| Popis: |
Major surgeries, such as cardiac or orthopaedic procedures in particular, expose the patient to extensive trauma, blood loss, and tissue injury; all of these factors effectively modulate the immune system to ultimately trigger an inflammatory response. Postoperative cognitive dysfunction (POCD), the condition being characterized by impairment of short and long-term memory, is one of common complicates following surgery. Recently, our data have demonstrated that neuroinflammation and microglia activation in the hippocampus following surgery are associated with cognitive decline. The aim of this thesis is to investigate the inflammatory signaling pathways specifically involved with POCD, with a particular interest between systemic inflammation and local inflammation in the brain following surgery. The data presented in this thesis introduce the general concepts and the involvement of inflammation in the etiology of cognitive dysfunctions using a mouse model of POCD. Upon the identification of specific pro-inflammatory markers both systemically and centrally and the delineation of the time course of events that characterize the inflammatory response following aseptic orthopaedic surgery, I describe how specific cellular signal pathways interact, mediate, and sustain this response. Following an initial non-specific approach using a general anti-inflammatory compound to identify whether inflammation plays a role in this scenario, I have exploited this model into a wide range of knockouts animals in the attempt of identifying specific signaling mechanisms and upstream receptors that mediate the behavioral abnormality following surgery. In order to achieve this, I have compared the inflammatory events after aseptic surgery with the response after a defined infectious stimulus, to ultimately joint the two in the context of a postoperative complication. In conclusion, inflammation clearly plays a pivotal role in mediating physiological as well as behavioral changes after surgery and infection. This thesis has started to unmask the signaling pathways involved with surgery and how anti-cytokine therapy can potentially ameliorate the associated cognitive dysfunction. |
