Myofibroblast Involvement in Chronic Transplant Rejection

Pedagogos, Eugenie; Hewitson, Tim D.; Walker, R G; Nicholis, K M; Becker, Gavin J.

doi:10.1097/00007890-199710270-00019

Cited by 41 publications

(23 citation statements)

References 18 publications

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“…As with other chronic fibrosing disorders in various organs, myofibroblasts appear to be a prominent feature in the histological characterization of those disorders (4,(25)(26)(27). Additionally, their significance in the context of human solid organ transplantation is increasingly being recognized (13,28), yet their source remains undetermined. It has been proposed that following lung transplantation, airway epithelial cells develop a fibroblastic phenotype, the so-called epithelialmesenchymal transition (29).…”

Section: Discussionmentioning

confidence: 99%

Myofibroblast Transdifferentiation in Obliterative Bronchiolitis: TGF-β Signaling Through Smad3-Dependent and -Independent Pathways

Ramirez

Shen

Ritzenthaler

et al. 2006

American Journal of Transplantation

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We have shown that Smad3, an intracellular signal transducer for transforming growth factor-b 1 (TGFb 1), is required to elicit the full histological manifestations of obliterative airway disease in a tracheal transplant model. This suggests that chronic allograft rejection results in TGF-b 1-induced Smad3 activation that leads to airway obliteration through fibroproliferation and increased matrix deposition. In other systems, these latter events are causally related to the transdifferentiation of fibroblasts into myofibroblasts, but their role in obliterative bronchiolitis (OB) after lung transplantation is unknown. We confirmed the presence of myofibroblasts inside affected airways associated with experimental OB using immunohistochemistry. Studying airway fibroblasts in vitro, we observed increased myofibroblast transdifferentiation in response to TGF-b 1, evidenced by increased a -smooth muscle actin mRNA and protein expression. In Smad3-null fibroblasts, TGF-b 1 induction of myofibroblast transdifferentiation was greatly diminished but not abolished, suggesting the presence of Smad3-independent pathways. Further studies revealed that small molecule inhibitors of p38 (SB203580) and MEK/ERK (U1026) further reduced the remaining effect of TGF-b 1 in Smad3-deficient fibroblasts. Together, these studies suggest that in chronic allograft rejection, TGF-b 1 stimulates myofibroblast transdifferentiation through Smad3-dependent and -independent signals, contributing to the excessive matrix deposition that characterizes obliterative bronchiolitis.

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Section: Discussionmentioning

confidence: 99%

Myofibroblast Transdifferentiation in Obliterative Bronchiolitis: TGF-β Signaling Through Smad3-Dependent and -Independent Pathways

Ramirez

Shen

Ritzenthaler

et al. 2006

American Journal of Transplantation

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“…The recruitment of myofibroblasts, which partially replaced the respiratory epithelium at day 84, was shown to be an inevitable condition for fibrous obliteration in heterotopic tracheal allografts [20]. The significance of this histological feature is increasingly recognised by others [21], and current literature provides evidence that the myofibroblast/a-SMA phenotype can be a result of the upregulation of TGF-b trough activation of various pathways, such as the mitogen-activated protein kinase and c-Jun pathway [22].…”

Section: Lung Transplantationmentioning

confidence: 98%

A model of chronic lung allograft rejection in the rat

Jungraithmayr

Vogt

İnci

et al. 2009

European Respiratory Journal

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Bronchiolitis obliterans, the pathological hallmark of chronic pulmonary rejection, severely impacts long-term survival following lung transplantation. However, experimental reproduction of this pathophysiological phenomenon has not been achieved with contemporary in vivo models. Here, a model of chronic rejection is described, with sensitised recipients receiving unilateral orthotopic rat lung transplants.Lewis rats, sensitised with skin from brown Norway rats 7 days before receiving left lung transplants from donors that were Lewis6brown Norway F 1 hybrids, were analysed during day 21-84. The development of chronic rejection was modulated by a treatment with rapamycin and cyclosporin, and characterised histologically, immunohistochemically and by reverse transcriptase PCR.Characteristic histopathological changes leading to chronic rejection were induced over time by an initial treatment with cyclosporin in the presence of continuous rapamycin application. At day 84, fibrotic lesions replaced the respiratory epithelium within small bronchioles, with strong expression of smooth muscle a-actin and upregulation of mRNA for T-helper cell type-1 cytokines, smooth muscle a-actin, transforming growth factor-b and CC chemokine ligand 5, but decreased forkhead box protein P3 gene expression.A reproducible and clinically relevant experimental set-up for progressive chronic rejection in rat pulmonary allografts is described. This model will permit better understanding of the pathological changes of small airways during the development of bronchiolitis obliterans, and may serve as an in vivo set-up for testing the efficacy of novel therapeutic interventions.

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“…One predominant observation made during chronic allograft rejection is an increase in the thickness of the intima, resulting in a decrease in vessel caliber with destruction of the internal elastic lamina. This thickening is also because of an accumulation of extracellular matrix and proliferation of myofibroblasts (Pedagogos et al 1997;Pilmore et al 2000;Ramirez et al 2006). An accumulation of macrophages and CD4 þ T cells has been observed at the periphery of the vessels (Thaunat and Nicoletti 2008;Thaunat et al 2005Thaunat et al , 2006, whereas CD8 þ T cells are rarely present.…”

Section: The Histological Lesionsmentioning

confidence: 99%