The Effects of Tumstatin on Vascularity, Airway Inflammation and Lung Function in an Experimental Sheep Model of Chronic Asthma

Joanne Van Der Velden,Emmanuel Koumoundouros,Heidi Bao,Garry J Barcham,Louise A Organ,Ana Tokanovic,Janette K Burgess,Louise M Harkness,Kenneth J Snibson,Cathryn L Ugalde,Donna M Barker

doi:10.1038/srep26309

Abstract

Tumstatin, a protein fragment of the alpha-3 chain of Collagen IV, is known to be significantly reduced in the airways of asthmatics. Further, there is evidence that suggests a link between the relatively low level of tumstatin and the induction of angiogenesis and inflammation in allergic airway disease. Here, we show that the intra-segmental administration of tumstatin can impede the development of vascular remodelling and allergic inflammatory responses that are induced in a segmental challenge model of experimental asthma in sheep. In particular, the administration of tumstatin to lung segments chronically exposed to house dust mite (HDM) resulted in a significant reduction of airway small blood vessels in the diameter range 10+–20 μm compared to controls. In tumstatin treated lung segments after HDM challenge, the number of eosinophils was significantly reduced in parenchymal and airway wall tissues, as well as in the bronchoalveolar lavage fluid. The expression of VEGF in airway smooth muscle was also significantly reduced in tumstatin-treated segments compared to control saline-treated segments. Allergic lung function responses were not attenuated by tumstatin administration in this model. The data are consistent with the concept that tumstatin can act to suppress vascular remodelling and inflammation in allergic airway disease.

Highlights

Vascular remodelling is a vital part of normal wound repair and as such is a tightly regulated process of vessel growth and regression
Our major findings were that intra-lung segmental administration of tumstatin reduced the induction of the development of new blood vessels by House Dust Mite (HDM) and attenuated allergic eosinophilic and macrophage responses to HDM challenge
The application of tumstatin but did not alter lung function indices for either the early-phase asthmatic response or the bronchial hyperresponsiveness. These findings suggest that tumstatin may be able to prevent the in vivo induction of angiogenesis and the allergic inflammatory response in small airways chronically exposed to allergen

Summary

Introduction

Vascular remodelling is a vital part of normal wound repair and as such is a tightly regulated process of vessel growth and regression This process is directed by a balance between endogenous pro- and anti-angiogenic factors. Pathological angiogenesis is thought to occur when this balance is disrupted Angiogenic factors such as vascular endothelial growth factor (VEGF), angiogenin and monocyte chemotactic protein-1 are increased in the bronchoalveolar lavage (BAL) fluid and induced sputum of asthmatics[7]. The changes to the vasculature and ASM in response to allergen, together with the fact that small airway structure and function in the sheep lung is comparable to the human lung, make the model relevant for examining the effects of tumstatin administration on vascular remodelling in asthma. The aim of the present study was to investigate whether the efficacy of tumstatin at impeding vascular remodelling and reducing airway inflammation reported for the mouse model could be verified in a large animal model of allergic asthma

Objectives

Methods

Results

Conclusion