Bronchial Smooth Muscle Cells of Asthmatics Promote Angiogenesis through Elevated Secretion of CXC-Chemokines (ENA-78, GRO-α, and IL-8)

Laura Keglowich,Thérèse Resink,Katrin Hostettler Haack,Gavin Tjin,Michael Roth,Reinoud Gosens,Maria Philippova,Peter Borger,Didier Lardinois,Sophie Dessus-Babus,Michael Tamm,Brian Oliver

doi:10.1371/journal.pone.0081494

Abstract

BackgroundAirway wall remodelling is a key pathology of asthma. It includes thickening of the airway wall, hypertrophy and hyperplasia of bronchial smooth muscle cells (BSMC), as well as an increased vascularity of the sub-epithelial cell layer. BSMC are known to be the effector cells of bronchoconstriction, but they are increasingly recognized as an important source of inflammatory mediators and angiogenic factors.ObjectiveTo compare the angiogenic potential of BSMC of asthmatic and non-asthmatic patients and to identify asthma-specific angiogenic factors.MethodsPrimary BSMC were isolated from human airway tissue of asthmatic and non-asthmatic patients. Conditioned medium (CM) collected from BSMC isolates was tested for angiogenic capacity using the endothelial cell (EC)-spheroid in vitro angiogenesis assay. Angiogenic factors in CM were quantified using a human angiogenesis antibody array and enzyme linked immunosorbent assay. ResultsInduction of sprout outgrowth from EC-spheroids by CM of BSMC obtained from asthma patients was increased compared with CM of control BSMC (twofold, p < 0.001). Levels of ENA-78, GRO-α and IL-8 were significantly elevated in CM of BSMC from asthma patients (p < 0.05 vs. non-asthmatic patients). SB 265610, a competitive antagonist of chemokine (CXC-motif) receptor 2 (CXCR2), attenuated the increased sprout outgrowth induced by CM of asthma patient-derived BSMC.ConclusionsBSMC isolated from asthma patients exhibit increased angiogenic potential. This effect is mediated through the CXCR2 ligands (ENA78, GRO-α and IL-8) produced by BSMC. ImplicationsCXCR2 ligands may play a decisive role in directing the neovascularization in the sub-epithelial cell layers of the lungs of asthma patients. Counteracting the CXCR2-mediated neovascularization by pharmaceutical compounds may represent a novel strategy to reduce airway remodelling in asthma.

Highlights

Asthma is a chronic inflammatory airway disease affecting over 300 million people worldwide with an expected increase of a further 100 million by 2025 [1,2]
This study has demonstrated that bronchial smooth muscle cells (BSMC) from asthma patients have an increased angiogenic potential compared to BSMC from non-asthma control subjects
Angiogenesis antibody arrays revealed that Conditioned medium (CM) of BSMC from asthma patients contained significantly higher levels of angiogenin, epithelial neutrophil-activating protein 78 (ENA-78), growth regulated oncogene α (GRO-α), IL-6, IL-8 and monocyte chemotactic protein-1 (MCP-1)

Summary

Introduction

Asthma is a chronic inflammatory airway disease affecting over 300 million people worldwide with an expected increase of a further 100 million by 2025 [1,2]. Airway remodelling includes epithelial goblet cell hypertrophy, enhanced collagen deposition and airway wall hyperplasia [4,5,6]. Airway wall remodelling is a key pathology of asthma. It includes thickening of the airway wall, hypertrophy and hyperplasia of bronchial smooth muscle cells (BSMC), as well as an increased vascularity of the sub-epithelial cell layer. Objective: To compare the angiogenic potential of BSMC of asthmatic and non-asthmatic patients and to identify asthma-specific angiogenic factors. Conclusions: BSMC isolated from asthma patients exhibit increased angiogenic potential. This effect is mediated through the CXCR2 ligands (ENA78, GRO-α and IL-8) produced by BSMC. Counteracting the CXCR2-mediated neovascularization by pharmaceutical compounds may represent a novel strategy to reduce airway remodelling in asthma

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