All ETDs from UAB

Advisory Committee Chair

C Roger White

Advisory Committee Members

G M Anantharamaiah

Susan Bellis

Kathleen Berecek

Suzanne Oparil

Document Type

Dissertation

Date of Award

2009

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Sepsis is among the top ten causes of death in the US, and it is associated with severe inflammatory tissue damage and organ dysfunction. Reduced plasma high density lipoprotein (HDL) is associated with increased mortality in septic patients. Since raising plasma apolipoprotein (apo) A-I and HDL may reduce sepsis complications, we tested the hypothesis that the apoA-I mimetic peptide 4F confers similar protective effects in two animal models of sepsis, and explored the possible mechanisms. In endotoxemic rats, inflammatory mediators were significantly induced while blood pressure was significantly reduced by 6hr. The impaired arterial response to vasoconstrictors was related to nitric oxide synthase 2 up-regulation and nitric oxide over-production. Concurrent 4F treatment significantly blunted inflammatory response and improved systolic blood pressure, while scrambled 4F (Sc-4F) was without effect. Cardiac performance was significantly impaired at 24hrs after the intervention as indicated by reduction in left ventricular enddiastolic volume, stroke volume, cardiac output (CO) by transthoracic echocardiography, without visible impairment in intrinsic contractile function (fractional shortening and +/- dP/dt). Concurrent 4F treatment significantly improved left ventricular filling as indicated by end-diastolic pressure. Both 4F and lipopolysaccharide were found to co-localize in the HDL fraction. In cecal ligation and puncture (CLP) rats, similar changes in cardiac function were noted and these changes were associated with reduced right atrial pressure which was improved by 4F treatment 6hr after the surgery when inflammatory pathways were already activated. Along with impaired cardiac performance, plasma HDLcholesterol was significantly reduced and lipid hydroperoxide level increased in both endotoxemic and CLP rats. HDL fractions were isolated by floating ultracentrifugation, and they were characterized by altered size and electrophoretic mobility, lower content of apoA-I, apoA-IV and apoC, and increased content of apoA-II, apoE and SAA. 4F treatment blunted all the above changes in septic animals and significantly improved survival rate after CLP. It is proposed that protective effects of 4F are related to an elevation of HDL concentration and function that effectively modulate inflammatory response and neutralizes pathogenetic factors, including endotoxin, in septic rats. This therapeutic modality may be extended to the treatment of other inflammatory diseases.

Share

COinS