Inhaled nintedanib is well-tolerated and delivers key pharmacokinetic parameters required to treat bleomycin-induced pulmonary fibrosis

Surber, Mark W.; Beck, Steve; Pham, Scott; Marsden, A. T. H.; Gandi, Senthil Kumar; Baily, James; McElroy, Mary C.

doi:10.1016/j.pupt.2020.101938

Cited by 26 publications

(18 citation statements)

References 22 publications

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“…These findings were tested in an in-vivo model, which included rats exposed to bleomycin, followed by treatment with oral or inhaled vehicle/nintedanib [12]. Results showed that nintedanib was associated with lower numbers and smaller foci of fibrosis resulting in a lower median fibrosis score for animals in this group compared to inhaled vehicle treated controls.…”

Section: Rat Bleomycin Model Shows Elevated Levels Of Hif1α Within Fibrotic Tissuementioning

confidence: 99%

“…The study consisted of 7 treatment groups with 10 animals per group as previously described [12]. Bleomycin (1 mg/kg in 100 µL) or vehicle was administered to animals on four occasions by oropharyngeal aspiration during Week 1 to induce lung fibrosis (Days 1, 2, 3 and 6).…”

Section: Rat Bleomycin Modelmentioning

confidence: 99%

“…For this aim, an inhaled version of nintedanib was recently described. Using two animal models [12,13], it was shown that oral-equivalent to superior effects could be obtained administering substantially reduced inhaled doses, with less adverse effects on general health. Moreover, the activity of inhaled pharmacokinetics were further supported using the in-vitro IPF-CM system wherein only short-duration nintedanib exposure was required to achieve similar effects [13].…”

Section: Introductionmentioning

confidence: 99%

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Hypoxia Inducible Factor 1A Supports a Pro-Fibrotic Phenotype Loop in Idiopathic Pulmonary Fibrosis

Shochet

Bardenstein-Wald

McElroy

et al. 2021

IJMS

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Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with poor prognosis. The IPF-conditioned matrix (IPF-CM) system enables the study of matrix–fibroblast interplay. While effective at slowing fibrosis, nintedanib has limitations and the mechanism is not fully elucidated. In the current work, we explored the underlying signaling pathways and characterized nintedanib involvement in the IPF-CM fibrotic process. Results were validated using IPF patient samples and bleomycin-treated animals with/without oral and inhaled nintedanib. IPF-derived primary human lung fibroblasts (HLFs) were cultured on Matrigel and then cleared using NH4OH, creating the IPF-CM. Normal HLF-CM served as control. RNA-sequencing, PCR and western-blots were performed. HIF1α targets were evaluated by immunohistochemistry in bleomycin-treated rats with/without nintedanib and in patient samples with IPF. HLFs cultured on IPF-CM showed over-expression of ‘HIF1α signaling pathway’ (KEGG, p < 0.0001), with emphasis on SERPINE1 (PAI-1), VEGFA and TIMP1. IPF patient samples showed high HIF1α staining, especially in established fibrous tissue. PAI-1 was overexpressed, mainly in alveolar macrophages. Nintedanib completely reduced HIF1α upregulation in the IPF-CM and rat-bleomycin models. IPF-HLFs alter the extracellular matrix, thus creating a matrix that further propagates an IPF-like phenotype in normal HLFs. This pro-fibrotic loop includes the HIF1α pathway, which can be blocked by nintedanib.

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Section: Rat Bleomycin Model Shows Elevated Levels Of Hif1α Within Fibrotic Tissuementioning

confidence: 99%

Section: Rat Bleomycin Modelmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Hypoxia Inducible Factor 1A Supports a Pro-Fibrotic Phenotype Loop in Idiopathic Pulmonary Fibrosis

Shochet

Bardenstein-Wald

McElroy

et al. 2021

IJMS

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“…Both drugs were reformulated as a solution for inhaled administration, which holds promise to reduce systemic side-effects, maximise local efficacy and possibly enable dose escalation for additional efficacy in IPF patients [90,91]. Inhaled pirfenidone and nintedanib proved to have good pharmacokinetics, delivering an oral-equivalent lung maximum concentration with lower systemic levels, and to be well-tolerated and effective in several animal models [90][91][92]. These promising observations have to be confirmed in human trials.…”

Section: Inhaled Antifibroticsmentioning

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 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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“…Inhaled therapy with TD139 (a novel and potent small-molecule inhibitor of Galectin (Gal)-3 a profibrotic β-galactoside-binding lectin that plays a key role in the pathogenesis of IPF and IPF exacerbations) has been recently tested in IPF patients with encouraging results [ 23 ]. Moreover, inhaled formulations of both pirfenidone and nintedanib have been successfully tested [ 24 , 25 ]. For both drugs, local administration in the lungs was associated with higher lung and lower plasma concentrations with a conserved anti-fibrotic efficacy [ 24 , 25 ].…”

Section: Discussionmentioning

confidence: 99%

HSPB5 Inhibition by NCI-41356 Reduces Experimental Lung Fibrosis by Blocking TGF-β1 Signaling

et al. 2023

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Idiopathic pulmonary fibrosis is a chronic, progressive and lethal disease of unknown etiology that ranks among the most frequent interstitial lung diseases. Idiopathic pulmonary fibrosis is characterized by dysregulated healing mechanisms that lead to the accumulation of large amounts of collagen in the lung tissue that disrupts the alveolar architecture. The two currently available treatments, nintedanib and pirfenidone, are only able to slow down the disease without being curative. We demonstrated in the past that HSPB5, a low molecular weight heat shock protein, was involved in the development of fibrosis and therefore was a potential therapeutic target. Here, we have explored whether NCI-41356, a chemical inhibitor of HSPB5, can limit the development of pulmonary fibrosis. In vivo, we used a mouse model in which fibrosis was induced by intratracheal injection of bleomycin. Mice were treated with NaCl or NCI-41356 (six times intravenously or three times intratracheally). Fibrosis was evaluated by collagen quantification, immunofluorescence and TGF-β gene expression. In vitro, we studied the specific role of NCI-41356 on the chaperone function of HSPB5 and the inhibitory properties of NCI-41356 on HSPB5 interaction with its partner SMAD4 during fibrosis. TGF-β1 signaling was evaluated by immunofluorescence and Western Blot in epithelial cells treated with TGF-β1 with or without NCI-41356. In vivo, NCI-41356 reduced the accumulation of collagen, the expression of TGF-β1 and pro-fibrotic markers (PAI-1, α-SMA). In vitro, NCI-41356 decreased the interaction between HSPB5 and SMAD4 and thus modulated the SMAD4 canonical nuclear translocation involved in TGF-β1 signaling, which may explain NCI-41356 anti-fibrotic properties. In this study, we determined that inhibition of HSPB5 by NCI-41356 could limit pulmonary fibrosis in mice by limiting the synthesis of collagen and pro-fibrotic markers. At the molecular level, this outcome may be explained by the effect of NCI-41356 inhibiting HSPB5/SMAD4 interaction, thus modulating SMAD4 and TGF-β1 signaling. Further investigations are needed to determine whether these results can be transposed to humans.

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Inhaled nintedanib is well-tolerated and delivers key pharmacokinetic parameters required to treat bleomycin-induced pulmonary fibrosis

Cited by 26 publications

References 22 publications

Hypoxia Inducible Factor 1A Supports a Pro-Fibrotic Phenotype Loop in Idiopathic Pulmonary Fibrosis

Hypoxia Inducible Factor 1A Supports a Pro-Fibrotic Phenotype Loop in Idiopathic Pulmonary Fibrosis

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

HSPB5 Inhibition by NCI-41356 Reduces Experimental Lung Fibrosis by Blocking TGF-β1 Signaling

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