Effects of inhaled fluticasone on angiogenesis and vascular endothelial growth factor in asthma

Feltis, Bryce; Wignarajah, D; Reid, David W.; Ward, Chris; Harding, Richard; Walters, E. Haydn

doi:10.1136/thx.2006.069229

Cited by 74 publications

(71 citation statements)

References 19 publications

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“…Indeed, both VEGF and expression of its receptor VEGFR-2 are increased in the nasal mucosa of patients with allergic rhinitis compared to nonallergic controls [12]. Moreover, in the bronchial mucosa of asthmatic patients, the number of VEGF-positive cells is significantly increased and correlates with the vessel counts and vascular area, and expression of VEGFR-1 and VEGFR-2 inversely correlates with airway function [16][17][18][19][20]23]. VEGF levels in BALF were increased in asthma in direct proportion to vascularity [19,20].…”

Section: Discussionmentioning

confidence: 97%

“…Others have shown that bronchoalveolar lavage fluid (BALF) from asthmatic patients exhibits enhanced in vitro angiogenic activity and increased FGF-2 [21] and VEGF levels [22]; the BALF angiogenic activity is blocked by an anti-VEGF antibody [22]. In addition, VEGF levels in the BALF of asthmatic patients were increased in proportion to the vessel number in the bronchial mucosa, which, indeed, showed intense VEGF, VEGF receptor (VEGFR)-1 and VEGFR-2 (or fetal liver kinase-1/kinase insert domain receptor) staining [20].…”

mentioning

confidence: 95%

“…Indeed, major structural and functional changes in the airway microcirculation include angiogenesis, increased blood flow and microvascular permeability, and oedema formation in the airway wall [11]. Increased expression of angiogenic molecules, such as VEGF, FGF-2 and angiogenin and their receptors, has been correlated with disease severity and accelerated decline in lung function [12][13][14][15][16][17][18][19][20]. Others have shown that bronchoalveolar lavage fluid (BALF) from asthmatic patients exhibits enhanced in vitro angiogenic activity and increased FGF-2 [21] and VEGF levels [22]; the BALF angiogenic activity is blocked by an anti-VEGF antibody [22].…”

mentioning

confidence: 99%

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Anti-angiogenic activity of carebastine: a plausible mechanism affecting airway remodelling

Luisi¹,

Mangialardi²,

Ria³

et al. 2009

Eur Respir J

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Ebastine is a well-known selective second-generation histamine H 1 receptor antagonist, which is used for seasonal and perennial allergic rhinitis and chronic urticaria. Angiogenesis plays a crucial role in the development of airway inflammation and remodelling in allergic rhinitis and asthmatic patients, in whom, indeed, the mucosa displays increased vascularity and overexpression of vascular endothelial growth factor (VEGF). The aim of the present study was to evaluate the anti-angiogenic properties of carebastine, the active metabolite of ebastine.The effects of carebastine on human umbilical vein endothelial cell (EC) (HUVEC) and human pulmonary artery EC (HPAEC) proliferation, migration and capillary-like tube formation were investigated in vitro, and in the chick embryo chorioallantoic membrane (CAM) assay in vivo. Moreover, the effect of carebastine on phosphorylation of the cell VEGF receptor fetal liver kinase-1, or VEGF receptor 2 (VEGFR-2), and Akt kinase (Akt) was evaluated by Western blotting.Carebastine inhibited VEGF-induced HUVEC and HPAEC proliferation, migration and angiogenesis in a dose-dependent manner in vitro. Cell proliferation was inhibited by 42 and 64% in HUVECs and 62 and 75% in HPAECs upon exposure for 48 and 72 h, respectively, to 20 mM carebastine (pf0.03), and even more with 30 mM carebastine. Cell migration was inhibited by 37 and 70% in HUVECs (pf0.03) and 60 and 78% in HPAECs (pf0.01) in the presence of 10 and 30 mM carebastine, respectively. Carebastine (20 mM) caused a significant reduction (70-86%; p,0.01) in topological parameters of the capillary network produced in vitro by both EC lines on a basement membrane extract. Carebastine (30 and 50 mM) inhibited the VEGF-induced angiogenesis in the CAM assay in vivo two-and three-fold, respectively (p,0.001). Finally, both EC lines, on exposure to 10 and 20 mM carebastine, showed a four-to six-fold reduction (pf0.01) in both VEGF-and H 1 receptor-induced VEGFR-2 and Akt phosphorylation.Overall, these data provide the first evidence regarding the anti-angiogenic activity of ebastine, and suggest its potential use as an anti-angiogenic molecule, besides its antihistaminic activity for the treatment of allergic diseases in which angiogenesis takes place.

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Section: Discussionmentioning

confidence: 97%

mentioning

confidence: 95%

mentioning

confidence: 99%

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Anti-angiogenic activity of carebastine: a plausible mechanism affecting airway remodelling

Luisi¹,

Mangialardi²,

Ria³

et al. 2009

Eur Respir J

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“…Importantly, the biological effects of overexpressed VEGF, such as angiogenesis, were reversed by cessation of the transgenic VEGF elaboration in that murine model, suggesting that the effects of VEGF on the development of airway hypervascularity are dependent upon its expression level. In humans, ICS treatment was found to effectively reduce VEGF production in the airways, thereby reducing the submucosal vascularity (Asai et al 2002;Chetta et al 2003Chetta et al , 2005Abdel-Rahman et al 2006;Feltis et al 2007). However, it should be noted that these studies were restricted to cases of mild to moderate asthma.…”

Section: Vegf In Copdmentioning

confidence: 99%

“…Although VEGF-mediated airway hypervascularity in patients with asthma is responsive to corticosteroid treatment (Asai et al 2002;Chetta et al 2003Chetta et al , 2005Abdel-Rahman et al 2006;Feltis et al 2007), several clinical studies have also demonstrated that airway hypervascularity is seen in fatal (Wilson 2000) and severe corticosteroid-dependent asthma (Vrugt et al 2000) and even in patients treated with ICS for more than 5 years (Tanaka et al 2003). Of note, structural abnormalities of airway remodeling are present in children with severe asthma.…”

Section: Chemokines In Asthmamentioning

confidence: 99%

Pathophysiological roles of microvascular alterations in pulmonary inflammatory diseases: possible implications of tumor necrosis factor-alpha and CXC chemokines

Orihara

Matsuda²

2008

COPD

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Chronic obstructive pulmonary disease (COPD) and bronchial asthma are common respiratory diseases that are caused by chronic infl ammation of the airways. Although these diseases are mediated by substantially distinct immunological reactions, especially in mild cases, they both show increased numbers of neutrophils, increased production of tumor necrosis factor-alpha (TNF-α) and poor responses to corticosteroids, particularly in patients with severe diseases. These immunological alterations may contribute strongly to airway structural changes, commonly referred to as airway remodeling. Microvascular alterations, a component of airway remodeling and caused by chronic infl ammation, are observed and appear to be clinically involved in both diseases. It has been well established that vascular endothelial growth factor (VEGF) plays important roles in the airway microvascular alterations in mild and moderate cases of both diseases, but any role that VEGF might play in severe cases of these diseases remains unclear. Here, we review recent research fi ndings, including our own data, and discuss the possibility that TNF-α and its associated CXC chemokines play roles in microvascular alterations that are even more crucial than those of VEGF in patients with severe COPD or asthma.

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Profibrotic and Angiogenic Factors in Asthma

Berkman

Levi‐Schaffer

2011

Inflammation and Allergy Drug Design

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Effects of inhaled fluticasone on angiogenesis and vascular endothelial growth factor in asthma

Cited by 74 publications

References 19 publications

Anti-angiogenic activity of carebastine: a plausible mechanism affecting airway remodelling

Anti-angiogenic activity of carebastine: a plausible mechanism affecting airway remodelling

Pathophysiological roles of microvascular alterations in pulmonary inflammatory diseases: possible implications of tumor necrosis factor-alpha and CXC chemokines

Profibrotic and Angiogenic Factors in Asthma

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