Modifiers of local and systemic inflammation and fibrosis

Abstract

In the first part of this thesis, we focus on different aspects of renal fibrosis. Chapter 1describes the role of three different growth factors during kidney disease: connective tissue growth factor (CTGF), epidermal growth factor (EGF), and platelet derived growth factor (PDGF). Their corresponding pathways and therapeutically targeting these growth factors to prevent progression of disease are reviewed. To gain more insight in one of these growth factors during renal disease, CTGF expression is investigated in ANCA associated glomerulonephritis in Chapter 2. In this study CTGF will be measured in renal biopsies as well as plasma, serum and urine samples during a follow up period of 2,5 years. In Chapter 3, a pilot study is performed where Gremlin (an inhibitor in the TGF-β pathway) is neutralized during an experimental mouse model of unilateral ureteral obstruction of renal fibrosis. The second part of this thesis describes the role of granzymes within inflammatory and fibrotic disorders. In Chapter 4, we review the role of granzymes in extracellular matrix remodeling and endothelial function with a focus on angiogenesis. Chapter 5 describes a previously unrecognized role of extracellular Granzyme K in endothelial cell function in angiogenesis. Chapter 6 shows how Granzyme A and Granzyme K differentially modulate monocyte signaling and proinflammatory cytokine release during anti-bacterial innate immune response in human monocytes. We investigate granzyme expression and potential biomarker roles of granzymes in autoimmune diseases such as Systemic Lupus Erythematosus (Chapter 7) and Rheumatoid Arthritis (Chapter 8). Next to granzyme expression in the circulation and synovial environment, the ability of granzymes to trigger proinflammatory cytokine response in rheumatoid arthritis cell subsets is described.