Vloga monocitov in poškodbe DNA v vnetnih procesih pri bolnikih s sistemsko sklerozo ter vpletenost adiponektina in resolvina v razvoj fibroze
The role of monocytes and DNA damage in inflammation of patients with systematic sclerosis and involvement of adiponectina and resolvin in fibrotic development : doktorska disertacija

english
slovenian

doktorska dela

2023

Univerza v Ljubljani, Fakulteta za farmacijo

Systemic sclerosis (SSc) is a systemic autoimmune rheumatic disease whose pathogenesis remains poorly understood, and pharmacotherapy for the major clinical manifestations - inflammation and fibrosis - is often ineffective. To better understand the pathogenesis and find new therapeutic options, we investigated oxidative stress and monocyte migration in SSc and effects of adiponectin and resolvin D1 on inflammation and fibrosis. Our methodological approach included work with samples from SSc patients, cell cultures, and animal models. SSc patients exhibited a higher oxidative stress index (based on increased serum reactive oxygen metabolites and/or antioxidant capacity), more DNA breaks in leukocytes, and impaired DNA damage repair mechanisms. We found increased surface expression of the adhesion molecule CD62L on SSc monocytes and showed that CD62L expression is stimulated by SSc serum components. Both the altered oxidative status and monocyte phenotype were consistent with lung involvement, autoantibodies, and pharmacotherapy in SSc patients. In skeletal muscle cells and skeletal muscle fibroblasts, adiponectin acted on inflammation and muscle regeneration by activating intracellular signalling pathways and stimulating secretion of interleukin-6 and sphingosine-1-phosphate, possibly due to increased ceramidase activity of adiponectin receptors. AdipoRon, an adiponectin analogue, did not show comparable effects. In a mouse model of peritoneal fibrosis, resolvin D1 decreased the proportion of polymorphonuclear cells in the systemic circulation, whereas locally in the abdominal wall it had no effect on inflammation and fibrosis. It also downregulated the expression of chemerin, an important regulator of inflammation that binds to the same receptor as resolvin E1. In our work, we show that oxidative stress and increased migratory potential of monocytes in SSc correspond to the clinical picture of the disease. We show that adiponectin has effects on muscle inflammation and regeneration and that resolvin D1 has the potential to promote resolution of inflammation by regulating the expression of other resolvin receptor ligands.

26.09.2023