Long-term clinical stabilization of scleroderma patients treated with a chronic and intensive IV iloprost regimen

Foti, Rosario; Visalli, Elisa; Amato, Giorgio; Benenati, Alessia; Converso, G.; Farina, Alberto; Bellofiore, S.; Mulè, Massimiliano; Gangi, M. Di

doi:10.1007/s00296-016-3582-4

Cited by 24 publications

(16 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Alternatively, our findings in this study and in [18] provide rationale for the use of GPCR agonists of G αs -coupled receptors as treatments that actively trigger YAP/TAZ inactivation and thus will have an antifibrotic potential. This is supported by reports that activating IP receptor by selexipag, treprostinil and iloprost [18,[83][84][85][86][87][88][89], β2-adrenoreceptors by oladaterol [90], or melatonin receptors by melatonin [91] is antifibrotic in vitro and in animal fibrosis models, and at the same time inhibits YAP/TAZ [18,23,91].…”

Section: Discussionsupporting

confidence: 55%

GPCR-induced YAP activation sensitizes fibroblasts to profibrotic activity of TGFβ1

et al. 2020

View full text Add to dashboard Cite

Tissue fibrosis is a pathological condition characterized by uncontrolled fibroblast activation that ultimately leads to organ failure. The TGFβ1 pathway, one of the major players in establishment of the disease phenotype, is dependent on the transcriptional co-activators YAP/ TAZ. We were interested whether fibroblasts can be sensitized to TGFβ1 by activation of the GPCR/YAP/TAZ axis and whether this mechanism explains the profibrotic properties of diverse GPCR ligands. We found that LPA, S1P and thrombin cooperate in human dermal fibroblasts with TGFβ1 to induce extracellular matrix synthesis, myofibroblast marker expression and cytokine secretion. Whole genome expression profiling identified a YAP/ TAZ signature behind the synergistic profibrotic effects of LPA and TGFβ1. LPA, S1P and thrombin stimulation led to activation of the Rho-YAP axis, an increase of nuclear YAP-Smad2 complexes and enhanced expression of profibrotic YAP/Smad2-target genes. More generally, dermal, cardiac and lung fibroblast responses to TGFβ1 could be enhanced by increasing YAP nuclear levels (with GPCR ligands LPA, S1P, thrombin or Rho activator) and inhibited by decreasing nuclear YAP (with Rho inhibitor, forskolin, latrunculin B or 2deoxy-glucose). Thus, we present here a conceptually interesting finding that fibroblast responses to TGFβ1 can be predicted based on the nuclear levels of YAP and modulated by stimuli/treatments that change YAP nuclear levels. Our study contributes to better understanding of fibrosis as a complex interplay of signalling pathways and proposes YAP/TAZ as promising targets in the treatment of fibrosis.

show abstract

Section: Discussionsupporting

confidence: 55%

GPCR-induced YAP activation sensitizes fibroblasts to profibrotic activity of TGFβ1

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Thus, developing strategies that would ensure or even enhance anti-inflammatory stimuli appears mandatory. Iloprost is a well-known drug to treat diseases of the vascular system like pulmonary arterial hypertension and scleroderma (25, 29, 30). Its main function is conducted via vasodilatation (widening of blood vessels).…”

Section: Discussionmentioning

confidence: 99%

Immune Modulation to Enhance Bone Healing—A New Concept to Induce Bone Using Prostacyclin to Locally Modulate Immunity

et al. 2019

View full text Add to dashboard Cite

Within an aging population, fracture incidences will rise and with the augmented risks of impaired healing the overall risk of delayed bone regeneration will substantially increase in elderly patients. Thus, new strategies to rescue fracture healing in the elderly are highly warranted. Modulating the initial inflammatory phase toward a reduced pro-inflammation launches new treatment options for delayed or impaired healing specifically in the elderly. Here, we evaluated the capacity of the prostacyclin analog Iloprost to modulate the inflammatory phase toward a pro-regenerative milieu using in vitro as well as in vivo model systems. In vitro , Iloprost administration led to a downregulation of potential unfavorable CD8+ cytotoxic T cells as well as their pro-inflammatory cytokine secretion profile. Furthermore, Iloprost increased the mineralization capacity of osteogenic induced mesenchymal stromal cells through both direct as well as indirect cues. In an in vivo approach, Iloprost, embedded in a biphasic fibrin scaffold, decreased the pro-inflammatory and simultaneously enhanced the anti-inflammatory phase thereby improving bone healing outcome. Overall, our presented data confirms a possible strategy to modulate the early inflammatory phase in aged individuals toward a physiological healing by a downregulation of an excessive pro-inflammation that otherwise would impair healing. Further confirmation in phase I/II trials, however, is needed to validate the concept in a broader clinical evaluation.

show abstract

“…Antiphospholipid screening was negative. A vasodilatative therapy with iloprost, initially 10 μg, followed by 20 μg was introduced: the first cycle consisting of 7 infusions, the second and third cycle 4 weeks apart each consisting of 5 infusions, followed by further separate infusions every 4 weeks [17].…”

Section: Case Reportmentioning

confidence: 99%

Response to Rituximab after Failure of Cyclophosphamide in the Induction Treatment in a Patient with cANCA-associated Vasculitis and Pachymeningitis: a Case Report

Psenak

Greil

2021

Sovremennaâ revmatologiâ

View full text Add to dashboard Cite

A 36-year-old male patient who originally presented with recurrent inflammations in the mastoid, otitis media and peripheral facial paralysis was diagnosed with sterile pachymeningitis, associated with high titres of antineutrophil cytoplasmic antibodies (cANCA) directed against proteinase 3 (PR3). Induction therapy with oral prednisolone 1 mg/kg body weight and cyclophosphamide (CYC) 750 mg/m 2 i.v. every 4 weeks was initiated. Due to side effects, increasing arthralgias and progressive meningitis after 5 doses of CYC, treatment was changed to rituximab (RTX), one cycle comprising two administrations of 1000 mg RTX i.v. two weeks apart, repeated every 6 months. After the very first cycle of RTX, we confirmed subjective improvement of the patient’s fitness as well as radiologic response. Methotrexate (MTX) was added to ease arthralgias. Painful bleeding ulcerations on finger tips were successfully treated with 22 iloprost infusions. Up to date, we have administered 7 cycles of RTX and achieved complete remission of the cANCA-associated vasculitis. After the induction therapy, maintenance treatment with MTX or rituximab will be performed for at least 18–24 months.We can demonstrate a complete remission with the use of RTX in a patient with cANCA-associated vasculitis and sterile pachymeningitis who failed to respond to the induction treatment with CYC. RTX has been well tolerated.

show abstract

Long-term clinical stabilization of scleroderma patients treated with a chronic and intensive IV iloprost regimen

Cited by 24 publications

References 21 publications

GPCR-induced YAP activation sensitizes fibroblasts to profibrotic activity of TGFβ1

GPCR-induced YAP activation sensitizes fibroblasts to profibrotic activity of TGFβ1

Immune Modulation to Enhance Bone Healing—A New Concept to Induce Bone Using Prostacyclin to Locally Modulate Immunity

Response to Rituximab after Failure of Cyclophosphamide in the Induction Treatment in a Patient with cANCA-associated Vasculitis and Pachymeningitis: a Case Report

Contact Info

Product

Resources

About