Vasohibin attenuates bleomycin induced pulmonary fibrosis via inhibition of angiogenesis in mice

Xingsheng, Wang; Zhu, Hai‐Lei; Xiong, Yijun; Bi, Yutian; She-huai, Cui

doi:10.3109/00313025.2010.493864

Cited by 18 publications

(13 citation statements)

References 36 publications

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“…The intratracheal instillation of BLM into rodents is widely used as an in vivo experimental model for the study of human pulmonary fibrosis. Emerging evidence has demonstrated that angiogenesis is important in the development and progression of pulmonary fibrosis [8,9,11,13]. In the present study, endostatin was administered at different phases of BLM-induced lung injury and fibrosis in rats.…”

Section: Discussionmentioning

confidence: 90%

“…Turner-Warwick [41] originally demonstrated the existence of morphologic neovascularisation in the lungs of IPF patients. Further evidence also strongly suggests a role for angiogenic vascular remodelling in pulmonary fibrosis, and emerging studies indicate that angiogenesis is a central hallmark for the progression of IPF [13,42]. Angiogenesis is regulated by a balance between the angiogenic and angiostatic regulators of blood vessel growth.…”

Section: Discussionmentioning

confidence: 99%

“…Although the aetiology remains unknown, aberrant angiogenesis plays an important role in the development of pulmonary fibrosis. Many studies have demonstrated that the inhibition of vascular remodelling attenuates pulmonary fibrosis in animal models [7-13]. …”

Section: Introductionmentioning

confidence: 99%

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Endostatin, an angiogenesis inhibitor, ameliorates bleomycin-induced pulmonary fibrosis in rats

et al. 2013

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BackgroundRecent evidence has demonstrated the role of angiogenesis in the pathogenesis of pulmonary fibrosis. Endostatin, a proteolytic fragment of collagen XVIII, is a potent inhibitor of angiogenesis. The aim of our study was to assess whether endostatin has beneficial effects on bleomycin (BLM)-induced pulmonary fibrosis in rats.MethodsThe rats were randomly divided into five experimental groups: (A) saline only, (B) BLM only, (C) BLM plus early endostatin treatment, (D) BLM plus late endostatin treatment, and (F) BLM plus whole-course endostatin treatment. We investigated the microvascular density (MVD), inflammatory response and alveolar epithelial cell apoptosis in rat lungs in each group at different phases of disease development.ResultsEarly endostatin administration attenuated fibrotic changes in BLM-induced pulmonary fibrosis in rats. Endostatin treatment decreased MVD by inhibiting the expression of VEGF/VEGFR-2 (Flk-1) and the activation of extracellular signal-regulated protein kinase 1/2 (ERK1/2). Endostatin treatment also decreased the number of inflammatory cells infiltrating the bronchoalveolar lavage fluid during the early inflammatory phase of BLM-induced pulmonary fibrosis. In addition, the levels of tumour necrosis factor-α (TNF-α) and transforming growth factor β1 (TGF-β1) were reduced by endostatin treatment. Furthermore, endostatin decreased alveolar type II cell apoptosis and had an epithelium-protective effect. These might be the mechanism underlying the preventive effect of endostatin on pulmonary fibrosis.ConclusionsOur findings suggest that endostatin treatment inhibits the increased MVD, inflammation and alveolar epithelial cell apoptosis, consequently ameliorating BLM-induced pulmonary fibrosis in rats.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

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Endostatin, an angiogenesis inhibitor, ameliorates bleomycin-induced pulmonary fibrosis in rats

et al. 2013

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“…Accumulating evidences indicate that antiangiogenesis therapy may be a promising treatment option for pulmonary fibrosis. 38,39,57 Notably, nintedanib, a triple angiokinase inhibitor (VEGFR, platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor (FGFR)), recently became the first approved drug for IPF treatment. 58 Therefore, our current data collectively indicate that DDR2 control of lung myofibroblast behaviors could produce impacts on both angiogenic and fibrotic processes.…”

Section: Discussionmentioning

confidence: 99%

Targeting of Discoidin Domain Receptor 2 (DDR2) Prevents Myofibroblast Activation and Neovessel Formation During Pulmonary Fibrosis

Zhao

Bian

et al. 2016

Molecular Therapy

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Idiopathic pulmonary fibrosis (IPF) is a lethal human disease with short survival time and few treatment options. Herein, we demonstrated that discoidin domain receptor 2 (DDR2), a receptor tyrosine kinase that predominantly transduces signals from fibrillar collagens, plays a critical role in the induction of fibrosis and angiogenesis in the lung. In vitro cell studies showed that DDR2 can synergize the actions of both transforming growth factor (TGF)-β and fibrillar collagen to stimulate lung fibroblasts to undergo myofibroblastic changes and vascular endothelial growth factor (VEGF) expression. In addition, we confirmed that late treatment of the injured mice with specific siRNA against DDR2 or its kinase inhibitor exhibited therapeutic efficacy against lung fibrosis. Thus, this study not only elucidated novel mechanisms by which DDR2 controls the development of pulmonary fibrosis, but also provided candidate target for the intervention of this stubborn disease.

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“…Burdick et al elegantly demonstrated that in the bleomycin model, the balance of pro- versus anti-angiogenic factors appears to favor angiogenesis, and inhibition of angiogenesis through administration of CXCL11 for the first twelve days following bleomycin administration attenuated fibrosis (39). Similar fibrosis attenuation has been accomplished in the bleomycin model using VEGFR2 antagonists and vasohibin, both of which target angiogenesis (40, 41). While these studies suggest that angiogenesis may be pathogenic in the development of fibrosis, we propose a more overarching hypothesis that physiologic angiogenesis is a critical component of normal repair following acute inflammatory lung injury.…”

Section: Discussionmentioning

confidence: 74%

Kinetics of the angiogenic response in lung endothelium following acute inflammatory injury with bleomycin

Yunt¹,

Mohning²,

Barthel³

et al. 2014

Experimental Lung Research

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Purpose/Aim Angiogenesis is a central component of normal wound healing but it has not been fully characterized in lung repair following acute inflammatory injury. The current literature lacks vital information pertaining to the extent, timing, and location of this process. This information is necessary for examining mechanisms that drive normal lung repair in resolving acute inflammatory injury. The goal of our study was to formally characterize lung angiogenesis over a time course of bleomycin induced lung injury. Materials and Methods Female C57BL/6 mice age 8-12 weeks were treated with a single dose of intratracheal bleomycin. Total lung endothelial cells were quantified with flow cytometry 0, 7, 14, 21, and 28 days following bleomycin administration, and endothelial cell replication was assessed using bromodeoxyuridine (BrdU) incorporation. Results Endothelial cell replication was maximal 14 days after bleomycin administration, while total lung endothelial cells peaked at day 21. Tissue analysis with stereology was performed to measure total lung vascular surface area in bleomycin at day 21 relative to controls and demonstrated a trend toward increased vasculature in the bleomycin group. Conclusions Angiogenesis begins shortly after injury in the bleomycin model and leads to an expansion in the lung endothelial cell population that peaks at day 21. This study offers the first longitudinal examination of angiogenesis following acute inflammatory lung injury induced by bleomycin. Information provided in this study will be vital for further investigating mechanisms of angiogenesis in both normal and abnormal lung repair.

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Vasohibin attenuates bleomycin induced pulmonary fibrosis via inhibition of angiogenesis in mice

Cited by 18 publications

References 36 publications

Endostatin, an angiogenesis inhibitor, ameliorates bleomycin-induced pulmonary fibrosis in rats

Endostatin, an angiogenesis inhibitor, ameliorates bleomycin-induced pulmonary fibrosis in rats

Targeting of Discoidin Domain Receptor 2 (DDR2) Prevents Myofibroblast Activation and Neovessel Formation During Pulmonary Fibrosis

Kinetics of the angiogenic response in lung endothelium following acute inflammatory injury with bleomycin

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