Date of Award

Spring 1-1-2012

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Integrative Physiology

First Advisor

Monika Fleshner

Second Advisor

Donald Bellgrau

Third Advisor

Benjamin N. Greenwood

Fourth Advisor

Linda Watkins

Fifth Advisor

Kenneth P. Wright

Abstract

Systemic sterile inflammatory responses (SSIRs) are characterized by an increase in concentrations of blood and tissue cytokines, chemokines and other inflammatory proteins. SSIRs are commonly evoked by trauma or exposure to severe stressors and may result in negative consequences including multi-organ failure and death. Current attempts to treat SSIRs are often ineffective, reflecting the need for additional characterization of the signals and pathways that drive these processes. Specifically, it is important to explore recent advances in our understanding of the underlying signaling pathways and inflammatory proteins involved in SSIRs such as those that follow stressor exposure. The goals of this dissertation, therefore, are the following: (1) characterize the network of diverse cytokines, chemokines, inflammatory proteins and their receptors involved in SSIRs; (2) discuss factors impacted by the stress response including danger- and microbe associated molecular patterns (DAMPs and MAMPs) that may contribute to signaling processes to stimulate SSIRs; and (3) highlight a recently discovered signaling complex, the inflammasome, and its role in stress-induced SSIRs. We propose that systemic sterile inflammatory processes are initiated by a wide variety of molecules and involve the release of a plethora of cytokines, chemokines, and other immunomodulatory proteins. Importantly, we present evidence that this cytokine storm, although initiated by many diverse signals, may converge on the inflammasome. Additional research is necessary to determine whether the inflammasome is a suitable pharmacological target for SSIRs.

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