The role of tumstatin in the asthmatic airway

Abstract

The extracellular matrix ECM is essentially the tissue microenvironment, orchestrating cell growth and behavior. An altered airway ECM has been implemented in many features of asthma pathophysiology. This thesis investigated properties of the ECM intrinsically deposited by asthmatic ASM cells to better understand factors driving altered protein deposition. This thesis also investigated the viability of the ECM microenvironment as a therapeutic target in asthma. In the presence of inflammatory stimuli asthmatic ASM cells are reported to deposit an ECM abnormal in composition and functionality. This thesis however revealed when all stimulation is removed these cells intrinsically deposit ‘healthy’ ECM the same in fibronectin and collagen I content and angiogenic potential as the non-asthmatic ASM-ECM, and suggest inflammatory stimuli may be driving the development and persistence of an irregular matrix. Unfortunately anti-inflammatory medications do not completely suppress airway inflammation in asthmatic individuals. This thesis thus explored additional alternative therapeutic avenues for the treatment of asthma. Tumstatin is a matrikine, reduced in asthma, which possesses asthma-resolving potential when administered in mouse models of asthma. This thesis revealed tumstatin utilises active MMPs to remodel the ECM from asthmatic ASM cells and establish an anti-inflammatory and anti-remodelling microenvironment. This thesis further demonstrates the therapeutic potential of tumstatin in an ‘asthmatic’ sheep model, resolving airway remodelling and eosinophilia in a pulmonary system closely representative of the human. This thesis revealed factors driving the altered ECM and therapeutic avenues to ‘normalise’ the ECM microenvironment for complete resolution of the asthmatic phenotype.