The activity of nintedanib in an animal model of allogenic left lung transplantation resembling aspects of allograft rejection

Suesskind-Schwendi, Marietta von; Boxhammer, Elke; Hirt, Stephan; Schreml, Stephan; Schmid, Çhristof; Wollin, Lutz; Lehle, Karla

doi:10.1080/01902148.2017.1354408

Cited by 8 publications

(5 citation statements)

References 33 publications

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“…In a rat model of left-lung allotransplantation, no reduction in fibrotic changes was observed in nintedanib-treated allografts compared to non-treated allografts, despite reduced expression of growth factors. Early and sustained treatment did not decrease the number of rats with histological signs of acute or chronic rejection [57].…”

Section: Mechanisms Of Antifibrotics On the Pathophysiological Processes After Ltx And In Clad Developmentmentioning

confidence: 79%

“…Adequate treatment of CLAD remains a significant unmet need. Based on the mechanisms of action, there is a particular interest in the use of antifibrotics in these patients, as pirfenidone and nintedanib could reduce development of obliterative and constrictive bronchiolitis, the histological correlate of BOS, and parenchymal and interstitial fibrosis, the histological correlate of RAS [57].…”

Section: Mechanisms Of Antifibrotics On the Pathophysiological Processes After Ltx And In Clad Developmentmentioning

confidence: 99%

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Antifibrotic drugs in lung transplantation and chronic lung allograft dysfunction: a review

Bos¹,

Sadeleer

Vanstapel

et al. 2021

Eur Respir Rev

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This review aims to provide an overview of pre-transplant antifibrotic therapy on peri-transplant outcomes and to address the possible role of antifibrotics in lung transplant recipients with chronic lung allograft dysfunction.Lung transplantation is an established treatment modality for patients with various end-stage lung diseases, of which idiopathic pulmonary fibrosis and other progressive fibrosing interstitial lung diseases are growing indications. Theoretically, widespread use of antifibrotics prior to lung transplantation may increase the risk of bronchial anastomotic complications and impaired wound healing.Long-term graft and patient survival are still hampered by development of chronic lung allograft dysfunction, on which antifibrotics may have a beneficial impact.Antifibrotics until the moment of lung transplantation proved to be safe, without increasing peri-transplant complications. Currently, best practice is to continue antifibrotics until time of transplantation. In a large multicentre randomised trial, pirfenidone did not appear to have a beneficial effect on lung function decline in established bronchiolitis obliterans syndrome. The results of antifibrotic therapy in restrictive allograft syndrome are eagerly awaited, but nonrandomised data from small case reports/series are promising.

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Section: Mechanisms Of Antifibrotics On the Pathophysiological Processes After Ltx And In Clad Developmentmentioning

confidence: 79%

Section: Mechanisms Of Antifibrotics On the Pathophysiological Processes After Ltx And In Clad Developmentmentioning

confidence: 99%

Antifibrotic drugs in lung transplantation and chronic lung allograft dysfunction: a review

Bos¹,

Sadeleer

Vanstapel

et al. 2021

Eur Respir Rev

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“…This is particularly relevant when considering that at this stage of the disease, the level of lung function is likely to be low and that the evidence from the clinical trials and the real-world data suggests that these patients are more likely to make it to the transplant if they are on anti-fibrotic treatment. A pre-clinical lung transplantation study in rats revealed no evidence of impaired wound healing despite nintedanib being administered before and after the surgical procedure [44] and a small case study in Belgium (nintedanib, n = 2) showed no problems with bleeding or delayed wound healing related to anti-fibrotic treatment. There were some mild complications with anastomosis between the transplanted organ and the trachea in some patients; however, these were mild or uneventful [45].…”

Section: Expert Statements and Recommendationsmentioning

confidence: 99%

Nintedanib in Idiopathic Pulmonary Fibrosis: Practical Management Recommendations for Potential Adverse Events

et al. 2018

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Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with a dismal survival rate of only 3 years and no curative pharmacological therapy. The recent approval of 2 anti-fibrotic drugs (nintedanib and pirfenidone) that slow disease progression has provided some hope for patients. However, effectively managing anti-fibrotic treatment can be a challenge due to tolerability issues, the presence of pulmonary and extra-pulmonary comorbidities, and the need for concomitant medications in many patients. In general, making clear evidence-based decisions can be difficult for physicians because patients with comorbidities are often excluded from clinical trials. Since currently anti-fibrotic drugs are the only effective therapeutics capable of slowing disease progression, it is imperative that all treatment options are thoroughly evaluated and exhausted in each individual, irrespective of complicating factors, to permit the best outcome for the patient. In this review, we present data from clinical trials, post hoc analyses, post-marketing surveillance, and real-world studies that are relevant to the management of nintedanib treatment. In addition, we also provide practical recommendations developed by a multidisciplinary panel of experts for the management of nintedanib treatment in patients with IPF associated complications and those experiencing gastrointestinal side effects.

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“…On the other hand, downregulation of both PDGFR subtypes in our experimental model might be the mechanistic link between nintedanib treatment and inhibition of SMC proliferation. Suesskind-Schwendi et al 44 used nintedanib in a rat lung transplantation model and also found receptor down-regulation (PDGFRα and VEGFR2), but interestingly did not reveal decreased fibrosis development after lung transplantation. This controversy to our results can be explained by a different pathomechanism in the aortic transplant model: neointima formation in CAV initially is driven by SMC proliferation and accumulation as well as leukocyte infiltration whereas fibrosis represents only a minor aspect in CAV.…”

Section: Discussionmentioning

confidence: 98%

Small Molecule Tyrosine Kinase Inhibitor Nintedanib Reduces Development of Cardiac Allograft Vasculopathy in Murine Aortic Allografts

Gocht

Spriewald

Distler

et al. 2018

Transplantation Direct

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BackgroundNintedanib is a small molecule tyrosine kinase inhibitor that blocks the action of the platelet-derived growth factor receptor (PDGFR), the vascular endothelial growth factor receptor (VEGFR) and the fibroblast growth factor receptor. All of these receptors have been shown to be involved in the development of cardiac allograft vasculopathy (CAV) after heart transplantation. We therefore hypothesized that blocking these tyrosine kinase receptors with nintedanib could prevent CAV.MethodsCBA/JRj (H2k) mice underwent an abdominal aortic transplantation with a graft derived from fully allogeneic C57BL/6JRj (H2b) mice. Nintedanib was given daily from the first day after transplantation until harvest on day 14 for polymerase chain reaction analysis of intragraft cytokine expression or harvest on day 30 for histological analysis of the graft.ResultsNintedanib treatment resulted in significantly reduced neointima formation in the aortic graft compared with untreated control allografts. Interestingly, the immigration of smooth muscle cells into the neointima was markedly reduced while graft infiltrating macrophages and T cells were not altered in nintedanib-treated animals. The expression of the growth factor PDGF was significantly reduced in the nintedanib group going along with a distinctly reduced expression of the corresponding receptors PDGFR α and -β.ConclusionsTreatment with nintedanib caused a significant reduction of CAV development after aortic transplantation in mice. We hypothesize the attenuated neointima formation in nintedanib-treated animals to be mediated by a direct inhibition of intimal smooth muscle cell proliferation via reduced expression of PDGF and the appropriate receptors PDGFR α + β.

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The activity of nintedanib in an animal model of allogenic left lung transplantation resembling aspects of allograft rejection

Abstract: In conclusion, while nintedanib reduced the expression of growth factors/receptors in a rat LTx model, a reduction in fibrotic alterations was not observed at POD 60.

Cited by 8 publications

References 33 publications

Antifibrotic drugs in lung transplantation and chronic lung allograft dysfunction: a review

Antifibrotic drugs in lung transplantation and chronic lung allograft dysfunction: a review

Nintedanib in Idiopathic Pulmonary Fibrosis: Practical Management Recommendations for Potential Adverse Events

Small Molecule Tyrosine Kinase Inhibitor Nintedanib Reduces Development of Cardiac Allograft Vasculopathy in Murine Aortic Allografts

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