Everolimus and mycophenolate mofetil are potent inhibitors of fibroblast proliferation after lung transplantation1

Azzola, Andrea; Havryk, A.; Chhajed, Prashant N.; Hostettler, Katrin; Black, Judith L.; Johnson, Patricia A.; Roth, Michael; Glanville, Allan R.; Tamm, Michael

doi:10.1097/01.tp.0000101822.50960.ab

Cited by 107 publications

(68 citation statements)

References 29 publications

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“…For this reason, the lack of success of current treatments for OB in lung transplantation is not surprising, given that they focus on the suppression of alloreactive cells, of which there are few in the OB lesion. In fact, very few studies have examined fibroblast proliferation in response to currently used immunosuppressant transplant medications (32,33). Studies testing these agents on myofibroblast transdifferentiation and proliferation, particularly, Smad3 and MAPK signaling, may be even more appropriate as these cells have a phenotype clearly distinct from that of undifferentiated fibroblasts.…”

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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“…Everolimus has been reported to induce a cell cycle arrest at the G 1 phase by blocking mTOR activity (Schuler et al, 1997;Azzola et al, 2004), but the effect of the association with fluvastatin has not been studied. We therefore investigated the effect of everolimus alone and in combination with fluvastatin on cell cycle progression using two different approaches: [ 3 H]thymidine incorporation assay and flow cytometry analysis of the cell cycle.…”

Section: The Synergistic Effect Of Combination Everolimusmentioning

confidence: 99%

Fluvastatin Synergistically Improves the Antiproliferative Effect of Everolimus on Rat Smooth Muscle Cells by Altering p27^Kip1/Cyclin E Expression

Ferri¹,

Granata²,

Pirola³

et al. 2008

Mol Pharmacol

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Multiple intracellular signaling pathways stimulate quiescent smooth muscle cells (SMCs) to exit from G 0 and re-enter the cell cycle. Thus, a combination of two drugs with different mechanisms of action may represent a suitable approach to control SMC proliferation, a prominent feature of in-stent restenosis. In the present study, we investigated the effect of everolimus, a mammalian target of rapamycin inhibitor, in combination with fluvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, on proliferation of rat SMCs. The antiproliferative action of everolimus was amplified by 2.5-fold by the addition of subliminal concentrations of fluvastatin (5 ϫ 10 Ϫ7

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“…In contrast to the report by Morizane et al [65], we used an immunosuppressive agent, namely, tacrolimus, at 0.05 mg/kg/day with subcutaneous injection. This dose is lower than the maintenance dose used for human organ transplantation [66][67][68]. Our results revealed that numerous grafted ESC-NS/PCs survived in the presence of a lowdose of tacrolimus after SCI.…”

Section: Discussionmentioning

confidence: 87%

Allogeneic Neural Stem/Progenitor Cells Derived From Embryonic Stem Cells Promote Functional Recovery After Transplantation Into Injured Spinal Cord of Nonhuman Primates

Iwai

Shimada

Nishimura

et al. 2015

Stem Cells Translational Medicine

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Previous studies have demonstrated that neural stem/progenitor cells (NS/PCs) promote functional recovery in rodent animal models of spinal cord injury (SCI). Because distinct differences exist in the neuroanatomy and immunological responses between rodents and primates, it is critical to determine the effectiveness and safety of allografted embryonic stem cell (ESC)-derived NS/PCs (ESC-NS/PCs) in a nonhuman primate SCI model. In the present study, common marmoset ESC-NS/PCs were grafted into the lesion epicenter 14 days after contusive SCI in adult marmosets (transplantation group). In the control group, phosphate-buffered saline was injected instead of cells. In the presence of a low-dose of tacrolimus, several grafted cells survived without tumorigenicity and differentiated into neurons, astrocytes, or oligodendrocytes. Significant differences were found in the transverse areas of luxol fast blue-positive myelin sheaths, neurofilament-positive axons, corticospinal tract fibers, and platelet endothelial cell adhesion molecule-1-positive vessels at the lesion epicenter between the transplantation and control groups. Immunoelectron microscopic examination demonstrated that the grafted ESC-NS/PC-derived oligodendrocytes contributed to the remyelination of demyelinated axons. In addition, some grafted neurons formed synaptic connections with host cells, and some transplanted neurons were myelinated by host cells. Eventually, motor functional recovery significantly improved in the transplantation group compared with the control group. In addition, a mixedlymphocyte reaction assay indicated that ESC-NS/PCs modulated the allogeneic immune rejection. Taken together, our results indicate that allogeneic transplantation of ESC-NS/PCs from a nonhuman primate promoted functional recovery after SCI without tumorigenicity. STEM CELLS TRANSLATIONAL MEDICINE 2015;4:708-719 SIGNIFICANCEThis study demonstrates that allogeneic embryonic stem cell (ESC)-derived neural stem/progenitor cells (NS/PCs) promoted functional recovery after transplantation into the injured spinal cord in nonhuman primates. ESC-NS/PCs were chosen because ESC-NS/PCs are one of the controls for induced pluripotent stem cell-derived NS/PCs and because ESC derivatives are possible candidates for clinical use. This translational research using an allograft model of a nonhuman primate is critical for clinical application of grafting NS/PCs derived from various allogeneic pluripotent stem cells, especially induced pluripotent stem cells, into injured spinal cord at the subacute phase.

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Everolimus and mycophenolate mofetil are potent inhibitors of fibroblast proliferation after lung transplantation1

Cited by 107 publications

References 29 publications

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

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

Fluvastatin Synergistically Improves the Antiproliferative Effect of Everolimus on Rat Smooth Muscle Cells by Altering p27^Kip1/Cyclin E Expression

Allogeneic Neural Stem/Progenitor Cells Derived From Embryonic Stem Cells Promote Functional Recovery After Transplantation Into Injured Spinal Cord of Nonhuman Primates

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Everolimus and mycophenolate mofetil are potent inhibitors of fibroblast proliferation after lung transplantation1

Cited by 107 publications

References 29 publications

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

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

Fluvastatin Synergistically Improves the Antiproliferative Effect of Everolimus on Rat Smooth Muscle Cells by Altering p27Kip1/Cyclin E Expression

Allogeneic Neural Stem/Progenitor Cells Derived From Embryonic Stem Cells Promote Functional Recovery After Transplantation Into Injured Spinal Cord of Nonhuman Primates

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Fluvastatin Synergistically Improves the Antiproliferative Effect of Everolimus on Rat Smooth Muscle Cells by Altering p27^Kip1/Cyclin E Expression