VEGFR-2 antagonist SU5416 attenuates bleomycin-induced pulmonary fibrosis in mice

Ou, Xuemei; Li, Wancheng; Liu, Daishun; Li, Yanping; Wen, Fuqiang; Feng, Yu; Zhang, Shangfu; Huang, Xuanping; Wang, Tao; Wang, Ke; Wang, Xun; Chen, Lei

doi:10.1016/j.intimp.2008.10.002

Cited by 59 publications

(40 citation statements)

References 46 publications

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“…Our findings contrast with two previous reports that suggest that statins could ameliorate bleomycin-induced lung injury (10,37). These studies differ in the type of statin and the dose of bleomycin used (Ou and coworkers used simvastatin and instilled bleomycin 15-to 20-fold higher [0.3 U/10 g] than standard dosing for such experiments) (37), and in the timing of statin administration (Kim and coworkers administered pravastatin coincident with bleomycin instillation) (10).…”

Section: Discussioncontrasting

confidence: 99%

“…These studies differ in the type of statin and the dose of bleomycin used (Ou and coworkers used simvastatin and instilled bleomycin 15-to 20-fold higher [0.3 U/10 g] than standard dosing for such experiments) (37), and in the timing of statin administration (Kim and coworkers administered pravastatin coincident with bleomycin instillation) (10). Importantly, it should be noted that pravastatin alone did not enhance NLRP3 inflammasome activation in vitro or aggravate the lung injury in vivo, in the absence of proinflammatory challenge.…”

Section: Discussionmentioning

confidence: 99%

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Statins and Pulmonary Fibrosis

Washko

Nakahira

et al. 2012

Am J Respir Crit Care Med

123

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Rationale: The role of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) in the development or progression of interstitial lung disease (ILD) is controversial. Objectives: To evaluate the association between statin use and ILD. Methods: We used regression analyses to evaluate the association between statin use and interstitial lung abnormalities (ILA) in a large cohort of smokers from COPDGene. Next, we evaluated the effect of statin pretreatment on bleomycin-induced fibrosis in mice and explored the mechanism behind these observations in vitro. Measurements and Main Results: In COPDGene, 38% of subjects with ILA were taking statins compared with 27% of subjects without ILA. Statin use was positively associated in ILA (odds ratio, 1.60; 95% confidence interval, 1.03-2.50; P ¼ 0.04) after adjustment for covariates including a history of high cholesterol or coronary artery disease. This association was modified by the hydrophilicity of statin and the age of the subject. Next, we demonstrate that statin administration aggravates lung injury and fibrosis in bleomycin-treated mice. Statin pretreatment enhances caspase-1-mediated immune responses in vivo and in vitro; the latter responses were abolished in bone marrow-derived macrophages isolated from Nlrp3 2/2 and Casp1 2/2 mice. Finally, we provide further insights by demonstrating that statins enhance NLRP3-inflammasome activation by increasing mitochondrial reactive oxygen species generation in macrophages. Conclusions: Statin use is associated with ILA among smokers in the COPDGene study and enhances bleomycin-induced lung inflammation and fibrosis in the mouse through a mechanism involving enhanced NLRP3-inflammasome activation. Our findings suggest that statins may influence the susceptibility to, or progression of, ILD. Clinical trial registered with www.clinicaltrials.gov (NCT 00608764).

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Statins and Pulmonary Fibrosis

Washko

Nakahira

et al. 2012

Am J Respir Crit Care Med

123

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“…Zhao et al (48) have also demonstrated that Smad3 deficiency attenuates bleomycin-induced PF in mice. In the present study, OM treatment effectively inhibited the expression of TGF-β1 and the BLM-activated Smad2 and Smad3, which is consistent with previous studies showing that amelioration of fibrosis is often associated with the inhibition of the TGF-β/Smad signaling pathway (49)(50)(51)(52). Moreover, our results are also in agreement with the findings of Wu et al (15) who found that OM has antifibrotic effects in the liver via the inhibition of the TGF-β/Smad pathway (15).…”

Section: Discussionsupporting

confidence: 93%

Oxymatrine attenuates bleomycin-induced pulmonary fibrosis in mice via the inhibition of inducible nitric oxide synthase expression and the TGF-β/Smad signaling pathway

Liu

Lü

et al. 2012

Int J Mol Med

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Abstract. Oxymatrine (OM) is an alkaloid extracted from the Chinese herb Sophora flavescens Ait. with a variety of pharmacological activities. The aim of this study was to investigate the preventive effects of OM on bleomycin (BLM)-induced pulmonary fibrosis (PF) and to further explore the underlying mechanisms. C57BL/6 mice were randomly assigned to five groups: the saline sham group; the BLM group, in which mice were endotracheally instilled with BLM (3.0 mg/kg); and the BLM plus OM groups, in which OM was given to mice daily (10, 20 or 40 mg/kg) one day after BLM instillation for 21 days. The bronchoalveolar lavage fluid (BALF) and lung tissues were collected at 15 and 22 days post BLM administration, respectively. Lung tissues were stained with hematoxylin and eosin (H&E) for histological evaluation. Levels of tumor necrosis factor (TNF)-α, interleukin-6 (IL-6) and nitric oxide (NO) in mouse BALF were measured, as well as myeloperoxidase (MPO) activity and malondialdehyde (MDA) content in lung homogenates. The inducible nitric oxide synthase (iNOS) expression in the lung tissues was determined by immunohistochemical staining, quantitative real-time PCR and western blot analysis. Moreover, the expression of transforming growth factor (TGF)-β1, Smad2, Smad3, p-Smad2 and p-Smad3 were also detected. We found that OM improved BLM-induced lung pathological changes, inhibited MPO activity and reduced MDA levels in a dose-dependent manner. OM also dose-dependently inhibited the release of TNF-α and IL-6, and decreased the expression of iNOS in lung tissues and thus prevented NO release in response to BLM challenge. In addition, OM decreased the expression of TGF-β1, p-Smad2 and p-Smad3, which are all important members of the TGF-β/ Smad signaling pathway. Our study provides evidence that OM significantly ameliorated BLM-induced PF in mice via the inhibition of iNOS expression and the TGF-β/Smad pathway.

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“…In contrast, previous studies using various approaches, including small molecule inhibitors, to inhibit angiogenesis in general and VEGF signaling in particular reported reduced pulmonary fibrosis (28)(29)(30). It is important to mention that the time point of VEGF inhibition in these studies is restricted to the early event of initial pulmonary injury or VEGF inhibition is more broadly enacted beyond the inhibition of angiogenesis.…”

Section: Discussionmentioning

confidence: 93%

“…In other studies using thalidomide (30) or the VEGFR2 inhibitor SU5416 (29) to ameliorate pulmonary fibrosis, not only angiogenesis but the infiltration of myeloid cells, and therefore the release of various inflammatory and profibrogenic cytokines by these cells, was markedly inhibited. Therefore, these results might be at least partially biased by abrogating the inflammatory phase during the development of pulmonary fibrosis.…”

Section: Discussionmentioning

confidence: 96%

Loss of myeloid cell-derived vascular endothelial growth factor accelerates fibrosis

Stockmann

Kerdiles

Nomaksteinsky

et al. 2010

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

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Tissue injury initiates a complex series of events that act to restore structure and physiological homeostasis. Infiltration of inflammatory cells and vascular remodeling are both keystones of this process. However, the role of inflammation and angiogenesis in general and, more specifically, the significance of inflammatory cell-derived VEGF in this context are unclear. To determine the role of inflammatory cell-derived VEGF in a clinically relevant and chronically inflamed injury, pulmonary fibrosis, we deleted the VEGF-A gene in myeloid cells. In a model of pulmonary fibrosis in mice, deletion of VEGF in myeloid cells resulted in significantly reduced formation of blood vessels; however, it causes aggravated fibrotic tissue damage. This was accompanied by a pronounced decrease in epithelial cell survival and a striking increase in myofibroblast invasion. The drastic increase in fibrosis following loss of myeloid VEGF in the damaged lungs was also marked by increased levels of hypoxia-inducible factor (HIF) expression and Wnt/β-catenin signaling. This demonstrates that the process of angiogenesis, driven by myeloid cell-derived VEGF, is essential for the prevention of fibrotic damage.

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VEGFR-2 antagonist SU5416 attenuates bleomycin-induced pulmonary fibrosis in mice

Cited by 59 publications

References 46 publications

Statins and Pulmonary Fibrosis

Statins and Pulmonary Fibrosis

Oxymatrine attenuates bleomycin-induced pulmonary fibrosis in mice via the inhibition of inducible nitric oxide synthase expression and the TGF-β/Smad signaling pathway

Loss of myeloid cell-derived vascular endothelial growth factor accelerates fibrosis

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