Kak-Ming Ling1, Luke W Garratt1, Balarka Banerjee1, Melanie A Lavender2, Jeremy P Wrobel2,3, Michael Musk2, Kelly M Martinovich1, Nicole C Shaw1, Thomas Iosifidis1, Kevin Looi1, Elizabeth Kicic-Starcevich1, Erika N Sutanto1, Stephanie T Yerkovich4, Daniel C Chambers5,6, Stephen M Stick1,4,7,8,9, Anthony Kicic1,5,4,7,8,9. 1. Telethon Kids Institute, Centre for Health Research, The University of Western Australia, Perth, WA, Australia. 2. Advanced Lung Disease Unit, Fiona Stanley Hospital, Perth, WA, Australia. 3. Department of Medicine, University of Notre Dame, Fremantle, WA, Australia. 4. School of Biomedical Science, The University of Western Australia, Perth, WA, Australia. 5. School of Medicine, The University of Queensland, Herston, Queensland, Australia. 6. Occupation and Environment, School of Public Health, Curtin University, Perth, WA, Australia. 7. Queensland Lung Transplant Service, The Prince Charles Hospital, Brisbane, Queensland, Australia. 8. Department of Respiratory and Sleep Medicine, Perth Children's Hospital, Perth, WA, Australia. 9. Centre for Cell Therapy and Regenerative Medicine, School of Medicine and Pharmacology, The University of Western Australia, Perth, WA, Australia.
Abstract
BACKGROUND: Dysregulated airway epithelial repair following injury is a proposed mechanism driving posttransplant bronchiolitis obliterans (BO), and its clinical correlate bronchiolitis obliterans syndrome (BOS). This study compared gene and cellular characteristics of injury and repair in large (LAEC) and small (SAEC) airway epithelial cells of transplant patients. METHODS: Subjects were recruited at the time of routine bronchoscopy posttransplantation and included patients with and without BOS. Airway epithelial cells were obtained from bronchial and bronchiolar brushing performed under radiological guidance from these patients. In addition, bronchial brushings were also obtained from healthy control subjects comprising of adolescents admitted for elective surgery for nonrespiratory-related conditions. Primary cultures were established, monolayers wounded, and repair assessed (±) azithromycin (1 µg/mL). In addition, proliferative capacity as well as markers of injury and dysregulated repair were also assessed. RESULTS: SAEC had a significantly dysregulated repair process postinjury, despite having a higher proliferative capacity than large airway epithelial cells. Addition of azithromycin significantly induced repair in these cells; however, full restitution was not achieved. Expression of several genes associated with epithelial barrier repair (matrix metalloproteinase 7, matrix metalloproteinase 3, the integrins β6 and β8, and β-catenin) were significantly different in epithelial cells obtained from patients with BOS compared to transplant patients without BOS and controls, suggesting an intrinsic defect. CONCLUSIONS: Chronic airway injury and dysregulated repair programs are evident in airway epithelium obtained from patients with BOS, particularly with SAEC. We also show that azithromycin partially mitigates this pathology.
BACKGROUND: Dysregulated airway epithelial repair following injury is a proposed mechanism driving posttransplant bronchiolitis obliterans (BO), and its clinical correlate bronchiolitis obliterans syndrome (BOS). This study compared gene and cellular characteristics of injury and repair in large (LAEC) and small (SAEC) airway epithelial cells of transplant patients. METHODS: Subjects were recruited at the time of routine bronchoscopy posttransplantation and included patients with and without BOS. Airway epithelial cells were obtained from bronchial and bronchiolar brushing performed under radiological guidance from these patients. In addition, bronchial brushings were also obtained from healthy control subjects comprising of adolescents admitted for elective surgery for nonrespiratory-related conditions. Primary cultures were established, monolayers wounded, and repair assessed (±) azithromycin (1 µg/mL). In addition, proliferative capacity as well as markers of injury and dysregulated repair were also assessed. RESULTS: SAEC had a significantly dysregulated repair process postinjury, despite having a higher proliferative capacity than large airway epithelial cells. Addition of azithromycin significantly induced repair in these cells; however, full restitution was not achieved. Expression of several genes associated with epithelial barrier repair (matrix metalloproteinase 7, matrix metalloproteinase 3, the integrins β6 and β8, and β-catenin) were significantly different in epithelial cells obtained from patients with BOS compared to transplant patients without BOS and controls, suggesting an intrinsic defect. CONCLUSIONS: Chronic airway injury and dysregulated repair programs are evident in airway epithelium obtained from patients with BOS, particularly with SAEC. We also show that azithromycin partially mitigates this pathology.
Authors: Andrew M Hallett; Yijing Feng; Miranda R Jones; Errol L Bush; Christian A Merlo; Dorry L Segev; Mara McAdams-DeMarco Journal: Transplantation Date: 2021-05-25 Impact factor: 5.385
Authors: Carlo J Iasella; Aki Hoji; Iulia Popescu; Jianxin Wei; Mark E Snyder; Yingze Zhang; Wei Xu; Vera Iouchmanov; Ritchie Koshy; Mark Brown; Monica Fung; Charles Langelier; Elizabeth A Lendermon; Daniel Dugger; Rupal Shah; Joyce Lee; Bruce Johnson; Jeffrey Golden; Lorriana E Leard; Mary Ellen Kleinhenz; Silpa Kilaru; Steven R Hays; Jonathan P Singer; Pablo G Sanchez; Matthew R Morrell; Joseph M Pilewski; John R Greenland; Kong Chen; John F McDyer Journal: Am J Transplant Date: 2020-11-20 Impact factor: 9.369