Vascular Remodeling Is Airway Generation-Specific in a Primate Model of Chronic Asthma

Abstract

Rationale: Changes in the density of bronchial vessels have been proposed as a part of airway remodeling that occurs in chronic asthma. Objectives: Using an established nonhuman primate model of chronic allergic asthma, we evaluated changes in vascular density as well as the contribution of bronchial epithelium to produce vascular endothelial growth factor (VEGF). Methods: Eight juvenile rhesus macaques were divided into two groups of four. One group was exposed to 11 cycles of aerosolized house dust mite allergen (HDMA), whereas the other was exposed to filtered air. Bronchial wall vasculature was identified using an immunohistochemical approach, and vascular density was quantified stereologically. A semiquantitative polymerase chain reaction approach was used to estimate VEGF splice variant gene expression at discrete airway generations. Cell culture of primary tracheal epithelial cells with varying concentrations of HDMA was used to quantify the direct contribution of the epithelium to VEGF production. Results: Bronchial vascular density was increased at mid-to lower airway generations, which was independent of changes in the interstitial compartment. The VEGF 121 splice variant was significantly increased at lower airway generations. VEGF protein increased in a dose-dependant fashion in vitro primarily by an increase in VEGF 121 gene expression. Conclusion: This study highlights that increased vascular density in an animal model of chronic allergic asthma is airway generation specific and associated with a unique increase of VEGF splice variant gene expression. Airway epithelium is the likely source for increased VEGF.

Asthma: a comparison of animal models using stereological methods

“…These studies [6,66,72] demonstrate that allergic asthma can be produced experimentally in a nonhuman primate, the rhesus macaque monkey, using a recognised human allergen, house dust mite, and provides a valuable model for human asthma. Design-based stereological approaches to the tracheobronchial airways A common problem observed in lung stereology is profile counting of cells as a representation of cell number.…”

“…Asthma manifests itself by altering not only the epithelial compartment or the airway smooth muscle but also other compartments (e.g. interstitial, vascular, immunological and nervous [6,7]). …”

“…Airway generation-specific remodelling Intrapulmonary proximal and distal bronchi of sensitised and challenged monkeys have focal mucous goblet cell hyperplasia, thickening of the BMZ, hypercellularity in the epithelium and subepithelial connective tissue, and increases in smooth muscle and bronchial microvessels [6,66]. These changes are site-specific and vary greatly within various portions of the airway wall in the same airway generation, between airway generations in an individual sensitised and challenged animal, and from animal to animal in the sensitised and challenged group.…”

“…Even patients with impaired left ventricular function have been shown to have increased airway hyperreactivity [105]. Rhesus monkeys with HDMA-induced allergic airways also show an increase in airway generation-specific bronchovascular density [6].…”

Persistence of Serotonergic Enhancement of Airway Response in a Model of Childhood Asthma

“…Previous research shows that vascular remodeling in HDMA-exposed airways is generation specific (60). It is possible that O 3 1 HDMA exposure may have differential effects along segments of the tracheobronchial tree.…”