Amelioration of liver fibrogenesis by dual inhibition of PDGF and TGF-β with a combination of imatinib mesylate and ACE inhibitor in rats

Yoshiji, Hitoshi; Kuriyama, Shigeki; Noguchi, Ryuichi; Ikenaka, Yasuhide; Yoshii, Junichi; Yanase, Koji; Namisaki, Tadashi; Kitade, Mitsuteru; Yamazaki, Masaharu; Asada, Kiyoshi; Akahane, Takemi; Tsujimoto, Tatsuhiro; Uemura, Mamoru; Fukui, Hiroshi

doi:10.3892/ijmm.17.5.899

Cited by 31 publications

(31 citation statements)

References 35 publications

(54 reference statements)

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“…These results are in agreement with the previous study of Yoshiji et al (2005), which demonstrated the prophylactic potential of imatinib to produce a significant hepatic fibrosis reduction via suppression of activated HSCs during 8 weeks of concomitant stimulation with pig serum. Combination treatment of imatinib and ACE-I inhibitor, perindopril, significantly attenuated liver fibrosis development (Yoshiji et al 2006). Also, it has been reported that daily IP injection of imatinib caused a marked decrease of proliferation in isolated HSCs in an experimental model of rats with 48 h of acute bile duct ligation liver injury (Kinnman et al 2001).…”

Section: Discussionmentioning

confidence: 98%

Prevention and treatment of Schistosoma mansoni-induced liver fibrosis in mice

2011

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The present study was designed to examine the potential preventive and curative effects of curcumin, resveratrol, imatinib, rosiglitazone, losartan and bosentan (BOS) on Schistosoma mansoni-induced liver fibrosis in mice. Induction of liver fibrosis was produced in male Swiss mice by subcutaneous injection of S. mansoni cercariae per mouse. Mice were left for 28 days before starting the experiment then mice were divided into two main groups. The first group was further subdivided into experimental groups and started drug treatment at day 28 after infection and continued for 2 weeks in order to evaluate the potential preventive effects of the mentioned drugs on S. mansoni-induced liver fibrosis. The second group of mice were left for 2 weeks and then treated with praziquantel for two consecutive days to eradicate the worms and so stop egg disposition and further fibrosis development. Mice were then subdivided into the experimental groups and drug treatment was started for 2 weeks to evaluate their efficacy to decrease the developed fibrosis. At the end of the experiment period, mice were killed and serum was collected for the estimation of alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin and albumin. Liver tissue was taken for the estimation of hepatic hydroxyproline content and histopathological examination to confirm the biochemical results. Results of the study indicate that curcumin and imatinib have potent antifibrotic activity both in suppressing and reversing S. mansoni-induced liver fibrosis, while resveratrol has beneficial effects only in suppressing the development of S. mansoni-induced liver fibrosis.

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Section: Discussionmentioning

confidence: 98%

Prevention and treatment of Schistosoma mansoni-induced liver fibrosis in mice

2011

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“…Lastly, but more importantly, since other growth factors (PDGF, IGF, epidermal growth factor, HFG as shown in fig. 4 ) can quite effectively signal via RTK by activating several molecules shared by TGF-Smad-independent pathways in certain cell types, it is not unusual for TGF-␤ to share its role with other growth factors in EMT in development [Yamane et al, 2003;Karihaloo et al, 2005;Mukherjee et al, 2005;Gwon, 2006;Yoshiji et al, 2006].…”

Section: Activation Of Tgf-␤ Receptormentioning

confidence: 99%

Complexity in Interpretation of Embryonic Epithelial-Mesenchymal Transition in Response to Transforming Growth Factor-β Signaling

Ahmed

Nawshad

2007

Cells Tissues Organs

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Epithelial-mesenchymal transition (EMT) is a highly conserved and fundamental process that governs morphogenesis in development and may also contribute to cancer metastasis. Transforming growth factor (TGF-β) is a potent inducer of EMT in various developmental and tumor systems. The analysis of TGF-β signal transduction pathways is now considered a critically important area of biology, since many defects occur in these pathways in embryonic development. The complexity of TGF-β signal transduction networks is overwhelming due to the large numbers of interacting constituents, complicated feedforward, feedback and crosstalk circuitry mechanisms that they involve in addition to the cellular kinetics and enzymatics that contribute to cell signaling. As a result of this complexity, apparently simple but highly important questions remain unanswered, that is, how do epithelial cells respond to such TGF-β signals? System biology and cellular kinetics play a crucial role in cellular function; omissions of such a critical contributor may lead to inaccurate understanding of embryonic EMT. In this review, we identify and explain why certain conditions need to be considered for a true representation of TGF-β signaling in vivo to better understand the controlled, yet delicate mechanism of embryonic EMT.

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“…Antifibrotic effects of imatinib have also been reported in other organ systems such as the liver (Yoshiji et al, 2006) and kidney (Wang et al, 2005). Daniels et al (2004) studied the effects of imatinib in female 129tsvems mice subjected to intratracheal bleomycin; imatinib at 50 mg/kg/day administered on day 1 after bleomycin injury for a period of 28 days mediated significant protection from fibrosis.…”

mentioning

confidence: 99%

Effects of the Protein Kinase Inhibitor, Imatinib Mesylate, on Epithelial/Mesenchymal Phenotypes: Implications for Treatment of Fibrotic Diseases

Vittal¹,

Zhang²,

Han³

et al. 2007

J Pharmacol Exp Ther

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Tissue injury in mammals triggers both inflammatory and repair responses that, in some contexts, results in fibrosis. Fibrosis is characterized by the persistence of activated myofibroblasts, ineffective re-epithelialization, and variable degrees of inflammation within injured tissues. The protein kinase inhibitor (PKI), imatinib mesylate, has been proposed as a potential antifibrotic therapeutic agent. In this study, the efficacy of imatinib mesylate to modulate fibrogenic responses, both in vitro and in vivo, was examined. In an in vitro fibroblast culture model, imatinib inhibits platelet-derived growth factor receptor activation and fibroblast proliferation but not the stably differentiated myofibroblast phenotype. Furthermore, imatinib inhibits lung epithelial cell proliferation and survival but not the induction of epithelial-mesenchymal transition. Imatinib does not alter transforming growth factor-␤/SMAD3 signaling in either cell type. In a murine model of lung fibrosis, bleomycin-induced injury to the pulmonary epithelium provokes an early inflammatory response with more delayed fibrosis during the late reparative phase of lung injury. Imatinib mesylate (10 mg/kg/day by i.p. injection or oral gavage), administered during the postinjury repair phase, failed to significantly alter fibrogenic responses assessed by histopathology, collagen content, and the accumulation of myofibroblasts within the injured lung. These studies indicate that the capacity of a PKI to inhibit fibroblast proliferation may be insufficient to mediate significant antifibrotic effects in late stages of tissue injury repair. Pharmacologic agents that modulate the activities and fate of differentiated (myo)fibroblasts, without interfering with the regenerative capacity of epithelial cells, are likely to be more effective for treatment of nonresolving, progressive fibrotic disorders.

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Amelioration of liver fibrogenesis by dual inhibition of PDGF and TGF-β with a combination of imatinib mesylate and ACE inhibitor in rats

Cited by 31 publications

References 35 publications

Prevention and treatment of Schistosoma mansoni-induced liver fibrosis in mice

Prevention and treatment of Schistosoma mansoni-induced liver fibrosis in mice

Complexity in Interpretation of Embryonic Epithelial-Mesenchymal Transition in Response to Transforming Growth Factor-β Signaling

Effects of the Protein Kinase Inhibitor, Imatinib Mesylate, on Epithelial/Mesenchymal Phenotypes: Implications for Treatment of Fibrotic Diseases

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