NP603, a novel and potent inhibitor of FGFR1 tyrosine kinase, inhibits hepatic stellate cell proliferation and ameliorates hepatic fibrosis in rats

Lin, Nan; Chen, Si; Pan, Weidong; Xu, Liang; Hu, Kunpeng; Xu, Rui‐hua

doi:10.1152/ajpcell.00452.2010

Cited by 40 publications

(46 citation statements)

References 31 publications

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“…Pirfenidone reduces fibrosis in animal models and inhibits increases in transforming growth factor (TGF)-b1, IL-1b, and FGF2 (7,8). Administration of a specific inhibitor of FGFR1 (NP603) inhibits carbon tetrachloride-induced hepatic fibrosis in rats (9), but has not been tested in models of pulmonary fibrosis. A soluble ectodomain of FGFR2c inhibits TGF-b1-induced primary lung fibroblast proliferation in vitro, as well as bleomycininduced fibrosis in vivo (10).…”

Section: Clinical Relevancementioning

confidence: 99%

“…A soluble ectodomain of FGFR2c inhibits TGF-b1-induced primary lung fibroblast proliferation in vitro, as well as bleomycininduced fibrosis in vivo (10). This ectodomain inhibits multiple FGFs known to bind to the IIIc splice variant of FGFR2, including FGFs 1,2,4,6,8,9,17,and 18 (11). Despite this, the cell-specific role of FGF signaling in the development of pulmonary fibrosis remains uncertain.…”

Section: Clinical Relevancementioning

confidence: 99%

See 1 more Smart Citation

Fibroblast Growth Factor 2 Is Required for Epithelial Recovery, but Not for Pulmonary Fibrosis, in Response to Bleomycin

Guzy

Stoilov

Elton³

et al. 2015

Am J Respir Cell Mol Biol

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The pathogenesis of pulmonary fibrosis involves lung epithelial injury and aberrant proliferation of fibroblasts, and results in progressive pulmonary scarring and declining lung function. In vitro, fibroblast growth factor (FGF) 2 promotes myofibroblast differentiation and proliferation in cooperation with the profibrotic growth factor, transforming growth factor-b1, but the in vivo requirement for FGF2 in the development of pulmonary fibrosis is not known. The bleomycin model of lung injury and pulmonary fibrosis was applied to Fgf2 knockout (Fgf2 2/2) and littermate control mice. Weight loss, mortality, pulmonary fibrosis, and histology were analyzed after a single intranasal dose of bleomycin. Inflammation was evaluated in bronchoalveolar lavage (BAL) fluid, and epithelial barrier integrity was assessed by measuring BAL protein and Evans Blue dye permeability. Fgf2 is expressed in mouse and human lung epithelial and inflammatory cells, and, in response to bleomycin, Fgf2 2/2 mice have significantly increased mortality and weight loss. Analysis of BAL fluid and histology show that pulmonary fibrosis is unaltered, but Fgf2 2/2 mice fail to efficiently resolve inflammation, have increased BAL cellularity, and, importantly, deficient recovery of epithelial integrity. Fgf2 2/2 mice similarly have deficient recovery of club cell secretory protein 1 bronchial epithelium in response to naphthalene. We conclude that FGF2 is not required for bleomycin-induced pulmonary fibrosis, but rather is essential for epithelial repair and maintaining epithelial integrity after bleomycin-induced lung injury in mice. These data identify that FGF2 acts as a protective growth factor after lung epithelial injury, and call into question the role of FGF2 as a profibrotic growth factor in vivo.Keywords: fibroblast growth factor 2; bleomycin; pulmonary fibrosis; lung injury; alveolar epithelial repair Clinical RelevanceFibroblast growth factors (FGFs) and, in particular, FGF2, are implicated in the pathogenesis of pulmonary fibrosis and recovery from airway epithelial cell (AEC) injury; however, the in vivo requirement for FGF2 in the development of pulmonary fibrosis is not known. In this study, we have found that mice lacking FGF2 do not show altered levels of fibrosis in response to bleomycin, indicating that FGF2 is dispensable for the generation of bleomycin-induced pulmonary fibrosis. In addition, we show that FGF2 knockout mice have increased mortality and weight loss in response to bleomycin, accompanied by deficient recovery of mature alveolar epithelium and epithelial barrier function. These findings suggest that FGF2 is required for lung epithelial recovery, that pharmacological inhibition of FGF signaling could impair the response to lung injury, and that FGF2 administration or augmentation may have therapeutic benefit for lung injury.Lung alveolar epithelial cell (AEC) injury can be caused by a variety of insults, including infection, trauma, aspiration, and sepsis. Chronic AEC injury of unknown origin is central to ...

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Section: Clinical Relevancementioning

confidence: 99%

Section: Clinical Relevancementioning

confidence: 99%

Fibroblast Growth Factor 2 Is Required for Epithelial Recovery, but Not for Pulmonary Fibrosis, in Response to Bleomycin

Guzy

Stoilov

Elton³

et al. 2015

Am J Respir Cell Mol Biol

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“…PIP3 совместно с киназой PDK активирует еще одну киназу -AKT [3,12,13]. Акти-вация пути RAS-RAF-MEK-ERK приводит к усиле-нию экспрессии циклина D [3,[14][15][16]. Кроме того, активация как пути RAS-ERK, так и пути PI3K-AKT ведет к подавлению активности ингибитора циклин-зависимой киназы р27 KIP1 [17,18].…”

Section: том 2 обзорные статьи 29unclassified

Перспективы Терапевтического Воздействия На Сигнальный Путь FGFR

Fedianin¹,

Khmelkova²,

Серебрийская³

et al. 2015

Usp. mol. onkol

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“…PIP3 совместно с киназой PDK активирует еще одну киназу -AKT [3,12,13]. Активация RAS-RAF-MEK-ERK пути приводит к усилению экспрессии циклина D [3,[14][15][16]. Кроме того, активация как RAS-ERK пути, так и PI3K-AKT ведет к подавле-нию активности ингибитора циклин-зависимой киназы р27KIP1 [17,18].…”

Section: фундаментальная онкология и экспериментальная медицинаunclassified