A Novel IκB Kinase-β Inhibitor Ameliorates Bleomycin-induced Pulmonary Fibrosis in Mice

Inayama, Mami; Nishioka, Yasuhiko; Azuma, Momoyo; Muto, Shoshi; Aono, Yoshinori; Makino, Hideki; Tani, Kenji; Uehara, Hisanori; Izumi, Kiyotaka; Itai, Akiko; Sone, Saburo

doi:10.1164/rccm.200506-947oc

Cited by 66 publications

(57 citation statements)

References 27 publications

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“…The predominant mechanism of NF-B activation involves phosphorylation, ubiquitination, and degradation of inhibitors of NF-B (IB), allowing NF-B dimers to translocate to the nucleus and promote transcription of target genes (13)(14)(15). Activation of NF-B is implicated in the pathogenesis of inflammatory disorders of the lungs, including COPD (16)(17)(18). In this regard, COPD patients have increased activation of NF-B in lung macrophages and epithelial cells (16,17).…”

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confidence: 99%

Epithelial NF-κB activation promotes urethane-induced lung carcinogenesis

Stathopoulos

Sherrill

Cheng

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

182

217

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confidence: 99%

Epithelial NF-κB activation promotes urethane-induced lung carcinogenesis

Stathopoulos

Sherrill

Cheng

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

182

217

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“…Furthermore, toll-like receptor 2 activation seems to be one of the initial critical events that triggers the release of inflammatory cytokine and chemokine secretion upon BLM challenge (Razonable et al, 2006). This suggests the possibility of using molecular modulators to attenuate lung inflammation and fibrosis induced by BLM, including NF-B inhibitors (Inayama et al, 2006).…”

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confidence: 99%

3-(2,4-Dichlorophenyl)-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione (SB216763), a Glycogen Synthase Kinase-3 Inhibitor, Displays Therapeutic Properties in a Mouse Model of Pulmonary Inflammation and Fibrosis

Gurrieri

Gnoato

Montini

et al. 2009

J Pharmacol Exp Ther

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Glycogen synthase kinase (GSK)-3 modulates the production of inflammatory cytokines. Because bleomycin (BLM) causes lung injury, which is characterized by an inflammatory response followed by a fibrotic degeneration, we postulated that blocking GSK-3 activity with a specific inhibitor could affect the inflammatory and profibrotic cytokine network generated in the BLM-induced process of pulmonary inflammation and fibrosis. Thus, here we investigated the effects of the GSK-3 inhibitor 3-(2,4-dichlorophenyl)-4-(1-methyl-

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“…9,21,22) This study revealed IMD-0354 dose-dependently attenuated neointimal formation after wire-mediated arterial injury in mice. Thus, IMD-0354 has the potential to prevent restenosis in humans with fewer adverse effects compared to conservative therapies.…”

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confidence: 65%

A Novel IKK Inhibitor Prevents Progression of Restenosis After Arterial Injury in Mice

et al. 2012

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SummaryRestenosis after percutaneous coronary intervention (PCI) is still a clinically serious problem. We examined the treatment efficacy of IMD-0354, a novel IKK inhibitor, on arteriopathy. Using C57BL/6J mice, a wire-injury model was prepared and the mice were intraperitoneally injected with IMD-0354 or vehicle twice a day. The vehicle-treated injured arteries showed significantly thickened intima (3.77 ± 0.59, n = 8), however, IMD-0354 suppressed its progression (1.62 ± 0.22, n = 10, P < 0.05) on day 28. While enhanced expression of PCNA and NF-κB was observed in the untreated injured arteries, IMD-0354 significantly suppressed their expressions. Quantitative RT-PCR revealed that the expression of several inflammatory factors was reduced in the arteries from mice which received IMD-0354 treatment compared with the control animals. Thus, this drug may effectively prevent restenosis after coronary intervention and other cardiovascular diseases. (Int Heart J 2012; 53: 133-138) Key words: IKK inhibitor, Chemical compound, Arterial remodeling, Inflammation, Smooth muscle R estenosis, which consists of neointimal formation after percutaneous coronary intervention (PCI), is a clinically serious problem. 1-3) Because inflammation is an essential pathological feature of neointimal formation, nuclear factor-kappa B (NF-κB) plays an important role in this process. 4) In humans, activated NF-κB is detected in restenotic lesions.5) Thus, NF-κB regulation has the potential to suppress its progression.Activation of NF-κB induces gene expression that leads to transactivation of adhesion molecules, cytokines and chemokines, promoting the inflammatory status involved in arterial injury. NF-κB is a dimer of the Rel family members and the most common active form is composed of p50 or p52 and p65. In resting cells, NF-κB is inactive and segregated in the cytoplasm, and bound to an inhibitory protein known as the inhibitor of NF-κB (IκB). NF-κB activation requires phosphorylation of IκB by IκB kinase (IKK) complex. The phosphorylated IκB is then ubiquitinated and degraded by proteasomes. Subsequently, the unbound NF-κB is translocated to the nucleus and binds to the promoter or enhancer of specific genes, including those involved in inflammatory reactions. 6)Recently, the first clinical use of an NF-κB decoy oligonucleotide at the site of coronary stenting for the prevention of restenosis was reported. 7,8) However, the indispensable role played by NF-κB in many biological processes has raised the concern that a complete shutdown of this pathway would have significant detrimental effects on normal cellular function. Instead, drugs that selectively target only inflammation-induced NF-κB activity would be of greater therapeutic value. IMD-0354, a novel NF-κB inhibitor, is a drug that specifically suppresses IKK-β activity.9) In this study, we investigated the effects of IMD-0354 on neointimal formation in vivo and VSMC proliferation in vitro. MethodsArterial injury models in mice: Male mice (C57BL/6, age 6-8 weeks, 20-25 g; Japa...

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A Novel IκB Kinase-β Inhibitor Ameliorates Bleomycin-induced Pulmonary Fibrosis in Mice

Abstract: These results suggest that IMD-0354 might be useful to ameliorate the inflammation in the lungs induced by fibrotic injury and the subsequent fibrogenesis via inhibiting the expression of profibrotic cytokines related to the activation of NF-kappaB.

Cited by 66 publications

References 27 publications

Epithelial NF-κB activation promotes urethane-induced lung carcinogenesis

Epithelial NF-κB activation promotes urethane-induced lung carcinogenesis

3-(2,4-Dichlorophenyl)-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione (SB216763), a Glycogen Synthase Kinase-3 Inhibitor, Displays Therapeutic Properties in a Mouse Model of Pulmonary Inflammation and Fibrosis

A Novel IKK Inhibitor Prevents Progression of Restenosis After Arterial Injury in Mice

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