Dysregulation of T cell activity in asthma : role of the ß2-adrenergic/cAMP system

A chronic inlammatory process is underlying the pathophysiology of asthma. T cells from the Th2-type are thought to play a crucial role in the development of the inlammatory reaction in the asthmatic airways in response to allergen exposure. Asthmatic subjects display enhanced activity of T(h2) cells, as relected by enhanced expression of Th2-like cytokines in lung tissue and enhanced expression of activation markers. After allergen inhalation, T cell activity is further upregulated and peripheral blood T cells are recruited to the lung tissue. Until now, the mechanisms responsible for enhanced Th2 activity in asthma are poorly understood. In this thesis, we examine the possible mechanisms leading to the dysregulation of T cell activity and the enhanced Th2-like activation profile. We propose that the release of inlammatory mediators into circulation is responsible for the dysregulation of T cell activity upon allergen exposure. For instance, the release of cytokines could be of interest in this respect. Cytokines play a pivotal role in the direction of T cell responses during allergen exposure. In addition, the activation profile of T cells is determined by negative regulatory mechanisms. In asthma, impaired negative feedback control by the β2-adrenergic/ AC system has been reported. We hypothesize that a dysfunction in the AC/cAMP system and possibly additional signal transduction pathways contributes to the aberrant activation of T cells as observed in asthma. In this thesis we investigate the effect of various soluble proinlammatory mediators on Th2-like cytokine expression and on the regulation of these cytokines by the cAMP-dependent pathway, in T cells from healthy controls as well as asthma patients and describe the involved signaling pathways.

Dynamic Reciprocity:The Role of the Extracellular Matrix Microenvironment in Amplifying and Sustaining Pathological Lung Fibrosis

When taken together fibrotic lung diseases are the leading cause of mortality worldwide, but our understanding of the underlying mechanisms driving these processes is limited. The lung consists of defined parts including the airways and parenchyma. The principal building blocks of these parts are the extracellular matrix (ECM). The ECM supports cells structurally while also acting as a bioactive environment directing cellular responses during pathological events in the lung. Airway and parenchymal tissue ECM alterations characterize the changes identified in many fibrotic lung diseases, including in asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF). Characterization of the profiles of changes and investigation into how these ECM changes contribute to the disease process has been the recent focus within the field. Studies suggest that the changes in the composition, organization, and stiffness of the ECM environment in the lung may drive functional responses of cells and thereby contribute to the pathological outcome. This chapter aims to summarize the state of the art regarding the dynamic interchange of the ECM in pulmonary fibrotic diseases and the approaches for modulating these aberrations in the future. The overarching goal is to expand knowledge of the contributions of the ECM to enable a better understanding of fibrotic lung diseases and to identify novel approaches for therapeutic targeting in this area

Mesenchymale stromale stamceltherapie voor emfyseem: Een kijkje in de toekomst

Verlies van longblaasjes bij longemfyseem is onherstelbaar. Regeneratie door stamcellen wordt als een veelbelovende toekomstige behandeling gezien voor patiënten met emfyseem. Een kenmerk van stamcellen is hun vermogen tot proliferatie en differentiatie; mesenchymale stromale stamcellen kunnen echter ook ontsteking remmen en reparatie bevorderen in hun directe omgeving. De extracellulaire matrix biedt daarbij niet alleen ruimtelijke structuur aan, maar bepaalt ook hoe mesenchymale stromale stamcellen zich gedragen en ontwikkelen. Toediening van mesenchymale stromale stamcellen aan diermodellen met emfyseem liet tekenen van weefselherstel zien, maar fundamentele vragen over de optimale dosering, herkomst, en toedieningsroute zijn tot nu toe helaas onvoldoende beantwoord. Ook het werkingsmechanisme is onduidelijk. Het fabriceren (bio-engeneering) van nieuwe longen is bij ratten gelukt door uitgenomen longen te ontdoen van cellen (decellulariseren), en de overblijvende eiwitvezelstructuur met eigen stamcellen te recellulariseren. Toediening van stamcellen aan patiënten met longemfyseem werd tot nu toe nauwelijks onderzocht. Intraveneuze toediening in kleine ‘safety studies’ bleek veilig maar klinisch niet effectief. (NED TIJDSCHR ALLERGIE & ASTMA 2017;17:12-1