Antisense oligonucleotide inhibition of Heat Shock Protein (HSP) 47 improves bleomycin-induced pulmonary fibrosis in rats

Hagiwara, Satoshi; Iwasaka, Hideo; Matsumoto, Shigekiyo; Noguchi, Takayuki

doi:10.1186/1465-9921-8-37

Cited by 34 publications

(25 citation statements)

References 29 publications

(25 reference statements)

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“…Therefore, TNF‐α has served as a candidate target for IPF treatment. Although systemic administration of anti‐TNF‐α Ab or soluble receptor in an animal model and an IPF patient resulted in sustained improvement , subcutaneous administration of etanercept did not bring about significant differences in the predefined endpoints among IPF patients who received etanercept or placebo . There were also studies that determined the risks of complications associated with the systemic immunosuppressive effects of systemic anti‐TNF‐α protein drug treatment, including granulomatous infections, bacterial infections, granulomatous disease, pulmonary nodules, interstitial pneumonitis, methotrexate pneumonitis and autoimmune disease .…”

Section: Discussionmentioning

confidence: 99%

Locally instilled tumor necrosis factor α antisense oligonucleotide contributes to inhibition of T_H2‐driven pulmonary fibrosis via induced CD4⁺CD25⁺Foxp3⁺ regulatory T cells

Luo

Wang

Pang

et al. 2013

The Journal of Gene Medicine

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These findings demonstrate that local administration of tumor necrosis factor α antisense oligonucleotide contributes to anti-fibrotic action via a sustained up-regulated level of regulatory T cells, which inhibits T(H)2-biased responses, pro-fibrotic mediator production and extracellular matrix deposition, with no systemic immunosupression associated with systemically induced regulatory T cells.

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Section: Discussionmentioning

confidence: 99%

Locally instilled tumor necrosis factor α antisense oligonucleotide contributes to inhibition of T_H2‐driven pulmonary fibrosis via induced CD4⁺CD25⁺Foxp3⁺ regulatory T cells

Luo

Wang

Pang

et al. 2013

The Journal of Gene Medicine

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“…This abnormal process of fibrosis is responsible for the pulmonary dysfunction associated with IPF. Supporting this idea, genetic inhibition of neutrophil elastase, of the TGF-␤1-dependent signal transduction pathway, or of collagen synthesis was reported to suppress the progress of bleomycin-induced pulmonary fibrosis (5,9,14,52). However, it is not clear whether pharmacological inhibition of these factors can improve the prognosis for IPF in humans.…”

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confidence: 90%

Therapeutic effect of lecithinized superoxide dismutase on bleomycin-induced pulmonary fibrosis

Tanaka

Ishihara

Azuma

et al. 2010

American Journal of Physiology-Lung Cellular and Molecular Phys

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Idiopathic pulmonary fibrosis (IPF) is thought to involve inflammatory infiltration of leukocytes, lung injury induced by reactive oxygen species (ROS), in particular superoxide anion, and fibrosis (collagen deposition). No treatment has been shown to improve definitively the prognosis for IPF patients. Superoxide dismutase (SOD) catalyzes the dismutation of superoxide anion to hydrogen peroxide, which is subsequently detoxified by catalase. Lecithinized SOD (PC-SOD) has overcome clinical limitations of SOD, including low tissue affinity and low stability in plasma. In this study, we examined the effect of PC-SOD on bleomycin-induced pulmonary fibrosis. Severity of the bleomycin-induced fibrosis in mice was assessed by various methods, including determination of hydroxyproline levels in lung tissue. Intravenous administration of PC-SOD suppressed the bleomycin-induced increase in the number of leukocytes in bronchoalveolar lavage fluid. Bleomycin-induced collagen deposition and increased hydroxyproline levels in the lung were also suppressed in animals treated with PC-SOD, suggesting that PC-SOD suppresses bleomycin-induced pulmonary fibrosis. The dose-response profile of PC-SOD was bell-shaped, but concurrent administration of catalase restored the ameliorative effect at high doses of PC-SOD. Intratracheal administration or inhalation of PC-SOD also attenuated the bleomycin-induced inflammatory response and fibrosis. The bell-shaped dose-response profile of PC-SOD was not observed for these routes of administration. We consider that, compared with intravenous administration, inhalation of PC-SOD may be a more therapeutically beneficial route of administration due to the higher safety and quality of life of the patient treated with this drug.

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“…Several therapeutic approaches have been used in order to suppress HSP47 signalling. Among them, antisense oligodeoxynucleotides (ODN) have been widely used for the suppression of the HSP47 gene in various animal models, such as wound healing, peritoneal fibrosis, pulmonary fibrosis, and anti-Thy-1.1-induced glomerulonephritis [30,31,32,33,34]; however, antisense ODN as a therapeutic tool has limitations, such as a short half-life and nonspecific activity. Recently, instead of ODN, RNA interference mediated by small interfering RNA (siRNA) was introduced as a powerful tool for silencing the gene expression [35,36,37,38].…”

Section: Introductionmentioning

confidence: 99%

Suppression of Renal Tubulointerstitial Fibrosis by Small Interfering RNA Targeting Heat Shock Protein 47

Xia¹,

Abe²,

Furusu³

et al. 2007

Am J Nephrol

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Background/Aim: Unilateral ureteral obstruction (UUO) is a well-established model for tubulointerstitial fibrosis. During the progression of tubulointerstitial fibrosis, upregulation of collagen synthesis and subsequent accumulation of collagen were observed in the tubulointerstitial area. Heat shock protein 47 (HSP47) is a collagen-specific molecular chaperone and plays an essential role in regulating collagen synthesis. We designed small interfering RNA (siRNA) sequences for HSP47 mRNA to examine whether HSP47 is involved in the progression of renal tubulointerstitial fibrosis in a mouse UUO model. Methods: The HSP47 siRNA was injected once via the ureter at the time of UUO preparation. We also applied a new gene delivery system for siRNA using cationized gelatin microspheres. The kidneys were harvested 7 and 14 days after UUO. The HSP47 and type I, III, and IV collagen expression levels were analyzed by immunohistochemistry and Western blotting. Results: Seven days after UUO, the expression levels of HSP47 and type I, III, and IV collagens were markedly upregulated in obstructed kidneys or green fluorescent protein siRNA treated obstructed kidneys. HSP47 siRNA injection significantly reduced the protein expression levels and significantly diminished the accompanying interstitial fibrosis. Moreover, cationized gelatin microspheres as a delivery system enhanced and lengthened the antifibrotic effect of HSP47 siRNA. Conclusions: Our results indicate that HSP47 is a candidate target for the prevention of tubulointerstitial fibrosis and that selective blockade of the HSP47 expression by using siRNA could be a potentially useful therapeutic approach for patients with renal disease.

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Antisense oligonucleotide inhibition of Heat Shock Protein (HSP) 47 improves bleomycin-induced pulmonary fibrosis in rats

Cited by 34 publications

References 29 publications

Locally instilled tumor necrosis factor α antisense oligonucleotide contributes to inhibition of T_H2‐driven pulmonary fibrosis via induced CD4⁺CD25⁺Foxp3⁺ regulatory T cells

Locally instilled tumor necrosis factor α antisense oligonucleotide contributes to inhibition of T_H2‐driven pulmonary fibrosis via induced CD4⁺CD25⁺Foxp3⁺ regulatory T cells

Therapeutic effect of lecithinized superoxide dismutase on bleomycin-induced pulmonary fibrosis

Suppression of Renal Tubulointerstitial Fibrosis by Small Interfering RNA Targeting Heat Shock Protein 47

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Antisense oligonucleotide inhibition of Heat Shock Protein (HSP) 47 improves bleomycin-induced pulmonary fibrosis in rats

Cited by 34 publications

References 29 publications

Locally instilled tumor necrosis factor α antisense oligonucleotide contributes to inhibition of TH2‐driven pulmonary fibrosis via induced CD4+CD25+Foxp3+ regulatory T cells

Locally instilled tumor necrosis factor α antisense oligonucleotide contributes to inhibition of TH2‐driven pulmonary fibrosis via induced CD4+CD25+Foxp3+ regulatory T cells

Therapeutic effect of lecithinized superoxide dismutase on bleomycin-induced pulmonary fibrosis

Suppression of Renal Tubulointerstitial Fibrosis by Small Interfering RNA Targeting Heat Shock Protein 47

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Locally instilled tumor necrosis factor α antisense oligonucleotide contributes to inhibition of T_H2‐driven pulmonary fibrosis via induced CD4⁺CD25⁺Foxp3⁺ regulatory T cells

Locally instilled tumor necrosis factor α antisense oligonucleotide contributes to inhibition of T_H2‐driven pulmonary fibrosis via induced CD4⁺CD25⁺Foxp3⁺ regulatory T cells