Extracellular Matrix Alterations in Patients with Different Phenotypes of Asthma.

AbstractAsthma is a chronic disease that affects approximately 300 million people worldwide, and the prevalence is increasing. It has become clear that asthma is a highly heterogeneous disease, with overlapping symptoms but with diverse immunopathology and clinical phenotypes. Also, a significant proportion of asthma patients have remaining symptoms despite treatment. In addition to different phenotypes, it is thus important to consider asthma control across the severity spectrum. Asthma control is determined by a combination of several factors such as symptoms, changes in lung function, functional ability and quality of life. Although remodeling is now generally accepted as a defining characteristic of asthma, its cause and role in the pathophysiology of asthma needs further elucidating. Chronic inflammation can be a driving force behind remodeling processes, though it is now recognized that inflammation and remodeling can also be two parallel processes independent of each other. Asthma was first considered a disease of the central airways, however there is now little doubt about the importance of small airways and the alveolar compartment in asthma pathology. More research is needed on differentiating pathological backgrounds of the diverse phenotypes of asthma to be able to develop more personalized therapies. The specific aims of the studies presented in this thesis were to:1. Examine if distal inflammation in asthmatics leads to structural alterations also in the alveolar parenchyma. Furthermore, we wanted to investigate whether patients with uncontrolled asthma had a distinct tissue composition compared to patients with controlled asthma.2. Examine the populations of mast cells and if there is a connection between a profibrotic subset of mast cells and collagen composition in central airways and alveolar parenchyma in patients with controlled and uncontrolled asthma.3. Investigate if there is a link between exhaled nitric oxide, inducible nitric oxide synthase and remodeling in the distal airways of patients with mild untreated asthma.4. Evaluate if patchy subepithelial remodeling in patients with severe asthma treated with oral corticosteroids could differentiate patients with sufficient control from those with remaining symptoms.5. Investigate recruitment of circulating fibrocyte subtypes and possible recruitment factors in a human allergen provocation study.We found that the lung matrix composition differs between uncontrolled and controlled asthmatics on equivalent doses of ICS, in both central and distal airways. Proteoglycans, including versican, decorin and biglycan, and collagen was altered, as well as matrix modulators. We also saw changes in number of myofibroblasts.Further, patients with uncontrolled atopic asthma, but not patients with controlled asthma, were found to have an altered pro-fibrotic mast cell phenotype in the alveolar parenchyma that is correlated to alveolar collagen VI deposition.When analyzing the link between NO, NO synthases and remodeling events in asthma, it was found that iNOS is linked to remodeling, with a possibly modulatory role, in the distal lung of patients with mild steroid-naïve asthma.Severe asthma was found to be associated with patchy remodeling and regeneration in the central airways. Also, it is unlikely that the detected remodeling accounts for the differences in asthma control between stable and symptomatic patients with severe asthma. Perhaps the determinants of asthma control should be sought after in small airways or alveolar parenchyma.Finally, we successfully isolated CD45+/lin-/CD115-/CD16-/CD34+/dim/CD11b+ fibrocytes from peripheral blood using FACS