Gefitinib Prevents Bleomycin-induced Lung Fibrosis in Mice

Ishii, Yoshiki; Fujimoto, Sakae; Fukuda, Takeshi

doi:10.1164/rccm.200509-1534oc

Cited by 100 publications

(92 citation statements)

References 31 publications

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“…In an animal model of liver fibrosis, AR expression is significantly induced, and the absence of AR markedly reduced ␣-SMA expression and collagen deposition in the liver, implicating AR contribution in the development or the progression of liver fibrosis (42). In support of this notion, the use of gefitinib, a EGFR blocker, significantly inhibits bleomycin-induced pulmonary fibrosis (22). On the other hand, Fukumoto et al (43) showed that administration of rAR suppressed bleomycin-induced pulmonary inflammation and fibrosis, suggesting a potential protective role of AR in tissue fibrosis.…”

Section: Discussionmentioning

confidence: 92%

“…Thus, overall fibrosis could be less in the ARtreated group of mice mainly due to less injury response compared with controls. In the studies done by Ishii's group (22), inhibition of EGFR signaling could have significant effects on the fibroproliferative phase, because EGFR signaling is essential for fibroblast proliferation. Although the inhibition of EGFR sig- naling may enhance the injury response, overall fibrosis can be protected due to the inhibition of fibroblast proliferation, a critical process in tissue fibrogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…TGF-␣ knock-out mice are protected from bleomycin-induced fibrosis whereas TGF-␣ over-expression in the murine lungs spontaneously induces progressive pulmonary fibrosis (20,21). The use of a selective EGFR tyrosine kinase inhibitor (Gefitinib) prevents the development of bleomycin-or TGF-␣-induced pulmonary fibrosis (22,23). These studies suggest that EGFR signaling plays an important role in the pathogenesis of pulmonary fibrosis.…”

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confidence: 97%

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Amphiregulin, an Epidermal Growth Factor Receptor Ligand, Plays an Essential Role in the Pathogenesis of Transforming Growth Factor-β-induced Pulmonary Fibrosis

Zhou

Lee

Cho

et al. 2012

Journal of Biological Chemistry

121

137

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

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confidence: 97%

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Amphiregulin, an Epidermal Growth Factor Receptor Ligand, Plays an Essential Role in the Pathogenesis of Transforming Growth Factor-β-induced Pulmonary Fibrosis

Zhou

Lee

Cho

et al. 2012

Journal of Biological Chemistry

121

137

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“…AG1478, a selective inhibitor of the EGFR tyrosine kinase (EGFR-TK), prevents ligand-induced EGFR phosphorylation and has antitumor activity [9]. AG1478 inhibits the proliferation of lung fibroblasts in vitro and has protective effects against bleomycin and vanadium pentoxide-induced pulmonary fibrosis [10,11]. Recently, we demonstrated that AG1478 prevented allergeninduced airway epithelial and airway smooth muscle remodeling mediated by cysteinyl leukotrienes in BN rats [4].…”

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confidence: 99%

EGF receptor activation during allergic sensitization affects IL‐6‐induced T‐cell influx to airways in a rat model of asthma

Tsuchiya

Takeda

et al. 2010

Eur J Immunol

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EGF receptor (EGFR) is involved in cell differentiation and proliferation in airways and may trigger cytokine production by T cells. We hypothesized that EGFR inhibition at the time of allergic sensitization may affect subsequent immune reactions. Brown Norway rats were sensitized with OVA, received the EGFR tyrosine kinase inhibitor, AG1478 from days 0 to 7 and OVA challenge on day 14. OVA-specific IgE in serum and cytokines and chemokines in BAL were measured 24 h after challenge. To evaluate effects on airway hyperresponsiveness (AHR), rats were sensitized, treated with AG1478, intranasally challenged, and then AHR was assessed. Furthermore chemotactic activity of BALF for CD4 1 T cells was examined. The eosinophils, neutrophils and lymphocytes in BAL were increased by OVA and only the lymphocytes were reduced by AG1478. OVA significantly enhanced IL-6 concentration in BAL, which was inhibited by AG1478. However AHR, OVA-specific IgE and IL-4 mRNA expression in CD4 1 T cells were not affected by AG1478. BALF from OVAsensitized/challenged rats induced CD4 1 T-cell migration, which was inhibited by both AG1478 treatment in vivo and neutralization of IL-6 in vitro. EGFR activation during sensitization may affect the subsequent influx of CD4 1 T cells to airways, mainly mediated through IL-6.Key words: Asthma . CD4 1 T cells . EGF receptors . IL-6Supporting Information available online IntroductionThe EGF receptor (EGFR) is involved in the regulation of cell differentiation and proliferation and in the pathogenesis of various diseases including epithelial tumors [1,2]. The importance of the EGFR axis in cancer has best been studied in breast malignancies. However, the EGFR signaling pathway is implicated in airway biology and EGFR is expressed by many cell types in the lung, including smooth muscle cells, endothelium, fibroblasts and epithelium [3,4]. Human asthmatic airways show increased EGFR immunoreactivity in airway epithelium, glands, and smooth muscle [5] and EGFR activation has been reported to promote epithelial repair and to induce mucin production and remodeling of airway tissues [6,7]. We previously reported that multiple OVA challenges increased protein expression of the EGFR ligand, heparin-binding EGF-like 1590growth factor (HB-EGF) in airway epithelium in Brown Norway (BN) rats [4]. The inhibition of the tyrosine kinase signaling cascade might have therapeutic effects in asthma [8].Ligands for the EGFR found in the lung include EGF, TGF-a, amphiregulin, epiregulin and HB-EGF, all of which are synthesized as transmembrane precursors and are proteolytically cleaved by metalloproteases such as ADAM 10 and ADAM 17 [3]. Binding of these ligands to the receptor causes activation of the tyrosine kinase and receptor autophosphorylation. AG1478, a selective inhibitor of the EGFR tyrosine kinase (EGFR-TK), prevents ligand-induced EGFR phosphorylation and has antitumor activity [9]. AG1478 inhibits the proliferation of lung fibroblasts in vitro and has protective effects against bleomycin and vanadium pento...

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“…This could be supportive evidence for our present case. On the contrary, another study that had a similar design, but it used three differential doses of gefitinib, showed its preventive effect on pulmonary fibrosis 15 . In addition, a recent retrospective analysis by Fujiwara et al 4 showed that all eleven patients with EGFR mutation didn't demonstrate any pulmonary toxicity with receiving gefitinib therapy.…”

Section: Discussionmentioning

confidence: 98%

Gefitinib-induced Acute Fatal Respiratory Failure in a Woman who Never Smoked and had Adenocarinoma of the Lung with EGFR Mutation

et al. 2008

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Gefitinib Prevents Bleomycin-induced Lung Fibrosis in Mice

Cited by 100 publications

References 31 publications

Amphiregulin, an Epidermal Growth Factor Receptor Ligand, Plays an Essential Role in the Pathogenesis of Transforming Growth Factor-β-induced Pulmonary Fibrosis

Amphiregulin, an Epidermal Growth Factor Receptor Ligand, Plays an Essential Role in the Pathogenesis of Transforming Growth Factor-β-induced Pulmonary Fibrosis

EGF receptor activation during allergic sensitization affects IL‐6‐induced T‐cell influx to airways in a rat model of asthma

Gefitinib-induced Acute Fatal Respiratory Failure in a Woman who Never Smoked and had Adenocarinoma of the Lung with EGFR Mutation

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