Cyclosporine induces different responses in human epithelial, endothelial and fibroblast cell cultures

Esposito, Ciro; Fornoni, Alessia; Cornacchia, Flavia; Bellotti, Nicoletta; Fasoli, Gianluca; Foschi, Annalisa; Mazzucchelli, Iolanda; Mazzullo, Tiziana; Semeraro, Luca; Canton, Antonio Dal

doi:10.1046/j.1523-1755.2000.00147.x

Cited by 93 publications

(71 citation statements)

References 30 publications

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“…Another study in neuronal cells also observed apoptosis inhibition (but sensitisation for necrosis) by cypD overexpression [123]. Moreover, there is accumulating evidence that cyclosporin A can induce apoptosis in certain cells [124][125][126][127]. In fact, the clinical use of CsA is still limited by its potential toxicity [128,129] and a specific inhibition of the PT-pore as observed with cypD [120,122] would be therapeutically of high interest.…”

Section: Overexpression Studies On Cypdmentioning

confidence: 92%

The permeability transition pore in cell death

2007

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The permeability transition pore (PT-pore) is a multi-component protein aggregate in mitochondria that comprises factors in the inner as well as in the outer mitochondrial membrane. This complex has two functions: firstly, it regulates the integration of oxidative phosphorylation into the cellular energy household and secondly, it induces cell death when converted into an unspecific channel. The latter causes a collapse of the mitochondrial membrane potential and activates a chain of events that culminate in the demise of the cell. It has been controversial for some time whether the PT-pore is causative for or only amplifies a signal of cell death but novel results confirm a central role of this protein complex for cell death induction. While a considerable body of data exist on its subunit composition, recent genetic knock-out experiments suggest that the identity of the core factors of the PT-pore is still unresolved. Moreover, accumulating evidence point to a much more complex composition of this protein complex than anticipated. Here, we review the current knowledge of its subunit composition, the evidence of a role in cell death, and we propose a model for the activation of the PT-pore for cell death. The role of the PT-pore in apoptosisThe permeability transitionThe permeability transition (PT) is a sudden and sustained increase of the permeability of the inner mitochondrial membrane for solutes smaller than 1.5 kD. This has catastrophic consequences for this organelle. The mitochondrial membrane potential m , which relies on the im-permeability of the inner membrane for protons, breaks down and with it the ability of the cell to synthesize ATP. The ensuing blockade of the respiratory chain leads to the generation of reactive oxygen intermediates (ROIs), most likely via the direct transfer of electrons to molecular oxygen. Also, the high concentration of solutes in the mitochondrial matrix generates an osmotic pressure, which drives the influx of water molecules and the expansion of the extensively folded inner membrane and eventually disrupts the outer membrane leading to the release of factors that execute the suicide programme of apoptosis. Thus, the self-destruction of mitochondria via the PT is followed by the demise of the cell as a whole. This process of mitochondrial destruction was first observed in vitro but was dismissed at the time as an artefact because, among other reasons, it was inconceivable why mitochondria should dispose of a process to dismantle themselves. This changed, however, when it was shown that the PT is mediated by a protein complex, the so-called permeability transition pore (PT-pore), and that various physiological and pharmacological reagents can act on this pore and modify the deadly response of mitochondria. Finally, the realisation that cells can mount an active suicide response that is mediated in large part by mitochondria placed the PT-pore firmly on the map of researchers. In particular, the use of cyclosporine A (CsA) that can inhibit the PT-pore subunit cyc...

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Section: Overexpression Studies On Cypdmentioning

confidence: 92%

The permeability transition pore in cell death

2007

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“…However, the effect upon nonlymphoid cells appears to be less straightforward, with variable effects upon epithelial cell proliferation between different organ systems. While anti-proliferative to renal tubular epithelium and implicated in the pathogenesis of tubular fibrosis observed in chronic renal allograft rejection (56), cyclosporin exerts a proliferative effect upon airway epithelium in rat tracheal isografts (57). In addition, cyclosporin may have direct effects upon epithelium (58).…”

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confidence: 99%

Epithelial Kinetics in Mouse Heterotopic Tracheal Allografts

Neuringer

Aris

Burns

et al. 2002

American Journal of Transplantation

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Obliterative bronchiolitis (OB) is the most important cause of graft dysfunction post-lung transplantation. It is likely that the small airway epithelium is a target of the alloimmune response, and that epithelial integrity is a crucial determinant of airway patency. Our goals are to elucidate epithelial cell kinetics in the heterotopic mouse trachea model and to determine potential mechanisms of cell death in allografts. Allografts and isografts were obtained by transplanting BALB/c tracheas into C57BL/6 and BALB/c immunosuppressed and nonimmunosuppressed hosts, respectively and harvested from day 3-20. Morphometry, BrdU and TUNEL labeling, and EM studies were performed. Columnar epithelium in isografts and allografts sloughs during day 0-3, but regenerates in both sets of grafts by day 10. Subsequently, allografts become inflamed and denuded, while isografts retain an intact epithelium. Prior to airway denudation, allografts exhibited significantly increased epithelial cell density, BrdU labeling index (LI), and TUNEL positive cells. Epithelial apoptosis was confirmed by electron microscopy. Allograft percent ciliated columnar epithelium and lumenal circumference were significantly decreased. Cyclosporin delayed airway fibrosis but did not alter the progression of the allograft through the phases of early ischemic injury, airway epithelial cell regeneration, and eventual cell death. These studies quantitatively demonstrate that the allograft epithelium actively regenerates in the alloimmune environment, but succumbs to increased apoptotic cell death, underscoring the importance of the airway epithelium as a self-renewing source of alloantigen.

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“…Cyclosporine may have adverse effects on the grafted vessels, resulting in accelerated atherosclerosis (Esposito et al, 2000). We did not see differences between the cyclosporine-treated and non-treated groups during the observation period.…”

Section: Discussionmentioning

confidence: 53%

Experimental results and clinical impact of using autologous rectus fascia sheath for vascular replacement

Kopper

Németh

Nagy

et al. 2008

Acta Veterinaria Hungarica

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Vascular complications are major causes of graft failure in liver transplantation. The use of different vascular grafts is common but the results are controversial. The aim of this study was to create an 'ideal' arterial interponate for vascular replacements in the clinical field. An autologous, tubular graft prepared from the posterior rectus fascia sheath was used for iliac artery replacement in dogs for 1, 3, 6 and 12 months. Forty-one grafts were implanted and immunosuppression was used in separate groups. The patency rate was followed by Doppler ultrasound. Thirty-seven grafts remained patent, 2 cases with thrombosis and 2 cases with stenosis occurred. There was no evidence of necrosis or aneurysmatic formation. The histological analysis included conventional light microscopic and immunohistochemical examinations for CD34 and factor VIII. The explanted grafts showed signs of arterialisation, appearance of elastin fibres, and smooth muscle cells after 6 months. Electron microscopy showed intact mitochondrial structures without signs of hypoxia. In conclusion, the autologous graft presents acceptable long-term patency rate. It is easy to handle and the concept of beneficial presence of the anti-clot mesothelium until endothelialisation seems to work. The first clinical use was already reported by our group with more than 2 years survival.

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Cyclosporine induces different responses in human epithelial, endothelial and fibroblast cell cultures

Cited by 93 publications

References 30 publications

The permeability transition pore in cell death

The permeability transition pore in cell death

Epithelial Kinetics in Mouse Heterotopic Tracheal Allografts

Experimental results and clinical impact of using autologous rectus fascia sheath for vascular replacement

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