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Title: The role of humoral and cellular mediators in the progression of peripheral arterial disease
Author: Chaparala, Ramakrishna P. C.
ISNI:       0000 0004 2740 3037
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2009
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Traditional risk factors for peripheral arterial disease (PAD) include smoking, hypertension, advanced age, diabetes and heart disease. These do not fully explain the differential nature of disease progression. Inflammatory and immunological factors have been increasingly implicated as active mediators of atherosclerotic disorders, including PAD. In particular, an imbalance between Thl and Th2 responses is thought to promote the progression of the atherosclerotic process. The extent of this imbalance in PAD is poorly understood. The aim of this study was therefore to examine the involvement of cytokines, anti- endothelial antibodies (AEA) such as anti-cardiolipin(a-CL) and anti-Bz-Glycoproteinl antibodiestanti-Bz-Gl'I) and antibodies to heat shock protein60 (aI?-ti-HSP60) as mediators of Thl and Th2 responses in the pathophysiology of this vascular disorder. Materials and Methods Patients included age-matched controls, stable claudicants (SC), critical limb ischaemics (Cl). Plasma baseline cytokine profiles, AEA and anti-HSP60 were analysed. Whole blood was stimulated with lipopolysaccharide (LPS) and analysed for interlukins by fluid-phase multiplex immunoassay. AEA and anti-HSP60 levels were determined by enzyme-linked immunosorbent assay. Data were analysed by Kruskall-Wallis tests and Mann-Whitney-U tests post hoc. 3 Results: Significantly higher levels of IL-6 were found in Cl compared to SC, which in turn were higher than in the Control group. IL-lO and IL-13 levels were higher in PAD subgroups (SC and Cl) versus control although there was no significant difference between PAD subgroups. AEA and anti-HSP60 levels tended to be higher in association with increasing PAD severity. However, while Cl Anti-B2-GPI levels were higher than in Control there was no significant difference in anti-CL levels. Anti-HSP60 was different in each of the three groups Clc-SCc-Control. Following an in vitro LPS challenge, unstandardized IL-8 and IL-13 production was higher in PAD patients compared to controls after 6h of incubation. However when these levels were standardized against the white cell count this effect was not seen. Conclusions: In conclusion, this study does not support either Thl or Th2 cytokines as being predominant in PAD (i.e., representing a Thl:Th2 imbalance), although inflammatory burden is more pronounced in severe manifestations of the disease. A minor degree of inflammatory hyper-responsiveness associated with cultured whole blood from SC and Cl patients appeared to relate to leukocytosis rather than being attributable to an inherent inflammatory dysfunction per se. The profile of all the mediators studied were however, seen to be influenced by disease severity.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available