Inflammation and epithelial to mesenchymal transition in lung transplant recipients: role in dysregulated epithelial wound repair.
Epithelial to mesenchymal transition (EMT) has been implicated in the pathogenesis of obliterative bronchiolitis (OB) after lung transplant. Although TNF-alpha accentuates TGF-beta1 driven EMT in primary human bronchial epithelial cells (PBECs), we hypothesized that other acute pro-inflammatory cytokines elevated in the airways of patients with OB may also accentuate EMT and contribute to dysregulated epithelial wound repair. PBECs from lung transplant recipients were stimulated with TGF-beta1+/-IL-1beta, IL-8, TNF-alpha or activated macrophages in co-culture and EMT assessed. The quality and rate of wound closure in a standardized model of lung epithelial injury was assessed in response to above stimuli. Co-treatment with TGF-beta1+TNF-alpha or IL-1beta significantly accentuates phenotypic and some functional features of EMT compared to TGF-beta1 alone. Co-treatment with TGF-beta1+TNF-alpha or IL-1beta accelerates epithelial wound closure however the quality of repair is highly dysregulated. Co-treatment with TGF-beta1+IL-8 has no significant effect on EMT or the speed or quality of wound healing. Activated macrophages dramatically accentuate TGF-beta1-driven EMT and cause dysregulated wound repair. Crosstalk between macrophage-derived acute inflammation in the airway and elevated TGF-beta1 may favor dysregulated airway epithelial repair and fibrosis in the lung allograft via EMT.
Borthwick
L A
LA
Applied Immunobiology and Transplantation Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle, UK.
McIlroy
E I
EI
Gorowiec
M R
MR
Brodlie
M
M
Johnson
G E
GE
Ward
C
C
Lordan
J L
JL
Corris
P A
PA
Kirby
J A
JA
Fisher
A J
AJ
D045744:Cell Line, Tumor; D018920:Coculture Techniques; D004848:Epithelium / Q000473:pathology*; D005355:Fibrosis / Q000473:pathology; D006801:Humans; D007249:Inflammation; D053583:Interleukin-1beta / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D016040:Lung Transplantation / Q000379:methods*; D008264:Macrophages / Q000378:metabolism; D008648:Mesoderm / Q000166:cytology*; D008954:Models, Biological; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014945:Wound Healing
D053583:Interleukin-1beta; D016209:Interleukin-8; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha