Suramin Inhibits the Development and Progression of Peritoneal Fibrosis

Xiong, Chengliang; Liu, Na; Lü, Fang; Zhuang, Songlin; H, Yan

doi:10.1124/jpet.114.215228

Cited by 23 publications

(31 citation statements)

References 45 publications

(43 reference statements)

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“…48 Briefly, peritoneal fibrosis in rats was generated by daily intraperitoneal injection of 0.1% CG. Control rats were injected with an equal volume of 0.9% saline.…”

Section: Establishment Of Rat Peritoneal Fibrosis Models and Gefitinimentioning

confidence: 99%

“…48 The densitometry analysis of immunoblot results was conducted using ImageJ software (National Institutes of Health, Bethesda, MD).…”

Section: Immunoblot Analysismentioning

confidence: 99%

“…48 For quantitative assessment, the positive staining area was measured by Image Pro-Plus software, and the average ratio to each microscopic field (original magnification, 3200) was calculated and graphed. Immunofluorescent staining was carried out according to the procedure described in our previous studies.…”

Section: Immunohistochemical Stainingmentioning

confidence: 99%

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Inhibition of EGF Receptor Blocks the Development and Progression of Peritoneal Fibrosis

Wang

Liu

Xiong

et al. 2015

JASN

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Inhibitors of EGF receptor (EGFR) have antifibrotic effects in several organs, but the effect of these inhibitors on the development of peritoneal fibrosis is unknown. Here, we explored the therapeutic effect of gefitinib, a specific inhibitor of EGFR, on the development and progression of peritoneal fibrosis in a rat model. Daily intraperitoneal injections of chlorhexidine gluconate induced peritoneal fibrosis, indicated by thickening of the submesothelial area with an accumulation of collagen fibrils and activation of myofibroblasts, accompanied by time-dependent phosphorylation of EGFR. Administration of gefitinib immediately after injury prevented the onset of peritoneal fibrosis and delayed administration after the onset of peritoneal fibrosis halted fibrosis progression. Gefitinib treatment abrogated the increased phosphorylation of EGFR, Smad3, signal transducer and activator of transcription 3, and NF-kB during peritoneal fibrosis; it also inhibited the accompanying overproduction of TGF-b1 and proinflammatory cytokines and the infiltration of macrophages to the injured peritoneum. Moreover, gefitinib significantly reduced the peritoneal increase of CD31-positive blood vessels and vascular EGF-positive cells after injury. Finally, gefitinib also attenuated high glucoseinduced peritoneal fibrosis in rats and abrogated TGF-b1-induced phosphorylation of Smad3 and the epithelial-to-mesenchymal transition of cultured human peritoneal mesothelial cells. These results demonstrate that EGFR contributes to peritoneal fibrosis, inflammation, and angiogenesis, suggesting that EGFR inhibitors may have therapeutic potential in attenuating peritoneal fibrosis.

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“…48 Briefly, peritoneal fibrosis in rats was generated by daily intraperitoneal injection of 0.1% CG. Control rats were injected with an equal volume of 0.9% saline.…”

Section: Establishment Of Rat Peritoneal Fibrosis Models and Gefitinimentioning

confidence: 99%

“…48 The densitometry analysis of immunoblot results was conducted using ImageJ software (National Institutes of Health, Bethesda, MD).…”

Section: Immunoblot Analysismentioning

confidence: 99%

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Inhibition of EGF Receptor Blocks the Development and Progression of Peritoneal Fibrosis

Wang

Liu

Xiong

et al. 2015

JASN

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“…Two antineoplastic drugs, suramin and FDA-approved imatinib mesylate (Gleevec®), have been shown to act as TFG-β antagonists in several chronic fibrotic diseases including kidney disease 93 , myocarditis 94 , and liver disease 95 . Intraperitoneal injection of suramin in 6-month old mdx mice has been shown to increase MMP-2 and MMP-9 activity 96 , decrease creatine kinase, and to attenuate fibrosis in skeletal muscle, but not cardiac muscle 97 .…”

Section: Drugs Targeting Fibrosismentioning

confidence: 99%

Pharmacological therapeutics targeting the secondary defects and downstream pathology of Duchenne muscular dystrophy

Spinazzola

Kunkel

2016

Expert Opinion on Orphan Drugs

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Introduction Since the identification of the dystrophin gene in 1986, a cure for Duchenne muscular dystrophy (DMD) has yet to be discovered. Presently, there are a number of genetic-based therapies in development aimed at restoration and/or repair of the primary defect. However, growing understanding of the pathophysiological consequences of dystrophin absence has revealed several promising downstream targets for the development of therapeutics. Areas covered In this review, we discuss various strategies for DMD therapy targeting downstream consequences of dystrophin absence including loss of muscle mass, inflammation, fibrosis, calcium overload, oxidative stress, and ischemia. The rationale of each approach and the efficacy of drugs in preclinical and clinical studies are discussed. Expert opinion For the last 30 years, effective DMD drug therapy has been limited to corticosteroids, which are associated with a number of negative side effects. Our knowledge of the consequences of dystrophin absence that contribute to DMD pathology has revealed several potential therapeutic targets. Some of these approaches may have potential to improve or slow disease progression independently or in combination with genetic-based approaches. The applicability of these pharmacological therapies to DMD patients irrespective of their genetic mutation, as well as the potential benefits even for advanced stage patients warrants their continued investigation.

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“…The main components of ECM are fibronectin and type I collagen [22]. In addition to ECM accumulation, fibroblast activation is also suggested to be one of the main mechanisms of peritoneal fibrosis [23]. Fibroblast activation is characterized by α-SMA expression.…”

Section: Discussionmentioning

confidence: 99%

Itraconazole Attenuates Peritoneal Fibrosis Through Its Effect on the Sonic Hedgehog Signaling Pathway in Mice

et al. 2018

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Background: Peritoneal fibrosis is a devastating complication of peritoneal dialysis. However, its precise mechanism is unclear, and specific treatments have not yet been established. Recent evidence suggests that the sonic hedgehog (SHH) signaling pathway is involved in tissue fibrogenesis. Drugs that inhibit this pathway are emerging in the field of anti-fibrosis therapy. Itraconazole, an anti-fungal agent, was also recently recognized as an inhibitor of the SHH signaling pathway. In this study, we used a mouse model to investigate whether the SHH signaling pathway is involved in the development of peritoneal fibrosis and the effects of itraconazole on peritoneal fibrosis. Methods: Peritoneal fibrosis was induced by intraperitoneal (IP) injection of 0.1% chlorhexidine gluconate (CG) solution every other day for 4 weeks, with or without itraconazole treatment (20 mg/kg, IP injection on a daily basis). Male C57BL/6 mice were divided into 4 groups: saline group, saline plus itraconazole group, CG group, and CG plus itraconazole group. Isotonic saline was administered intraperitoneally to the control group. The peritoneal tissues were evaluated for histological changes, expression of fibrosis markers, and the main components of the SHH signaling pathway. Results: Peritoneal thickening was evident in the CG group and was significantly decreased by itraconazole administration (80.4 ± 7.7 vs. 28.2 ± 3.8 µm, p < 0.001). The expression of the following SHH signaling pathway components was upregulated in the CG group and suppressed by itraconazole treatment: SHH, patched, smoothened, and glioma-associated oncogene transcription factor 1. The IP injection of CG solution increased the expression of fibrosis markers such as α-smooth muscle actin and transforming growth factor-β1 in the peritoneal tissues. Itraconazole treatment significantly decreased the expression of these markers. Conclusion: Our study provides the first evidence that the SHH signaling pathway may be implicated in peritoneal fibrosis. It also demonstrates that itraconazole treatment has protective effects on peritoneal fibrosis through the regulation of the SHH signaling pathway. These findings suggest that blockage of the SHH signaling pathway is a potential therapeutic strategy for peritoneal fibrosis.

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Suramin Inhibits the Development and Progression of Peritoneal Fibrosis

Cited by 23 publications

References 45 publications

Inhibition of EGF Receptor Blocks the Development and Progression of Peritoneal Fibrosis

Inhibition of EGF Receptor Blocks the Development and Progression of Peritoneal Fibrosis

Pharmacological therapeutics targeting the secondary defects and downstream pathology of Duchenne muscular dystrophy

Itraconazole Attenuates Peritoneal Fibrosis Through Its Effect on the Sonic Hedgehog Signaling Pathway in Mice

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