Elevated Levels of Interleukin-8 and Transforming Growth Factor-Beta in Bronchoalveolar Lavage Fluid From Patients With Bronchiolitis Obliterans Syndrome:

Elssner, Andreas; Jaumann, F.; Dobmann, Sandra; Behr, Jürgen; Schwaiblmair, Martin; Reichenspurner, Hermann; Fürst, H.; Briegel, Josef; Vogelmeier, Claus

doi:10.1097/00007890-200007270-00022

Cited by 134 publications

(136 citation statements)

References 27 publications

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“…Furthermore, TGF-β1 has been shown to be elevated in the airways of patients with idiopathic pulmonary fibrosis (IPF), bronchiolitis obliterans syndrome (BOS) and chronic obstructive pulmonary disease (COPD) [9,[36][37][38][39][40]. Interestingly, it is well recognised clinically that exacerbations in patients with chronic fibrotic lung disease often lead to an increased rate of disease progression and these exacerbations are commonly associated with an increase in the level of pro-inflammatory cytokines including TNFα [41].…”

Section: Discussionmentioning

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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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%

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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“…Consistent with our findings, others have also demonstrated epithelial cell expression of inflammatory mediators during allograft dysfunction. For example, epithelial cell production of monocyte chemoattractant protein-1, IL-8, and inducible nitric oxide synthase has been demonstrated in recipients with acute vascular rejection and/or allograft dysfunction (16,(45)(46)(47). In addition, epithelial cell upregulation of intercellular adhesion molecule-1 as well as class I and II major histocompatibility complex antigens has been observed in some (48)(49)(50), but not all, human studies (51,52).…”

Section: Discussionmentioning

confidence: 99%

IL-12 p80 Is an Innate Epithelial Cell Effector That Mediates Chronic Allograft Dysfunction

Mikols

Yan

Norris

et al. 2006

Am J Respir Crit Care Med

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Rationale: Bronchiolitis obliterans syndrome is the leading cause of chronic lung allograft dysfunction. We have demonstrated that respiratory viral infection is a bronchiolitis obliterans syndrome risk factor and virus-dependent injury induces expression of innate airway epithelial genes belonging to the interleukin (IL)-12 family. Thus, we hypothesized that epithelial cell IL-12 family members could mediate lung allograft dysfunction. Objectives: We used mouse and human allograft specimens to evaluate the role of epithelial cell IL-12 family members in allograft dysfunction associated with and without viral infection. Methods: Murine and human IL-12 family members were characterized and manipulated in allografts and then correlated with epithelial cell injury, immune cell accumulation, and collagen deposition. Results: In a mouse model of lung transplantation, concurrent viral infection and allogeneic transplantation increased epithelial injury and this was followed by exaggerated accumulation of macrophages and collagen deposition. This virus-driven allograft dysfunction was associated with an epithelial innate response manifested by a synergistic increase in the production of the macrophage chemoattractant IL-12 p80 (p80), but not IL-12 or IL-23. Blockade or overexpression of donor epithelial p80 resulted in a corresponding abrogation or enhancement of macrophage accumulation and allograft dysfunction. We extended these findings to human recipients with viral infection and transplant bronchitis and again observed excessive epithelial p80 expression that correlated with increased macrophage accumulation. Conclusions: These experiments support a role for an enhanced epithelial innate response as a central process in allograft dysfunction and identify the macrophage chemoattractant p80 as an innate epithelial effector of disease progression.

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“…LR-MSCs isolated from the BAL fluid of normal lung allografts were exposed to TGF-␤, a profibrotic mediator implicated in BOS pathogenesis. 24,25 Of the LR-MSCs exposed to TGF-␤1 (2 ng/mL), 79.31% Ϯ 2.81% demonstrated ␣-SMA expression by immunofluorescence compared with 15.09% Ϯ 1.18% ␣-SMA-positive cells noted at baseline (P Ͻ 0.0001, Figure 1B). The up-regulation of ␣-SMA protein expression in LR-MSCs treated with TGF-␤1 compared with controls was also noted by Western blot analysis (P ϭ 0.0002, Figure 1C).…”

Section: Lr-mscs Isolated From Normal Human Lung Allografts Demonstramentioning

confidence: 96%

Resident Tissue-Specific Mesenchymal Progenitor Cells Contribute to Fibrogenesis in Human Lung Allografts

Walker

Badri

Wettlaufer

et al. 2011

The American Journal of Pathology

101

105

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Fibrotic obliteration of the small airways leading to progressive airflow obstruction, termed bronchiolitis obliterans syndrome (BOS), is the major cause of poor outcomes after lung transplantation. We recently demonstrated that a donor-derived population of multipotent mesenchymal stem cells (MSCs) can be isolated from the bronchoalveolar lavage (BAL) fluid of human lung transplant recipients. Herein, we study the organ specificity of these cells and investigate the role of local mesenchymal progenitors in fibrogenesis after lung transplantation. We demonstrate that human lung allograft-derived MSCs uniquely express embryonic lung mesenchyme-associated transcription factors with a 35,000-fold higher expression of forkhead/winged helix transcription factor forkhead box ( Chronic allograft rejection develops in up to 60% of patients who undergo lung transplantation by 5 years and is the leading cause of poor long-term outcomes after lung transplantation.1 As with other solid organ transplants, chronic allograft rejection in the lung manifests as a fibrotic response to repeated immune and nonimmune insults, leading to narrowing and obliteration of the small airways, a lesion termed bronchiolitis obliterans (BO). 2Subepithelial and/or intraluminal infiltration by myofibroblasts, differentiated mesenchymal cells with augmented collagen secretory and contractile functions, 3 is noted in human biopsy specimens that demonstrate BO.4 BO presents clinically as an obstructive ventilatory defect termed BO syndrome (BOS).5 BOS is the major cause of graft failure and long-term mortality, with no effective treatment options. 6,7 Understanding the origin of effector myofibroblasts in fibrotic lesions of BO is critical for therapeutic targeting of mechanisms of cell recruitment/differentiation.One potential source of mesenchymal cells participating in this disorganized repair response is the mesenchymal progenitors residing in the graft. The embryonic lung mesenchyme is derived from splanchnic mesoderm during orSupported by grants (R01DK082481 to P.H.K.; RO1HL094311 to M.P.-G.; RO1HL094622

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Elevated Levels of Interleukin-8 and Transforming Growth Factor-Beta in Bronchoalveolar Lavage Fluid From Patients With Bronchiolitis Obliterans Syndrome:

Abstract: We assume that IL-8 and TGF-beta may act as key mediators for airway inflammation and fibroproliferation in the pathogenesis of OB, with bronchial epithelial cells serving as a relevant source of IL-8.

Cited by 134 publications

References 27 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

IL-12 p80 Is an Innate Epithelial Cell Effector That Mediates Chronic Allograft Dysfunction

Resident Tissue-Specific Mesenchymal Progenitor Cells Contribute to Fibrogenesis in Human Lung Allografts

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