Recent advances in the field of immunology have revealed an unexpected role for the autonomic nervous system, specifically the vagus nerve, in controlling challenges to homeostasis. This work has reinforced the necessity to study disease within the context of whole-animal physiology, and has identified several approaches to develop novel therapeutic agents for inflammatory disease. While well-defined molecular responses to tissue injury can be modulated to therapeutic advantage, significant morbidity and mortality subsequent to traumatic injury remains a daunting clinical challenge. Application of physiological approaches to management of hemostasis may identify previously unrecognized pathways that can be harnessed to control hemorrhage. To this end, studies were performed to determine whether the vagus nerve controls hemostasis and homeostasis in mice and pigs. Electrical vagus nerve stimulation attenuated systemic inflammatory responses in a porcine model of septic shock, as indicated by significantly reduced circulating levels of tumor necrosis factor and inhibition of systemic coagulopathy, as well an improved mean arterial blood pressure. Vagus nerve stimulation also regulated hemostasis in a porcine model of soft tissue injury, as indicated by decreased bleeding time and total shed blood volume, and increased coagulation factor activity. In a murine model of soft tissue injury, vagus nerve regulation of hemostasis was dependent upon the α7 subunit of the nicotinic acetylcholine receptor, and pharmacological agents selective for α7 were similarly able to reduce bleeding times in mice. Together, these observations indicate that a previously unrecognized neural pathway mediated via the vagus nerve, and a molecular mechanism requiring the α7 subunit of the acetylcholine receptor, regulates hemostasis in vivo. A greater understanding of cholinergic regulation of hemorrhage may provide new opportunities to develop more effective hemostatic agents.
|Advisor:||Tracey, Kevin J.|
|School:||State University of New York at Stony Brook|
|School Location:||United States -- New York|
|Source:||DAI-B 71/04, Dissertation Abstracts International|
|Keywords:||Bleeding, Hemostasis, Inflammation, Thrombin, Vagus nerve|
Copyright in each Dissertation and Thesis is retained by the author. All Rights Reserved
The supplemental file or files you are about to download were provided to ProQuest by the author as part of a
dissertation or thesis. The supplemental files are provided "AS IS" without warranty. ProQuest is not responsible for the
content, format or impact on the supplemental file(s) on our system. in some cases, the file type may be unknown or
may be a .exe file. We recommend caution as you open such files.
Copyright of the original materials contained in the supplemental file is retained by the author and your access to the
supplemental files is subject to the ProQuest Terms and Conditions of use.
Depending on the size of the file(s) you are downloading, the system may take some time to download them. Please be