Histological evaluation of nintedanib in non-alcoholic steatohepatitis mice

Susutlertpanya, Warinda; Wakuda, Hirokazu; Otani, Naoyuki; Kuramoto, Takuya; Li, Li; Kuranari, Masae; Sekiguchi, Ai; Kudo, Hideo; Uchida, Tomohisa; Imai, Hiromitsu; Uemura, Naoto

doi:10.1016/j.lfs.2019.05.014

Cited by 11 publications

(7 citation statements)

References 41 publications

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“…Similar to our findings, another preclinical model of CCL 4 -induced liver fibrosis found that nintedanib significantly attenuated collagen accumulation and hepatic stellate cell activation, inhibiting intrahepatic inflammation and angiogenesis [15]. In a choline-deficient, L-amino aciddefined, high-fat diet-fed mouse model of nonalcoholic steatohepatitis, nintedanib also showed anti-inflammatory and antifibrotic effects [17].…”

supporting

confidence: 86%

Effects of Nintedanib in an Animal Model of Liver Fibrosis

Wollin

Togbé²,

Ryffel

2020

BioMed Research International

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Systemic sclerosis can affect multiple internal organs, including the liver and lungs. Nintedanib, an antifibrotic approved for treatment of interstitial lung disease associated with systemic sclerosis, may have activity outside of the lungs. This study explored the effect of preventive and therapeutic nintedanib treatment in a 3-week carbon tetrachloride (CCL4)-induced (500 mg/kg/day twice weekly for 3 weeks) model of hepatic inflammation and fibrosis in C57Bl/6 mice (aged 8 weeks, n=5 per group). Mice also received nintedanib (30 or 60 mg/kg/day) either each day for 21 days (preventive treatment) or from day 7 or day 14 (therapeutic treatment). Preventive nintedanib treatment at both doses significantly reduced CCL4-induced increases in myeloperoxidase (p<0.01), hepatic collagen (p<0.001), and interleukin (IL)-6 (p<0.01) in the liver. Nintedanib also significantly reduced hepatic necrosis (p<0.01 and p<0.05), inflammation (p<0.001 and p<0.05), fibrosis (p<0.001 and p<0.05) and IL-1β (p<0.05 and p<0.001) at both 30 and 60 mg/kg/day, respectively. Therapeutic treatment with nintedanib at 30 and 60 mg/kg/day significantly reduced CCL4-induced serum alanine aminotransferase from day 7 (p<0.05 and p<0.001) and day 14 (p<0.01 and p<0.05), respectively. Increases in tissue inhibitor of metalloproteinase-1 were significantly reduced by nintedanib at 60 mg/kg/day from day 7 only (p<0.001), and nintedanib completely blocked elevation of IL-6 and IL-1β levels regardless of dose or start of treatment (p<0.05–p<0.001). In both the preventive and therapeutic treatment schedules of the study, nintedanib treatment was beneficial in attenuating CCL4-induced pathology and reducing hepatic injury, inflammation, and fibrosis, demonstrating that nintedanib has antifibrotic and anti-inflammatory activity outside of the lungs.

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supporting

confidence: 86%

Effects of Nintedanib in an Animal Model of Liver Fibrosis

Wollin

Togbé²,

Ryffel

2020

BioMed Research International

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“…Treatment of idiopathic pulmonary fibrosis (IPF) has been transformed by the use of the small molecule inhibitors pirfenidone and nintedanib (King et al, 2014;Flaherty et al, 2019), and tranilast has been used in the treatment of asthma and keloid scars for over 30 years in Japan (Darakhshan & Pour, 2015). All three drugs also have antifibrotic effects outside the lung in animals (Seniutkin et al, 2018;Susutlertpanya et al, 2019), and repurposing these drugs for the treatment of cardiac fibrosis is being actively explored.…”

Section: Small Molecule Inhibitors Of Generic Fibrosis Pathwaysmentioning

confidence: 99%

Targeting cardiac fibrosis in heart failure with preserved ejection fraction: mirage or miracle?

2020

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Cardiac fibrosis is central to the pathology of heart failure, particularly heart failure with preserved ejection fraction (HFpEF). Irrespective of the underlying profibrotic condition (e.g. ageing, diabetes, hypertension), maladaptive cardiac fibrosis is defined by the transformation of resident fibroblasts to matrix-secreting myofibroblasts. Numerous profibrotic factors have been identified at the molecular level (e.g. TGFb, IL11, AngII), which activate gene expression programs for myofibroblast activation. A number of existing HF therapies indirectly target fibrotic pathways; however, despite multiple clinical trials in HFpEF, a specific clinically effective antifibrotic therapy remains elusive. Therapeutic inhibition of TGFb, the master-regulator of fibrosis, has unfortunately proven toxic and ineffective in clinical trials to date, and new approaches are needed. In this review, we discuss the pathophysiology and clinical implications of interstitial fibrosis in HFpEF. We provide an overview of trials targeting fibrosis in HFpEF to date and discuss the promise of potential new therapeutic approaches and targets in the context of underlying molecular mechanisms.

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“…Liver fibrosis can also be reduced in animal models given CCl4 for 3 weeks post-treatment using nintedanib (Wollin et al 2020). Susutlertpanya et al, (2019) also stated that there was a reduction in fibrotic lesions on microscopic examination of the liver in mice with NASH given nintedanib for two weeks. Liver fibrosis that does not get proper treatment will lead to cirrhosis, the final condition of liver damage in which the liver is no longer functioning at all.…”

Section: Discussionmentioning

confidence: 99%

Fibrosis and Collagen-I Accumulation in Bali Cattle Liver Tissue Infected with Fasciola gigantica

2022

Int J Vet Sci

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This study aims to determine the histopathological changes of fibrosis and accumulation of collagen I in liver tissue of Bali cattle infected with Fasciola gigantica in the Badung district, Bali Indonesia. On examination of 100 Bali cattle livers at the traditional abattoir of Badung, 37 of them were found to contain F. gigantica worms in both the bladder and bile ducts. The liver tissue was then fixed with 10% formalin for processing and stained with hematoxylin-eosin dyes. The liver sample preparation in the coating slide was also reacted with rabbit anti-collagen-I antibody. On histopathological examination, it was found that the distribution of fibrosis varied in the portal, interlobular, and bridging fibrosis areas. Immunohistochemical examination showed an immunoreactive reaction using rabbit anti-collagen I in the portal area with strong and weak intensity in the interlobular area and in bridging fibrosis. Fibrosis and accumulation of collagen I in Bali cattle infected with F. gigantica at the traditional abattoir of Badung district, Bali Indonesia was found in the portal, interlobular, and bridging fibrosis areas.

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Histological evaluation of nintedanib in non-alcoholic steatohepatitis mice

Cited by 11 publications

References 41 publications

Effects of Nintedanib in an Animal Model of Liver Fibrosis

Effects of Nintedanib in an Animal Model of Liver Fibrosis

Targeting cardiac fibrosis in heart failure with preserved ejection fraction: mirage or miracle?

Fibrosis and Collagen-I Accumulation in Bali Cattle Liver Tissue Infected with Fasciola gigantica

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