title: Pseudomonas aeruginosa Induced Airway Epithelial Injury Drives Fibroblast Activation: A Mechanism in Chronic Lung Allograft Dysfunction.
abstract: Bacterial infections after lung transplantation cause airway epithelial injury and are associated with an increased risk of developing bronchiolitis obliterans syndrome. The damaged epithelium is a source of alarmins that activate the innate immune system, yet their ability to activate fibroblasts in the development of bronchiolitis obliterans syndrome has not been evaluated. Two epithelial alarmins were measured longitudinally in bronchoalveolar lavages from lung transplant recipients who developed bronchiolitis obliterans syndrome and were compared to stable controls. In addition, conditioned media from human airway epithelial cells infected with Pseudomonas aeruginosa was applied to lung fibroblasts and inflammatory responses were determined. Interleukin-1 alpha (IL-1α) was increased in bronchoalveolar lavage of lung transplant recipients growing P. aeruginosa (11.5 [5.4-21.8] vs. 2.8 [0.9-9.4] pg/mL, p < 0.01) and was significantly elevated within 3 months of developing bronchiolitis obliterans syndrome (8.3 [1.4-25.1] vs. 3.6 [0.6-17.1] pg/mL, p < 0.01), whereas high mobility group protein B1 remained unchanged. IL-1α positively correlated with elevated bronchoalveolar lavage IL-8 levels (r(2)  = 0.6095, p < 0.0001) and neutrophil percentage (r(2)  = 0.25, p = 0.01). Conditioned media from P. aeruginosa infected epithelial cells induced a potent pro-inflammatory phenotype in fibroblasts via an IL-1α/IL-1R-dependent signaling pathway. In conclusion, we propose that IL-1α may be a novel therapeutic target to limit Pseudomonas associated allograft injury after lung transplantation.
authors.affiliation: Tissue Fibrosis and Repair Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: L A
authors.initials: LA
authors.lastname: Borthwick
authors.affiliation: Tissue Fibrosis and Repair Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: M I
authors.initials: MI
authors.lastname: Suwara
authors.affiliation: Tissue Fibrosis and Repair Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: S C
authors.initials: SC
authors.lastname: Carnell
authors.affiliation: Tissue Fibrosis and Repair Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: N J
authors.initials: NJ
authors.lastname: Green
authors.affiliation: Tissue Fibrosis and Repair Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: R
authors.initials: R
authors.lastname: Mahida
authors.affiliation: Tissue Fibrosis and Repair Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: D
authors.initials: D
authors.lastname: Dixon
authors.affiliation: School of Mathematics and Statistics, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: C S
authors.initials: CS
authors.lastname: Gillespie
authors.affiliation: Tissue Fibrosis and Repair Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: T N
authors.initials: TN
authors.lastname: Cartwright
authors.affiliation: Tissue Fibrosis and Repair Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: J
authors.initials: J
authors.lastname: Horabin
authors.affiliation: Tissue Fibrosis and Repair Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: A
authors.initials: A
authors.lastname: Walker
authors.affiliation: Tissue Fibrosis and Repair Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: E
authors.initials: E
authors.lastname: Olin
authors.affiliation: Tissue Fibrosis and Repair Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.|Institute of Transplantation, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK.
authors.forename: M
authors.initials: M
authors.lastname: Rangar
authors.affiliation: Tissue Fibrosis and Repair Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: A
authors.initials: A
authors.lastname: Gardner
authors.affiliation: Tissue Fibrosis and Repair Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: J
authors.initials: J
authors.lastname: Mann
authors.affiliation: Tissue Fibrosis and Repair Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.|Institute of Transplantation, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK.
authors.forename: P A
authors.initials: PA
authors.lastname: Corris
authors.affiliation: Tissue Fibrosis and Repair Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: D A
authors.initials: DA
authors.lastname: Mann
authors.affiliation: Tissue Fibrosis and Repair Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.|Institute of Transplantation, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK.
authors.forename: A J
authors.initials: AJ
authors.lastname: Fisher
mesh_terms: D055371:Acute Lung Injury / Q000209:etiology* / Q000473:pathology; D000328:Adult; D064591:Allografts; D001989:Bronchiolitis Obliterans / Q000209:etiology* / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid; D004847:Epithelial Cells / Q000276:immunology / Q000382:microbiology* / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000473:pathology*; D006084:Graft Rejection / Q000209:etiology* / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000473:pathology; D053582:Interleukin-1alpha / Q000276:immunology; D016040:Lung Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000276:immunology; D011552:Pseudomonas Infections / Q000150:complications / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000472:pathogenicity*; D020545:Respiratory Mucosa / Q000276:immunology / Q000382:microbiology* / Q000473:pathology; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: D053582:Interleukin-1alpha