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.