Inflammation and Epithelial to Mesenchymal Transition in Lung Transplant Recipients: Role in Dysregulated Epithelial Wound Repair

Borthwick, Lee A.; McIlroy, E. I.; Gorowiec, Marta R.; Brodlie, Malcolm; Johnson, Gail; Ward, Chris; Lordan, Jim; Corris, Paul A.; Kirby, John A.; Fisher, Andrew J.

doi:10.1111/j.1600-6143.2009.02953.x

Cited by 62 publications

(49 citation statements)

References 46 publications

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“…Recently TNFα has been shown to accentuate TGF-β1 driven EMT in a range of cell types highlighting a potential link between EMT and inflammation [17][18][19][20][21][22][23]. However, the mechanisms responsible have been ill-defined and further studies are required to elucidate the signalling pathways involved so potential therapeutic targets to limit or even reverse inflammatory driven EMT can be identified.…”

Section: Discussionmentioning

confidence: 99%

“…However, there is compelling evidence that TNFα is able to accentuate TGF-β1 driven EMT in a range of cell types [17,19,20]. For example it has previously shown that TNFα can accentuate TGF-β1 driven EMT in primary bronchial epithelial cells causing dysregulated wound repair of the injured lung epithelium [21] and that TNFα can increase metastatic potential in human colonic epithelial organoid models of colon cancer by accentuating EMT [22]. These results suggest that a pro-inflammatory microenvironment rich in TNFα may play an important role in modulating EMT in both tissue fibrosis and cancer in vivo.…”

Section: Introductionmentioning

confidence: 99%

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Transforming Growth Factor-β1 (TGF-β1) Driven Epithelial to Mesenchymal Transition (EMT) is Accentuated by Tumour Necrosis Factor α (TNFα) via Crosstalk Between the SMAD and NF-κB Pathways

Borthwick

Gardner

Soyza

et al. 2011

Cancer Microenvironment

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process by which an epithelial cell alters its phenotype to that of a mesenchymal cell and plays a critical role in embryonic development, tumour invasion and metastasis and tissue fibrosis. Transforming growth factor-β1 (TGF-β1) continues to be regarded as the key growth factor involved in driving EMT however recently tumour necrosis factor α (TNFα) has been demonstrated to accentuate TGF-β1 driven EMT. In this study we investigate how various signalling pathways contribute to this accentuated effect. A549 cells were treated with TGF-β1 (10 ng/ml), TNFα (20 ng/ml) or a combination of both for 72 h and EMT assessed. The effect of selective inhibition of the SMAD, MAPK and NF-κB pathways on EMT was assessed. A549 cells treated with TGF-β1 downregulate the expression of epithelial markers, increase the expression of mesenchymal markers, secrete matrix-metalloproteinases and become invasive. Significantly, TGF-β1 driven EMT is accentuated by co-treatment with TNFα. SMAD 3 inhibition attenuated effect of TNFα. However, inhibiting IKKβ blocked both TGF-β1 driven EMT and the accentuating action of TNFα. Inhibiting p38 and ERK signalling had no effect on EMT. TNFα accentuates TGF-β1 driven EMT in A549 cells via a SMAD 2/3 independent mechanism involving the NF-κB pathway independent of p38 and ERK 1/2 activation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Transforming Growth Factor-β1 (TGF-β1) Driven Epithelial to Mesenchymal Transition (EMT) is Accentuated by Tumour Necrosis Factor α (TNFα) via Crosstalk Between the SMAD and NF-κB Pathways

Borthwick

Gardner

Soyza

et al. 2011

Cancer Microenvironment

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“…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].…”

Section: Emt and Bo Following Lung Transplantationmentioning

confidence: 99%

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

Pain

Bermúdez

Lacoste

et al. 2014

European Respiratory Review

171

128

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Airway remodelling is a critical feature of chronic bronchial diseases, characterised by aberrant repair of the epithelium and accumulation of fibroblasts, which contribute to extracellular matrix (ECM) deposition resulting in fixed bronchial obstruction. Recently, epithelial-mesenchymal transition (EMT) has been identified as a new source of fibroblasts that could contribute to the remodelling of the airways. This phenomenon consists of the loss of the epithelial phenotype by bronchial epithelial cells and the acquisition of a mesenchymal phenotype. These cells are then able to migrate and secrete ECM molecules. Herein, we review the different types of EMT. We will then focus on the signalling pathways that are involved, such as transforming growth factor-b and Wnt, as well as the more recently described Sonic Hedgehog pathway. Finally, we will highlight the implication of EMT in airway remodelling in specific chronic bronchial pathologies, such as asthma, chronic obstructive pulmonary disease and bronchiolitis obliterans following lung transplantation. Despite the limitations of in vitro models, future studies of EMT in vivo are warranted to shed new light on the pathomechanisms of bronchial obstruction. @ERSpublications Epithelial-mesenchymal transition in chronic bronchial remodelling diseases

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“…Aberrant epithelial repair is a key event in the transplanted lung (1,9) in which bronchioles lose resident epithelial cells and become occluded by granulation tissue. Abnormal epithelial repair eventually causes an epithelial-to-mesenchymal transition (EMT), a functional and phenotypic change of epithelial cells into spindle-shaped, migratory (43) and matrix-component-secreting mesenchymal cells (10,41), and a process associated with lung fibrosis (15,27).…”

mentioning

confidence: 99%

IL-17 induces type V collagen overexpression and EMT via TGF-β-dependent pathways in obliterative bronchiolitis

Vittal¹,

Fan²,

Greenspan³

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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erative bronchiolitis (OB), a fibrotic airway lesion, is the leading cause of death after lung transplantation. Type V collagen [col(V)] overexpression and IL-17-mediated anti-col(V) immunity are key contributors to OB pathogenesis. Here, we report a previously undefined role of IL-17 in inducing col(V) overexpression, leading to epithelial mesenchymal transition (EMT) and subsequent OB. We observed IL-17-mediated induction of col(V) ␣1 chains [␣1 (V)] in normal airway epithelial cells in vitro and detected ␣1 (V)-specific antibodies in bronchoalveolar lavage fluid of lung transplant patients. Overexpression of IL-17 and col(V) was detected in OB lesions in patient lung biopsies and in a murine OB model. IL-17 is shown to induce EMT, TGF-␤ mRNA expression, and SMAD3 activation, whereas downregulating SMAD7 expression in vitro. Pharmacological inhibition of TGF-␤RI tyrosine kinase, p38 MAPK, or focal adhesion kinase prevented col(V) overexpression and EMT. In murine orthotopic lung transplants, neutralizing IL-17 significantly decreased TGF-␤ mRNA and protein expression and prevented epithelial repair/ OB. Our findings highlight a feed-forward loop between IL-17 and TGF-␤, leading to induction of col(V) and associated epithelial repair, thus providing one possible link between autoimmunity and OB after lung transplantation. autoimmunity; p38 MAPK; focal adhesion kinase; small-airway epithelial cells; RLE-6TN; mouse transplant model; epithelial-mesenchymal transition OBLITERATIVE BRONCHIOLITIS (OB) is characterized by extensive peribronchiolar fibrosis with plugs of granulation tissues (fibroblasts and collagen) that occlude small airways. OB is the key reason that the 5-yr survival of lung transplant recipients is only 50%, the worst of all major solid organ transplants (42,48).Aberrant epithelial repair is a key event in the transplanted lung (1, 9) in which bronchioles lose resident epithelial cells and become occluded by granulation tissue. Abnormal epithelial repair eventually causes an epithelial-to-mesenchymal transition (EMT), a functional and phenotypic change of epithelial cells into spindle-shaped, migratory (43) and matrix-component-secreting mesenchymal cells (10, 41), and a process associated with lung fibrosis (15,27). However, the direct connection between EMT and the in vivo phenomena of fibrosis and fibro-obliterative disease remains controversial.We and others previously reported that OB is associated with dysregulation of two types of collagen: 1) marked increase in type V collagen [col(V)], a quantitatively minor lung collagen (8,14,40), and 2) a decrease in the major lung collagen type I [col(I)] (2, 53). We have shown that prospective monitoring of patients with human lung transplant revealed a critical role of col(V)-specific cellular immunity in OB pathogenesis (14,40). Although overexpression of col(V), an otherwise quantitatively minor collagen, is involved in OB pathology, mechanisms leading to col(V) overexpression are unknown. Thus a mechanistic understanding of the triggers of col(V)...

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Inflammation and Epithelial to Mesenchymal Transition in Lung Transplant Recipients: Role in Dysregulated Epithelial Wound Repair

Abstract: Epithelial to mesenchymal transition (EMT) has been

Cited by 62 publications

References 46 publications

Transforming Growth Factor-β1 (TGF-β1) Driven Epithelial to Mesenchymal Transition (EMT) is Accentuated by Tumour Necrosis Factor α (TNFα) via Crosstalk Between the SMAD and NF-κB Pathways

Transforming Growth Factor-β1 (TGF-β1) Driven Epithelial to Mesenchymal Transition (EMT) is Accentuated by Tumour Necrosis Factor α (TNFα) via Crosstalk Between the SMAD and NF-κB Pathways

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

IL-17 induces type V collagen overexpression and EMT via TGF-β-dependent pathways in obliterative bronchiolitis

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