Versican in inflammation and tissue remodelling: the impact on lung disorders.

Versican is a proteoglycan that has many different roles in tissue homeostasis and inflammation. The biochemical structure is comprised of four different types of the core protein with attached glycosaminoglycans that can be sulphated to various extents and has the capacity to regulate differentiation of different cell types, migration, cell adhesion, proliferation, tissue stabilization and inflammation. Versican's regulatory properties are of importance during both homeostasis and changes that lead to disease progression. The glycosaminoglycans that are attached to the core protein are of the chondroitin sulfate/dermatan sulfate type and are known to be important in inflammation through interactions with cytokines and growth factors. For a more complex understanding of versican it is of importance to study the tissue niche, where the wound healing process in both healthy and diseased conditions take place. In previous studies our group has identified changes in the amount of the multifaceted versican in chronic lung disorders such as asthma, chronic obstructive pulmonary disease and bronchiolitis obliterans syndrome, which could be a result of pathologic, transforming growth factor β driven, on-going remodelling processes. Reversely, the context of versican in its niche is of great importance since versican has been reported to have a beneficial role in other contexts e.g. emphysema. Here we explore the vast mechanisms of versican in healthy lung and in lung disorders

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

Comparison of Normal and Metaplastic Epithelium in Patients with Stable versus Persistently Symptomatic Severe Asthma Using Laser-Capture Microdissection and Data-Independent Acquisition–Mass Spectrometry

A proportion of patients with severe asthma (SA) show poor responses to traditional asthma medications; however, it remains unknown why some patients remain persistently symptomatic. Our objective was to explore the use of laser-capture microdissection of specific epithelial structures combined with quantitative data-independent acquisition mass spectrometry to elucidate differences in protein composition in patients with SA with varying symptom control. Unbiased label-free quantitative proteome analyses were performed on laser-capture–microdissected areas of specific epithelial structures from patients with SA with varying degrees of symptom control. A total of 1993 stable SA and 1652 symptomatic SA proteins in normal epithelium and 1458 stable SA and 1647 symptomatic SA proteins in metaplastic epithelium were quantified. When comparing proteome profiles based on symptom control, 33 proteins in patients with stable SA (≥twofold change; P ≤ 0.05) and 13 proteins in patients with persistently symptomatic SA (≥twofold change; P ≤ 0.05) were enriched significantly. When comparing proteome profiles based on epithelial status, 21 proteins in normal epithelium (≥twofold change; P ≤ 0.05) and 6 proteins in metaplastic epithelium (≥twofold change; P ≤ 0.05) were enriched significantly. New treatment strategies are needed for patients with severe asthma and exploratory studies of unbiased nature such as this may help when searching for new mechanisms and potential targets involved in the disease pathology

Controlled and uncontrolled asthma display distinct alveolar tissue matrix compositions

Objective: Whether distal inflammation in asthmatics also leads to structural changes in the alveolar parenchyma remains poorly examined, especially in patients with uncontrolled asthma. We hypothesized that patients who do not respond to conventional inhaled corticosteroid therapy have a distinct tissue composition, not only in central, but also in distal lung. Methods: Bronchial and transbronchial biopsies from healthy controls, patients with controlled atopic and patients with uncontrolled atopic asthma were processed for immunohistochemical analysis of fibroblasts and extracellular matrix molecules: collagen, versican, biglycan, decorin, fibronectin, EDA-fibronectin, matrix metalloproteinase (MMP)-9 and tissue-inhibitor of matrix metalloproteinase (TIMP)-3. Results: In central airways we found increased percentage areas of versican and decorin in patients with uncontrolled asthma compared to both healthy controls and patients with controlled asthma. Percentage area of biglycan was significantly higher in both central airways and alveolar parenchyma of patients with uncontrolled compared to controlled asthma. Ratios of MMP-9/TIMP-3 were decreased in both uncontrolled and controlled asthma compared to healthy controls. In the alveolar parenchyma, patients with uncontrolled asthma had increased percentage areas of collagen, versican and decorin compared to patients with controlled asthma. Patients with uncontrolled asthma had significantly higher numbers of myofibroblasts in both central airways and alveolar parenchyma compared to patients with controlled asthma. Conclusions: Tissue composition differs, in both central and distal airways, between patients with uncontrolled and controlled asthma on equivalent doses of ICS. This altered structure and possible change in tissue elasticity may lead to abnormal mechanical properties, which could be a factor in the persistent symptoms for patients with uncontrolled asthma

Plasma proteome changes linked to late phase response after inhaled allergen challenge in asthmatics

Background: A subset of individuals with allergic asthma develops a late phase response (LPR) to inhaled allergens, which is characterized by a prolonged airway obstruction, airway inflammation and airway hyperresponsiveness. The aim of this study was to identify changes in the plasma proteome and circulating hematopoietic progenitor cells associated with the LPR following inhaled allergen challenge. Methods: Serial plasma samples from asthmatics undergoing inhaled allergen challenge were analyzed by mass spectrometry and immunosorbent assays. Peripheral blood mononuclear cells were analyzed by flow cytometry. Mass spectrometry data were analyzed using a linear regression to model the relationship between airway obstruction during the LPR and plasma proteome changes. Data from immunosorbent assays were analyzed using linear mixed models. Results: Out of 396 proteins quantified in plasma, 150 showed a statistically significant change 23 h post allergen challenge. Among the most upregulated proteins were three protease inhibitors: alpha-1-antitrypsin, alpha-1-antichymotrypsin and plasma serine protease inhibitor. Altered levels of 13 proteins were associated with the LPR, including increased factor XIII A and decreased von Willebrand factor. No relationship was found between the LPR and changes in the proportions of classical, intermediate, and non-classical monocytes. Conclusions: Allergic reactions to inhaled allergens in asthmatic subjects were associated with changes in a large proportion of the measured plasma proteome, whereof protease inhibitors showed the largest changes, likely to influence the inflammatory response. Many of the proteins altered in relation to the LPR are associated with coagulation, highlighting potential mechanistic targets for future treatments of type-2 asthma

iNOS affects matrix production in distal lung fibroblasts from patients with mild asthma.

A high level of exhaled nitric oxide (NO) is a marker for inflammation in the airways of asthmatic subjects. However, little is known about how NO and inducible nitric oxides synthase (iNOS) activity may affect remodelling in the distal lung. We hypothesized that there is a link between iNOS and ongoing remodelling processes in the distal lung of mild asthmatics

Social stratification in the dissemination of statins after stroke in Sweden

PURPOSE: Since 2005, statins have been recommended to patients with ischaemic stroke. The objective of this study was to analyse how statin treatment has been disseminated in different patient groups (age, sex, socioeconomic status and country of birth) in Sweden between 2004 and 2009. METHODS: The Swedish Stroke Register (Riks-Stroke) has been linked to the Longitudinal Integration Database for Health Insurance and Labour Market Studies. Approximately 85 % of stroke patients in Sweden are included in Riks-Stroke. Odds ratios for statin prescribing were calculated using a multivariable logistic regression model including age, sex, socioeconomic status and risk factors. RESULTS: During the study period, 108,950 ischaemic stroke patients were discharged alive from hospital. The proportion with statins at discharge increased from 32.9 % in 2004 to 60.1 % in 2009. Patients with secondary school or university education had slightly higher odds [odds ratio (OR) 1.07, 95 % confidence interval (CI) 1.04-1.11 and OR 1.05, 95 % CI 1.01-1.10 respectively] than patients with primary school education. Patients on a high income were prescribed more statins than those on a low income (OR 1.24, 95 % CI 1.19-1.28). Compared with patients born in Sweden, patients born in other countries were prescribed more statins (Nordic countries excepting Sweden: OR 1.07, 95 % CI 1.01-1.14; Europe: OR 1.31, 95 % CI 1.22-1.40; Outside Europe: OR 1.20, 95 % CI 1.08-1.34). CONCLUSIONS: Statin prescribing after ischaemic stroke has increased from 2004 to 2009. Our results also show a social stratification in the dissemination of statins, with patients having a higher income and patients with higher education receiving statins more often than those with a lower income and education, and patients born in Sweden receiving statins less often than those born outside of Sweden

Ethnic differences in psychological well-being in adolescence in the context of time spent in family activities

Background In Britain and elsewhere there is ethnic variation in mental health in adulthood but less is known about adolescence. Few studies examining the role of family life in adolescent mental well-being have been based on a multi-ethnic UK sample. We explored whether family activities explain ethnic differences in mental health among adolescents in London, UK. Method These analyses are based on 4,349 Black Caribbean, Black African, Indian, Pakistani and Bangladeshi and White UK boys and girls aged 11–13, in 51 schools. Psychological well-being was measured as the total difficulties score from Goodman’s strengths and difficulties questionnaire (increasing score represents increasing difficulties). Results Participation in family activities varied by ethnicity. Compared with the White UK group, all minority groups were more likely to visit friends and relatives and go other places as a family. Black Caribbeans and Nigerian/Ghanaians were less likely and South Asian groups more likely to eat a meal together as a family. In multivariate analyses all minority groups had better well-being scores compared to Whites, independent of family type and socio-economic status (SES). Although adjusting for family activities slightly attenuated the association for South Asians, the minority ethnic advantage in psychological well-being remained [regression coefficients for Black Caribbeans = −0.66 (95% CI = −1.13, −0.20); Nigerian/Ghanaians = −1.27 (−1.81, −0.74); Other Africans = −1.43 (−2.00, −0.86); Indians = −1.15 (−1.73, −0.58); Pakistani/Bangladeshis = −0.66 (−1.20, −0.12)]. In analyses based on the whole group, all activity variables were independent correlates of psychological well-being. Multivariate models, stratified by ethnicity, showed that ≤weekly compared to daily family meals was associated with poorer mental health for all groups, except Black Caribbeans, independent of family type and SES. Conclusion Despite ethnic patterning of the frequency of family activities, adjusting for differences in these variables did not account for the better psychological well-being of minorities. Family activities were, however, important independent correlates of psychological well-being for all groups in this sample