist to investigate the airway epithelium's role in repair, regeneration, and pathology of chronic obstructive lung diseases. We introduce a human asthmatic airway epithelial xenograft system integrating a proliferating and differentiating airway epithelium with an actively remodeling rodent mesenchyme in an immunocompromised murine host. We hypothesized that epithelial regeneration in asthma induces underlying matrix fibrosis.Methods UsedHuman airway epithelial cells from asthmatic and non-asthmatic donors (n=5 per group) were seeded into decellularized rat tracheas. Tracheas were ligated to a sterile tubing cassette and implanted subcutaneously in the flanks of athymic nude mice. Grafts were harvested at 2, 4, or 6 weeks for analysis of tissue histology, fibrillar collagen deposition, and TGFβ1 activation. Non-transplantable human lungs from asthmatic and non-asthmatic donor FFPE sections were analyzed using similar methods.Summary of ResultsGrafted epithelial cells generated a differentiated epithelium with basal, ciliated, and mucus cells. By 4 weeks post-engraftment, asthmatic-derived epithelia showed decreased numbers of ciliated cells and E-cadherin expression compared to non-asthmatic controls, similar to human lung biopsy tissue. While there was no evidence of matrix remodeling in acellular xenografts, grafts seeded with asthmatic-derived epithelial cells had 3 times as much fibrillar collagen at 6 weeks post-engraftment as non-asthmatic epithelial seeded grafts. This was accompanied by a >2-fold induction of matrix TGFβ1 [with evidence of pSMAD3 activity] in asthmatic grafts at 4 weeks (positive pixels/total field pixels=0.12±0.001 vs. 0.05±0.001; p=0.003) and 6 weeks (0.09±0.02 vs. 0.04±0.01; p=0.044) post-engraftment.ConclusionsWe show in this model that asthmatic epithelium alone is sufficient to drive aberrant mesenchymal remodeling, specifically with fibrillar collagen deposition in asthmatic-derived xenografts.These xenografts are a major advance over current animal models of asthma in that they permit direct assessment of the epithelial-mesenchymal trophic unit.
Details
- Title: Subtitle
- 9: AN IN VIVO MODEL OF HUMAN AIRWAYS FOR INVESTIGATING FIBROSIS
- Creators
- S Ferrante - Children's NationalT Hackett - St. Paul's HospitalC Hoptay - Children's NationalJ Engelhardt - University of IowaJ Ingram - Duke UniversityY Zhang - University of IowaS Alcala - Children's NationalF Shaheen - St. Paul's HospitalE Matz - Children's NationalD Pillai - Children's NationalR Freishtat - Children's National
- Resource Type
- Abstract
- Publication Details
- Journal of investigative medicine, Vol.64(3), pp.802-803
- DOI
- 10.1136/jim-2016-000080.9
- ISSN
- 1081-5589
- eISSN
- 1708-8267
- Language
- English
- Date published
- 03/2016
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Internal Medicine; Anatomy and Cell Biology; Radiation Oncology
- Record Identifier
- 9984288850902771
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