Epithelial to mesenchymal transition (EMT) and airway remodelling after human lung transplantation

Abstract

Background: Aberrant epithelial repair is a key event in the airway remodelling which characterises obliterative bronchiolitis (OB) in the transplanted lung. The potential for airway epithelium from lung transplant recipients to undergo epithelial to mesenchymal cell transition (EMT) was assessed in culture and in vivo in lung allograft tissue. Methods: Change in epithelial and mesenchymal marker expression was assessed after stimulation with transforming growth factor b 1 (TGF-b 1 ) alone or in combination with tumour necrosis factor a (TNFa) and compared with untreated controls. The ability of cells to deposit extracellular matrix, secrete matrix metalloproteinases (MMPs) and invade collagen was investigated. Immunolocalisation of epithelial and mesenchymal markers was compared in airway tissue from stable recipients and those with OB. Results: Untreated cells maintained epithelial morphology and phenotype. TGF-b 1 reduced expression of epithelial markers, increased expression of vimentin and fibronectin, promoted collagen I and fibronectin deposition and increased MMP-9 production. Co-treatment with TNFa dramatically accentuated phenotypic and some functional features of EMT. Airway epithelial biopsies from recipients with OB demonstrated significantly increased staining for mesenchymal markers and significantly reduced Ecadherin staining compared with stable recipients.Conclusions: These observations demonstrate the ability of human airway epithelium to undergo EMT and suggest this phenomenon may be a potential link between inflammatory injury and TGF-b 1 -driven airway remodelling in the development of OB.

Tissue remodelling in chronic bronchial diseases: from the epithelial to mesenchymal phenotype

“…Lung fibroblasts can be derived from fibroblasts in situ or from the recruitment of circulating precursors in the site of inflammation. Recent studies suggest that EMT is implicated during the development of BO [29,30,155,156], as has been demonstrated for chronic kidney rejection [157][158][159][160]. A study with biopsies and ex vivo cultures from lung transplant recipients showed that BEC expressed S100A4 [30].…”

“…BORTHWICK et al [29] reported that BEC isolated from BO patients could undergo EMT, characterised by a decrease in the expression of E-cadherin and an increase in the expression of vimentin and a-SMA. Cotreatment with TGF-b and TNF-a accentuates the mesenchymal phenotype.…”

“…In the first stages of the pathology TGF-b acts as a tumour suppressor, but in the late stages of cancer TGF-b favours type III EMT contributing to the dissemination of metastases. In vitro studies in different pulmonary epithelial cells obtained from healthy donors have shown that exposure to TGF-b induces a mesenchymal phenotype in these cells [29,[63][64][65][66][67][68].…”

“…The role of EMT in these pathologies is not well described but this phenomenon could contribute to the pool of mesenchymal cells, allowing the activation and proliferation of fibroblasts and resident myofibroblasts that are responsible for the accumulation of ECM [27][28][29][30]. In this review we propose the description of different types of EMT and will highlight the different signalling pathways involved, including the TGF-b, Wnt and Sonic Hedgehog (Shh) pathways.…”

Models of Lung Transplant Research: a consensus statement from the National Heart, Lung, and Blood Institute workshop

“…While in vitro models of OB have utility in showing how individual populations, such as bronchial epithelial cells, mesenchymal stromal cells, and airway smooth muscle cells, may contribute to disease (95)(96)(97)(98), animal models can provide a window into the events from transplant to the final fibrotic obliteration of small airways and is key to investigating the pathogenesis of OB and conducting preclinical studies of potential therapeutic interventions. Utilized models of post-lung-transplant OB are based on allogeneic lung tissue transplantation with a goal of reproducing fibrotic airway remodeling.…”