Use this URL to cite or link to this record in EThOS:
Title: The innate immune system in blood vessels and its relevance to septic shock
Author: Cartwright, Neil
ISNI:       0000 0001 3523 7890
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2008
Availability of Full Text:
Full text unavailable from EThOS.
Please contact the current institution’s library for further details.
Septic shock is a common condition with a high mortality rate. The pathophysiology of sepsis is complex, although inappropriate vasodilation, leading to a fall in systemic vascular resistance (SVR), is pivotal to the development of shock and multi-organ dysfunction syndrome (MODS). The molecular pathways and mediators underlying this vascular dysfunction are not clearly understood. . I investigate the role of pattern-recognition receptors, including Toll-like receptors (TLRs) and NOD domain containing proteins with a leucine rich repeat (NLRs), in blood vessels and their contribution to vascular dysfunction. I show that Gram positive Staphylococcus aureus signals exclusively through a TLR2I6 heterodimer in murine vessels to induce nitric oxide synthase (NOS) II, through a MyD88 and tumor necrosis factor a. (TNFa.) dependent pathway. Lipopolysaccharide (LPS) signals through TLR4, but signalling is not exclusively dependent on MyD88/Mal, TRIF or TNFa. Escherichia coli induced NOSII in blood vessels is partially independent of TLR4: this may be due to peptidoglycan, which is sensed through NOD1. I show that, in rats, NOD1 agonists cause shock in vivo and induction of NOSII in blood vessels. The shock caused by NOD1 agonists differ from that caused by LPS as it has a different cytokine profile and causes less end organ injury. NOD1 agonists do not directly activate macrophages and other immune cells: I investigate the role of stromal versus radiosensitive cells in a chimeric mouse model of LPS induced systemic inflammation and show that stromal cells play an important role in the induction of cytokines and development of systemic inflammatory response. Blood vessels sense pathogens through different pathways than macrophages. These differences may be exploited in the development of new drugs for sepsis and other vascular diseases.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available