Angiogenesis In Asthma Research Articles

Role of Matrix Metalloproteinases in Angiogenesis and Its Implications in Asthma.

Asthma is a chronic airway disorder associated with aberrant inflammatory and remodeling responses. Angiogenesis and associated vascular remodeling are one of the pathological hallmarks of asthma. The mechanisms underlying angiogenesis in asthmatic airways and its clinical relevance represent a relatively nascent field in asthma when compared to other airway remodeling features. Matrix metalloproteinases (MMPs) are proteases that play an important role in both physiological and pathological conditions. In addition to facilitating extracellular matrix turnover, these proteolytic enzymes cleave bioactive molecules, thereby regulating cell signaling. MMPs have been implicated in the pathogenesis of asthma by interacting with both the airway inflammatory cells and the resident structural cells. MMPs also cover a broad range of angiogenic functions, from the degradation of the vascular basement membrane and extracellular matrix remodeling to the release of a variety of angiogenic mediators and growth factors. This review focuses on the contribution of MMPs and the regulatory role exerted by them in angiogenesis and vascular remodeling in asthma as well as addresses their potential as therapeutic targets in ameliorating angiogenesis in asthma.

Experimental research The effects of budesonide on angiogenesis in a murine asthma model

IntroductionThe aim of this study is to determine the effects and mechanisms of budesonide on angiogenesis in a murine asthma model.Material and methodsMurine asthma models were established and mice were divided into three groups: the model group (OVA-sensitized and challenged mice), the BUD group (budesonide-treated mice) and the PBS group (normal control mice). Mice in the BUD group were administered with inhaled budesonide (100 µg/kg) daily. The effects on airway inflammation, angiogenesis, expression of hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) were examined.ResultsAdministration of budesonide ameliorated allergic airway inflammation (2.90 ±0.18 vs. 4.80 ±0.20, p < 0.01) and significantly reduced the percentage vascularity (0.78 ±0.14 vs. 2.83 ±0.90, p < 0.01) compared with those in the asthmatic model mice. It also reduced the expression of HIF-1α (immunohistochemistry results: 71.70 ±1.40 vs. 89.60 ±0.79, p < 0.001; western blotting results: 0.88 ±0.41 vs. 0.97 ±0.47, p < 0.05), as well as that of VEGF (immunohistochemistry results: 26.30 ±1.03 vs. 93.30 ±1.54, p < 0.001; western blotting results: 1.12 ±0.22 vs. 2.08 ±0.30, p < 0.01). Percentage vascularity had positive correlation with both HIF-1α (r = 0.785, p < 0.01) and VEGF (r = 0.693, p < 0.01) expression. Furthermore, there is positive relationship between HIF-1α and VEGF expression (r = 0.641, p < 0.05).ConclusionsThe results demonstrate that budesonide has an important inhibitory effect on angiogenesis in asthma. Inhaled administration of budesonide achieved anti-angiogenic activity through inhibition of HIF-1α and VEGF expression. The results support a potential anti-remodeling role for budesonide in the treatment of human asthma.

Angiogenesis in asthma: Altered angiogenic potential of bronchial smooth muscle cells of asthmatic patients

Aims: Airway remodeling, a key pathology in asthma, includes thickening of the airway wall, hypertrophy and hyperplasia of bronchial smooth muscle cells (BSMC), and increased vascularity. BSMC are known to produce angiogenic factors.

Increased vascular density is a persistent feature of airway remodeling in a sheep model of chronic asthma

ABSTRACTBackground: Increases in blood vessel density and vascular area are now recognized as important features of remodeled airways in asthma. However, the time sequence for these vascular changes and whether they resolve in the absence of continued antigenic exposure is not well elucidated. The aim of the present study was to correlate progressive changes in airway vascularity with changes in functional airway responses in sheep chronically challenged with house dust mite (HDM) allergen, and to examine the resolution of vascular remodeling following allergen withdrawal. Methods: Progressive changes in vascular indices were examined in four spatially separate lung segments that received weekly challenges with HDM allergen for 0, 8, 16, or 24 weeks. Reversibility of these changes was assessed in a separate experiment in which two lung segments received 24 weeks of HDM challenges and either no rest or 12 weeks rest. Lung tissue was collected from each segment 7 days following the final challenge and vascular changes assessed by a morphometric analysis of airways immunohistochemically stained with an antibody against type IV collagen. Results: Blood vessel density and percent airway vascularity were significantly increased in bronchi following 24 weeks of HDM challenges compared to untreated controls (P < .05), but not at any of the other time-points. There was no significant correlation between vascular indices and airway responses to allergic or nonspecific stimuli. The increase in blood vessel density induced by repeated allergen exposures did not return to baseline levels following a 12-week withdrawal period from allergen. Conclusions: Our results show for the first time that the airways of sheep chronically exposed to HDM allergen undergo vascular remodeling. These findings show the potential of this large animal model for investigating airway angiogenesis in asthma.

T-helper cell type 2 (Th2) memory T cell-potentiating cytokine IL-25 has the potential to promote angiogenesis in asthma

IL-25 (IL-17E) is a T-helper cell type 2 (Th2) cytokine best described as a potentiator of Th2 memory responses. Reports of expression of its receptor, IL-25R, on airways structural cells suggest a wider role for IL-25 in remodeling. We hypothesized that IL-25 stimulates local angiogenesis in the asthmatic bronchial mucosa. Immunoreactive IL-25(+), IL-25R(+), and CD31(+) (endothelial) cells in sections of bronchial biopsies from asthmatics and controls were detected by immunohistochemistry. The effect of IL-25 on angiogenesis was examined using an in vitro assay. Real-time PCR was used to detect expression of IL-25R and VEGF mRNA in cultured human vascular endothelial cells (HUVEC), and a cell proliferation kit (WST-8) was used to measure the effect of IL-25 on HUVEC proliferation. Immunostaining showed that IL-25(+), IL-25R(+), and CD31(+)/IL-25R(+) cells were significantly elevated in the bronchial mucosa of asthmatics compared with controls (P < 0.003). In asthmatics, the numbers of IL-25(+) cells correlated inversely with the forced expiratory volume in 1 s (r = -0.639; P = 0.01). In vitro, HUVEC constitutively expressed IL-25R, which was up-regulated further by TNF-α. IL-25 and TNF-α also increased expression of VEGF and VEGF receptors. IL-25 increased HUVEC proliferation and the number, length, and area of microvessel structures in a concentration-dependent manner in vitro. VEGF blockade, the PI3K-specific inhibitor LY294002, and the MAPK/ERK1/2 (MEK1/2)-specific inhibitor U0126 all markedly attenuated IL-25-induced angiogenesis, and the inhibitors also reduced IL-25-induced proliferation and VEGF expression. Our findings suggest that IL-25 is elevated in asthma and contributes to angiogenesis, at least partly by increasing endothelial cell VEGF/VEGF receptor expression through PI3K/Akt and Erk/MAPK pathways.

Angiogenesis in asthma

Asthma is a chronic inflammatory disease of the airways characterized by infiltration and activation of inflammatory cells and by structural changes, including subepithelial fibrosis, smooth muscle cells hypertrophy/hyperplasia, epithelial cell metaplasia and angiogenesis. These structural changes are thought to correlate with asthma severity and to account for the development of progressive lung function deterioration. The mechanism underlying airway angiogenesis in asthma and its precise clinical relevance have not yet been completely elucidated. This review provides recent data showing the contribution of allergic inflammation in increased airway vascularity and potential therapeutical approaches in asthma treatment by acting on bronchial microvascular changes.

Review: Tissue remodeling and angiogenesis in asthma: the role of the eosinophil

This review covers the role of eosinophils in asthma-associated tissue remodeling and angiogenesis focusing on angiogenesis which is a recently discovered feature of asthma. In addition, novel directions for eosinophil-targeted/angiogenesis-targeted pharmacological intervention are discussed as new approaches in the treatment of asthma.

Neovastat (Æ-941) inhibits the airway inflammation via VEGF and HIF-2α suppression

Vascular endothelial growth factor (VEGF) contributes to airway inflammation and angiogenesis in asthma. Hypoxia inducible factor (HIF), the most potent regulator of VEGF, is a heterodimer of a constitutively expressed β subunit and an oxygen-regulated α subunit (HIF-α). Three HIF-α isoforms have been described, of which HIF-2α are abundantly expressed in lung tissue. Neovastat is a naturally occurring inhibitor of angiogenesis derived from marine cartilage. We previously reported that Neovastat can inhibit the airway inflammation in asthma. In this study, we hypothesized that the anti-inflammatory effect of Neovastat is mediated with inhibition of VEGF and HIF-2α. BALB/c mice were immunized subcutaneously and challenged with inhaled ovalbumin (OVA). Neovastat was administrated by gavage three times with 12-h interval, beginning at 30 min before OVA inhalation. VEGF concentration in bronchoalveolar lavage fluid was measured by ELISA. We evaluate the expression of VEGF and HIF-2α in lung tissue by immunohistochemistry. Mice treated with Neovastat had significantly reduced inflammatory cell count in BAL fluid compared with untreated asthmatic mice. Furthermore, Mice treated with Neovastat showed significantly reduced VEGF and HIF-2α expression on lung tissue. These results suggest that anti-inflammatory effects of Neovastat could be linked to inhibition of VEGF and HIF-2α.

Vascular Remodelling and Angiogenesis in Asthma: Morphological Aspects and Pharmacological Modulation

Tissue remodelling can affect the entire bronchial wall, including the vascular component of the mucosa, in bronchial asthma. The bronchial mucosa is more vascularized in asthmatic patients than in healthy subjects, showing an increase in the number and dimension of vessels and vascular area. In addition, vascular changes can contribute to obstructing the airway flow in asthma. Vascular Endothelial Growth Factor, a mediator derived from endothelial cells, but also from most inflammatory cells in asthma, plays a primary role in vascular remodelling and angiogenesis. Studies on lung biopsies showed that anti-asthma drugs can decrease to varying degrees the vascular component of airway remodelling in asthma. Among asthma medications, inhaled corticosteroids effectively reverse all aspects of vascular remodelling such as vasodilatation, increased vascular permeability and angiogenesis. A better knowledge of angiogenetic mechanisms in asthma will support the selection of specific medications acting on this aspect of airway remodelling. The aim of this review is to analyze the morphological aspects of the vascular component in airway remodelling in asthma, as well as its pharmacological modulation.

The importance of the airway microvasculature in asthma

The microvasculature in asthma has been known to contribute to airway-wall thickening and oedema from early post-mortem series. Current concepts of airway inflammation in asthma highlight the importance of the role of the Th2 lymphocyte in the atopic response to aeroallergens, the importance of mast-cell mediators in airway remodelling, potential actions of the vascular response in determining airway thickness and mechanisms of angiogenesis involving endogenous as well as homing progenitor cells with angioblastic potential. The development of animal models of asthmatic airway inflammation and remodelling have given new insight into mechanisms of angiogenesis in asthma. The central role of vascular endothelial growth factor in angiogenesis, vessel leakage and vascular homeostasis is now recognized. A more recent finding is the influence of this factor in enhancing the Th2 response in airway inflammation. The ability of bone marrow-derived angioblasts to migrate to sites of inflammation and contribute to angiogenesis indicates a pivotal role of stem cells in this process. These findings now provide logical links between the inflammatory response, stem-cell mobilization, angiogenesis and airflow obstruction in the remodelled airway of asthma. Future studies examining airway-wall thickness will be able to account for the contribution of the vasculature and airway-wall oedema. Therapies aimed at vascular mechanisms may be useful adjuncts to current treatments and the recognition of stem cells as key players in airway remodelling may provide strategies to reduce fixed airflow obstruction in severe disease.

A three-dimensional in vitro model of angiogenesis in the airway mucosa

Bronchial asthma is an inflammatory disease characterized by chronic intermittent bronchoconstriction. A key feature of the disease is structural changes in the airway wall (airway remodeling) consistent with tissue growth and chronic wound healing including angiogenesis. The epithelium directs mesenchymal processes during both embryogenesis and wound healing, and thus we hypothesized that the bronchial epithelium plays a critical role in directing angiogenesis. To study angiogenesis in the airways, we have developed a three-dimensional (3-D) in vitro model of the airway mucosa that consists of normal differentiated human bronchial epithelial cells (NHBE), normal human lung fibroblasts (NHLF), and human umbilical vein endothelial cells (HUVEC). The HUVEC are coated on dextran beads and suspended in a fibrin gel approximately 2 mm beneath a confluent monolayer of NHLF which are just beneath the confluent monolayer of differentiated NHBE. In the presence of fibroblasts, visible capillaries reaching lengths of up to 1 mm sprout from the HUVEC-coated beads. Over 11 days in culture, the bronchial epithelium produces transforming growth factor- β2 (TGF β2, 60 pg/ml), significantly increases vascular endothelial growth factor (VEGF) more than 6-fold to a concentration of 1.85 ng/ml, but does not significantly impact total network formation. Exogenous TGF β2 stimulates VEGF production in a dose-dependent fashion (0–400 pg/ml) through a MAPK-dependent pathway, but also inhibits capillary network formation. We conclude that the bronchial epithelium produces biologically relevant concentrations of VEGF and TGF β2 in a 3-D model of the airway mucosa that may be useful in probing mechanisms of angiogenesis in asthma.

Increased immunoreactivity of stromal cell-derived factor-1 and angiogenesis in asthma.

Stromal cell-derived factor-1 (SDF-1) acts as a chemoattractant for leukocytes and can induce neovascularisation. To examine the role of SDF-1 in the development of angiogenesis, immunohistochemical studies were performed on bronchial biopsy specimens from asthmatic and control subjects. Bronchial biopsy specimens were obtained from 13 asthmatic and eight control subjects. The number of vessels and the percentage area they occupied were estimated after staining for type-IV collagen. In addition the number of SDF-1-positive cells was determined. There was a significant increase in the number of vessels and the percentage vascularity in the submucosa of asthmatic subjects compared with control subjects. Asthmatic subjects exhibited a greater number of SDF-1-positive cells in the airway mucosa than control subjects. The degree of vascularity was associated with the number of SDF-1-positive cells. Furthermore, the number of SDF-1-positive cells was inversely correlated with airway calibre and airway hyperresponsiveness. Colocalisation studies revealed that endothelial cells, macrophages and T-lymphocytes were the major sources of SDF-1. These findings suggest that increased vascularity of bronchial mucosa in asthmatic subjects is closely related to the expression of stromal cell-derived factor-1 positive cells, which may play a role in remodelling of airways via angiogenesis.