EM703 improves bleomycin-induced pulmonary fibrosis in mice by the inhibition of TGF-β signaling in lung fibroblasts

Li, Ying Ji; Azuma, Arata; Usuki, Jiro; Abe, Shinji; Matsuda, Kuniko; Sunazuka, Toshiaki; Shimizu, Takako; Hirata, Yukiyo; Inagaki, Hirofumi; Kawada, Tomoyuki; Takahashi, Satoru; Kudoh, Shoji; Ōmura, Satoshi

doi:10.1186/1465-9921-7-16

Cited by 65 publications

(53 citation statements)

References 49 publications

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“…EM703 is a derivate of erythromycin and has been reported to exhibit anti-inflammatory activity independent from anti-bacterial activity by suppressing nuclear factor-κ B and inhibiting interleukin-8 expression (Y. Li et al, 2006). Previously, 14-membered macrolides have been shown to attenuate leukocyte migration in the early inflammatory phase and thereby prevent bleomycin induced lung fibrosis (Y.…”

Section: Em703mentioning

confidence: 99%

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The bleomycin animal model: A useful tool to investigate treatment options for idiopathic pulmonary fibrosis?

Moeller

Ask

Warburton

et al. 2008

The International Journal of Biochemistry & Cell Biology

822

724

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Different animal models of pulmonary fibrosis have been developed to investigate potential therapies for idiopathic pulmonary fibrosis (IPF). The most common is the bleomycin model in rodents (mouse, rat and hamster). Over the years, numerous agents have been shown to inhibit fibrosis in this model. However, to date none of these compounds are used in the clinical management of IPF and none has shown a comparable antifibrotic effect in humans. We performed a systematic review of publications on drug efficacy studies in the bleomycin model to evaluate the value of this model regarding transferability to clinical use. Between 1980 and 2006 we identified 246 experimental studies describing beneficial antifibrotic compounds in the bleomycin model. In 221 of the studies we found enough details about the timing of drug application to allow inter-study comparison. 211 of those used a preventive regimen (drug given ≤ day 7 after last bleomycin application), only 10 were therapeutic trials (> 7 days after last bleomycin application). It is critical to distinguish between drugs interfering with the inflammatory and early fibrogenic response from those preventing progression of fibrosis, the latter likely much more meaningful for clinical application. All potential antifibrotic compounds should be evaluated in the phase of established fibrosis rather than in the early period of bleomycin-induced inflammation for assessment of its antifibrotic properties. Further care should be taken in extrapolation of drugs successfully tested in the bleomycin model due to partial reversibility of bleomycin induced fibrosis over time. The use of alternative and more robust animal models, which better reflect human IPF, is warranted.

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Section: Em703mentioning

confidence: 99%

“…The authors concluded that EM703 improves bleomycin-induced pulmonary fibrosis in mice by acting as an antiinflammatory agent and regulating TGF-β signaling (Y. Li et al, 2006).…”

Section: Em703mentioning

confidence: 99%

The bleomycin animal model: A useful tool to investigate treatment options for idiopathic pulmonary fibrosis?

Moeller

Ask

Warburton

et al. 2008

The International Journal of Biochemistry & Cell Biology

822

724

View full text Add to dashboard Cite

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“…Consistent with that interpretation, antibiotics reduce the rate of aseptic loosening [10,23] and periprosthetic inflammation [89] in patients as well as particle-induced osteolysis in mice [91]. However, those results do not conclusively support the PAMP hypothesis because antibiotics can have antiinflammatory effects that are independent of their bactericidal effects [58,61,90,94]. The PAMP hypothesis depends on the presence of these molecules, at least episodically, during aseptic loosening.…”

Section: Toll-like Receptorsmentioning

confidence: 99%

“…3) and whether the reported effects of antibiotics on aseptic loosening [10,23,89,91] are the result of bactericidal effects or the antiinflammatory effects of antibiotics that are independent of bacteria [58,61,90,94]. Further in vivo murine studies are also needed to determine (1) whether PAMPs are required for TLR activation; (2) the roles of pathogen recognition receptors other than TLR2 and TLR4; and (3) the mechanisms responsible for particle-induced osteolysis in the absence of PAMPs.…”

Section: Where Do We Need To Go?mentioning

confidence: 99%

“…Highest priority should also be given to studies to replicate the reported correlation between bacterial biofilms and the severity of aseptic loosening [98]. Side-by-side testing of antibiotics with the available structurally related molecules that lack the bactericidal effects but retain the antiinflammatory effects [58] are needed to resolve whether the results with antibiotics [10,23,89,91] provide strong support of the PAMP hypothesis.…”

Section: How Do We Get There?mentioning

confidence: 99%

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Do Genetic Susceptibility, Toll-like Receptors, and Pathogen-associated Molecular Patterns Modulate the Effects of Wear?

Greenfield

2014

Clin Orthop Relat Res

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Background Overwhelming evidence supports the concept that wear particles are the primary initiator of aseptic loosening of orthopaedic implants. It is likely, however, that other factors modulate the biologic response to wear particles. This review focuses on three potential other factors: genetic susceptibility, Toll-like receptors (TLRs), and bacterial pathogen-associated molecular patterns (PAMPs). Where Are We Now? Considerable evidence is emerging that both genetic susceptibility and TLR activation are important factors that modulate the biologic response to wear particles, but it remains controversial whether bacterial PAMPs also do so. Where Do We Need to Go? Detailed understanding of the roles of these other factors may lead to identification of novel therapeutic targets for patients with aseptic loosening. How Do We Get There? Highest priority should be given to polymorphism replication studies with large numbers of patients and studies to replicate the reported correlation between bacterial biofilms and the severity of aseptic loosening.

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Using RNA interference to identify the different roles of SMAD2 and SMAD3 in NIH/3T3 fibroblast cells

Zheng

Xiong

Zuo

et al. 2008

Cell Biochemistry & Function

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Smad proteins are principal intracellular signaling mediators of transforming growth factor beta (TGF-beta) that regulate a wide range of biological processes. However, the identities of Smad partners mediating TGF-beta signaling are not fully understood. We firstly examined the expression of Smad2 and Smad3 induced by TGF-beta 1 in normal NIH/3T3 cells. The expression of Smad2 and Smad3 was assessed by RT-PCR and Western blotting. The results showed that the expression of Smad2 was increased after treatment with TGF-betaI, but Smad3 was more sensitive to TGF-betaI than Smad2. RNA interference (RNAi) provides a new approach for elucidation of gene function. Use of hairpin siRNA expression vectors for RNAi has provided a rapid and versatile method for assessing gene function in mammalian cells. Here, we have constructed Smad2 and Smad3 hairpin siRNA expression plasmids, and then transfected them into mouse NIH/3T3 cells. Endogenous Smad2 and Smad3 proteins decreased significantly at 48 h after transfection. We found the expression of Smad3 in Smad2-depleted cells was increased, however, the expression of Smad2 in Smad3-depleted cells was not changed. Consistently, the expression of Smad4 mRNA was also attenuated in Smad3-depleted cells. From these data, we suggest that Smad3, but not Smad2, may play a key role in TGF-beta signaling.

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EM703 improves bleomycin-induced pulmonary fibrosis in mice by the inhibition of TGF-β signaling in lung fibroblasts

Cited by 65 publications

References 49 publications

The bleomycin animal model: A useful tool to investigate treatment options for idiopathic pulmonary fibrosis?

The bleomycin animal model: A useful tool to investigate treatment options for idiopathic pulmonary fibrosis?

Do Genetic Susceptibility, Toll-like Receptors, and Pathogen-associated Molecular Patterns Modulate the Effects of Wear?

Using RNA interference to identify the different roles of SMAD2 and SMAD3 in NIH/3T3 fibroblast cells

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