Abstract
HIF-1α is a transcription factor that is activated during hypoxia and inflammation and is a key regulator of angiogenesis in vivo. During the development of asthma, peribronchial angiogenesis is induced in response to aeroallergens and is thought to be an important feature of sustained chronic allergic inflammation. Recently, elevated HIF-1α levels have been demonstrated in both the lung tissue and bronchoalveolar lavage of allergic patients, respectively. Therefore, we investigated the role of HIF-1α on the development of angiogenesis and inflammation following acute and chronic allergen exposure. Our data shows that intranasal exposure to house dust mite (HDM) increases the expression of HIF-1α in the lung, whilst reducing the expression of the HIF-1α negative regulators, PHD1 and PHD3. Blockade of HIF-1α in vivo, significantly decreased allergic inflammation and eosinophilia induced by allergen, due to a reduction in the levels of IL-5 and Eotaxin-2. Importantly, HIF-1α blockade significantly decreased levels of VEGF-A and CXCL1 in the lungs, which in turn led to a profound decrease in the recruitment of endothelial progenitor cells and a reduction of peribronchial angiogenesis. Furthermore, HDM or IL-4 treatment of primary lung macrophages resulted in significant production of both VEGF-A and CXCL1; inhibition of HIF-1α activity abrogated the production of these factors via an up-regulation of PHD1 and PHD3. These findings suggest that novel strategies to reduce the expression and activation of HIF-1α in lung macrophages may be used to attenuate allergen-induced airway inflammation and angiogenesis through the modulation of VEGF-A and CXCL1 expression.Clinical RelevanceThis study provides new insights into the role of HIF-1α in the development of peribronchial angiogenesis and inflammation in a murine model of allergic airway disease. These findings indicate that strategies to reduce activation of macrophage derived HIF-1α may be used as a target to improve asthma pathology.
Highlights
Asthma is a heterogeneous chronic inflammatory disease of the airways, characterized by airway hyperresponsiveness, eosinophilic inflammation and is associated with airway remodeling
house dust mite (HDM) or IL-4 treatment of primary lung macrophages resulted in significant production of both vascular endothelial growth factor A (VEGF-A) and CXCL1; inhibition of Hypoxiainducible factor-1a (HIF-1a) activity abrogated the production of these factors via an up-regulation of PHD1 and PHD3
Since HIF-1a has a key role in the production of pro-angiogenic factors and in endothelial progenitor cells (EPCs) function, we evaluated whether blockade of HIF-1a activation in vivo could alter EPC recruitment to the lungs, angiogenesis and inflammation induced by the clinically relevant allergen, house dust mite
Summary
Asthma is a heterogeneous chronic inflammatory disease of the airways, characterized by airway hyperresponsiveness, eosinophilic inflammation and is associated with airway remodeling. Airway remodeling consists of structural changes in the lungs typified by deposition of extracellular matrix proteins, mucus hypersecretion, and airway smooth muscle hypertrophy and importantly, the formation of new peribronchial blood vessels. The formation of new blood vessels (named angiogenesis) is believed to be necessary to sustain chronic inflammation [1], [2]. The most numerous immune cell-type present in the non-diseased lung, macrophages are ideally placed to influence pulmonary inflammation, airway remodeling and angiogenesis. Macrophages have been shown to be a major source of pro-angiogenic factors, in both human and mouse studies [3], [4]. The role of macrophages in HDM-driven angiogenesis is not well understood
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