Remodelling of the pulmonary circulation – a novel response to allergic airway inflammation

Abstract

AbstractIntroduction: Asthma is known to be associated with the structural alterations of the airways – airway remodelling. The features of these alterations had been well described; however, the effects of airway inflammation on the adjacent vessels have been virtually unknown. One exception is a study from 1922 by Huber and Koessler describing the structural alterations of bronchial and pulmonary arteries in cases of fatal asthma, and a study by Saetta et al. describing the involvement of the pulmonary arteries in inflammation. Most studies of vascular involvement in asthma have focused on the tracheal and bronchial microcirculation, as these vessels are relatively easy to obtain, whereas the bronchial and pulmonary vessels have been far less investigated.Objective: The overall aim of the thesis project was to investigate the vascular remodelling of the extra‐bronchial/tracheal vasculature following allergic airway inflammation, and to investigate the effects of different allergens and resolution periods.Materials and Methods: Two established mouse models of allergic airway inflammation, the ovalbumin (OVA) and house dust mite (HDM) models, were used. Allergic airway inflammation was induced by inhalation of the allergen, and airway remodelling has previously been described and characterised in both models; however, the remodelling of the pulmonary vasculature has not been equally extensively investigated. The papers included in the thesis describe and histologically characterise the structural alterations of the pulmonary vasculature, at different time points following allergen exposure in different parts of the pulmonary circulation. Staining for α‐smooth muscle actin, procollagens I and III, proliferation markers Ki‐67 and proliferating cell nuclear antigen (PCNA), von Willebrand factor and total collagen (picrosirius red) was used to investigate vascular remodelling. Vessels were divided, based on the length of the basement membrane, into groups: small (≤249 µm in perimeter) and midsized (250–500 µm) solitary vessels (>150 µm from any bronchi), and bronchial‐associated vessels (>250 µm and in close contact with the bronchi).Results: We discovered marked remodelling in all types of vessels following allergic airway inflammation, and both bronchial‐associated and solitary vessels were affected. Smooth muscle mass increased, in similarity to the number of proliferating smooth muscle and endothelial cells. The number of procollagen I‐producing cells also increased, as did the number of myofibroblasts. Additionally, normally poorly muscularised small solitary vessels changed phenotype to a more muscularised type. Furthermore, structural alterations, resembling the luminal occlusion found in pulmonary hypertension, were identified in bronchial‐associated vessels following a long‐term HDM exposure.Conclusions: This thesis concludes that allergic airway inflammation is associated with vascular remodelling as well as bronchial remodelling, and the features are similar in both compartments. All parts of the pulmonary circulation appear to be affected, and the alterations are present irrespective of the allergen and the protocol used to initiate airway inflammation. In addition, vascular remodelling appears to be partially irreversible, as some structural alterations remain even when the allergic inflammation is resolved. In summary, this thesis describes the involvement of the vasculature in airway inflammation, characterises vascular remodelling and shows that similar structural alterations are induced by two different allergens.