In vitro biosynthesis of plasma proteins under ischemic conditions of closed-circuit perfusion of healthy and intoxicated rabbit liver.

We are elaborating on the kinetics and mechanisms of septic rabbit liver to de novo biosynthesize acute-phase response (APR) proteins under in vitro conditions of deepening ischemia in reference to their in vivo prevalence in serum and cerebrospinal fluids (CSF) collected at predetermined times. The significance of the data is interpreted as relevant to grafting cadaveric liver into end-stage liver diseased patients and APR-induced ischemic heart diseases (IHD). Hepatic APR was induced by CCl(4)-intubation, and the administration of cholera toxin (CT) or scorpion venom (SV), or both, to rabbits. Hepatic functional efficiency, in terms of biosynthesis of APR proteins in closed circuit perfusion of the isolated intoxicated liver with oxygenated saline or L-15 media paralleled the two-dimensional immunoelectrophoresis (2D-IEP) spectrum of APR serum proteins at time of liver isolation. We are suggesting: (a) in vitro biosynthesis of plasma proteins by isolated perfused liver is the result of in vivo decoded and retained APR inflammatory signals; and (b) decoded inflammatory signals are expressed not withstanding the perfusate's organic composition. Furthermore, 90 min of ischemic perfusion in saline or L-15 medium precipitated mitochondrial aberrations which resulted in further deterioration of de novo biosynthesis of APR plasma proteins. Regardless of the nature of the inflammatory stimuli, mitochondrial aberrations rendered the perfused organ a biologically inert tissue mass that was incapable of resuming biological function upon perfusion with oxygenated L-15 medium. This is most likely due to ischemia-induced irreversible hepatic necrosis. Thus, in vitro aberrations of mitochondrial function(s) critically limit the capability of the isolated liver to resume its organic function to sustain biosynthesis of de novo plasma proteins. Extrapolation of these results to the surgical management of end-stage liver diseases points to the importance of the status and the handling protocol(s) of the cadaver donor liver prior to successful grafting. We conclude that although histology of a cadaver liver may reveal well-preserved hepatic cellular organelles with at least minimal intra- and intercellular communication required for viable hepatic function, we deem it essential to further define acceptable minimal capabilities to de novo biosynthesize plasma proteins by a cadaver liver as a measure of its functional viability and suitability for transplantation. Ultimately, this measure may improve the success of liver transplants with minimal surgical and drug interventions.

Cardiac heart disease in the era of sucrose polyester, Helicobacter pylori and Chlamydia pneumoniae.

Recent evidence associates inflammatory mediators with coronary heart disease. Elevation of acute-phase reaction (APR) proteins such as serum amyloid A, fibrinogen, CRP and haptoglobin in response to Helicobacter pylori (H. pylori) infection was shown to initiate gastritis and ischemic heart disease. Positive Chlamydia pneumoniae (C. pneumoniae) serology is associated with increased levels of inflammatory cytokines and tumor necrosis factor-alpha (TNF-alpha), which stimulates endothelial cell activation, procoagulant activity and angiogenesis in patients with coronary heart disease. As a final example, interleukin-6 (IL-6) has been proposed to mediate cardiovascular disorders. Public awareness of risks of excessive body weight and high levels of serum cholesterol propelled the development of synthetic dietary components such as sucrose polyester (SPE) to substitute for natural lipids. SPE is a synthetic lipid whose physical properties are similar to a natural triacylglycerol with a similar assortment of fatty acids and is resistant to lipolysis by gastric and pancreatic enzymes. Intake of SPE in lieu of natural lipids is expected to decrease absorption of essential fatty acids (EFA) and fat-soluble vitamins among other essentials. Deficiency of EFA leads to the formation of faulty cellular membranes, which is manifested as skin lesions, growth failure, erythrocyte fragility, impairment of fertility and uncoupling of oxidation and phosphorylation. Possibilities of absorption of these synthetic lipids into the circulation may represent an unexpected health hazard. We have shown that subcutaneous (sc) administration to rabbits of a range of lipolysis-resistant lipid-like sorbitol, mannitol and arabitol esters of palmitic (P) and lauric (L) acids was found to evoke a mild APR, which in humans could contribute to CHD incidence. We suggest a reversal in the commonly accepted role of SPE as a sequestor of dietary lipid: SPE may be the lipophilic solute contained within the dietary lipid solvent micelle. An alternative conclusion regarding the biological effects of excessive dose of SPE in human and pig for a short time span should be considered.