Damage associated molecular patterns and toll like receptors in inflammation mediated vascular remodeling : mechanistic insights and therapeutic potentials

Karper, J.C.

Atherosclerosis, restenosis and cardiac remodeling after myocardial infarction can cause serious clinical problems that greatly contribute to both high morbidity and mortality. In all these processes, the inflammatory responses caused by activation of the immune system play a very prominent role. This thesis elaborates on the role of specific components of the immune system and the therapeutic possibilities that lay hidden therein. This was done by focussing on the pathophysiological process in which Damage Associated Molecular Patterns (DAMPs) are released upon cell stress and cell death or other tissue damage, and may play an important role via different mechanisms. The data in this thesis illustrates specific involvement of DAMPs recognizing factors such as Toll-like Receptors in vascular remodeling and the therapeutic potential that lies within these findings. We show that endogenous activation of the immune s ystem plays an important role in the post-interventional vascular...Show moreAtherosclerosis, restenosis and cardiac remodeling after myocardial infarction can cause serious clinical problems that greatly contribute to both high morbidity and mortality. In all these processes, the inflammatory responses caused by activation of the immune system play a very prominent role. This thesis elaborates on the role of specific components of the immune system and the therapeutic possibilities that lay hidden therein. This was done by focussing on the pathophysiological process in which Damage Associated Molecular Patterns (DAMPs) are released upon cell stress and cell death or other tissue damage, and may play an important role via different mechanisms. The data in this thesis illustrates specific involvement of DAMPs recognizing factors such as Toll-like Receptors in vascular remodeling and the therapeutic potential that lies within these findings. We show that endogenous activation of the immune s ystem plays an important role in the post-interventional vascular remodeling process. Multiple DAMPs such as HMGB1 are absent before intervention however they were found highly up regulated locally in the vessel wall after intervention indicating a specific relation with the intervention procedure. The presence and involvement of a variety of Toll Like Receptors in different models of vascular remodeling is interesting since these receptors are considered to be important recognizers of the DAMPs locally found in the vessel wall. Different intracellular signalling pathways and TLR accessory molecules seem to mediate the outcome of the specific DAMP-TLR interactions on vascular remodeling majorly. Protective effects of TLR3 and different outcomes of RP105 deficiency on vascular remodeling processes indicate the complexity of the underlying pathophysiological processes. These results can be partly explained by downstream TLR signalling and involvement of specific cell subtypes. The exploration of these underlying mechanisms offers new opportunities for biomarker selection and therapy development.Show less

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Damage associated molecular patterns and toll like receptors in inflammation mediated vascular remodeling : mechanistic insights and therapeutic potentials

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