Piero Foresta

LPS-induced serum TNF production and lethality in mice: effect of L-carnitine and some acyl-derivatives

The effect of L-carnitine and some of its acyl derivatives on serum TNF production and lethality in a murine experimental endotoxin shock model was investigated. In some instances, serum IL-6 production was also evaluated. In this experimental model, C57BL/6 mice received 30 mg/kg LPS (E. cell 055:B5) injected intraperitoneally, while L-carnitine and its derivatives were administered according to different schedules. Serum levels of TNF and IL-6 were evaluated 1 h following LPS injection. The treated animals were also monitored daily for differences in body temperature, feeding, and survival for 10 days after LPS injection. Although some derivatives were able to significantly affect TNF production, the marked decrease in serum TNF levels of LPS-treated mice was not paralleled by a substantial increase in survival.

In vitro activation of murine peritoneal exudate cells (PEC) and peritoneal macrophages by ST 789

ST 789 is a new synthetic compound characterized by an amino acidic group joined to the N9 position of the hypoxanthine ring, which has been shown recently to have immunomodulating properties and minimal toxicity. The drug has been reported to protect immunosuppressed mice from microbial infections and tumour growth, and to restore the mitogen-induced proliferation of splenocytes from immunosuppressed young mice. In this study, we show that in vitro addition of ST 789 is able to markedly augment the sheep red blood cells (SRBC) phagocytosis by PEC, and to potentiate the cytotoxic activity of peritoneal exudate (PE) macrophages (M phi) vs the L-M tumour cell line. We also found that ST 789 enhanced the rIFN-gamma-induced NO2- release from cultured PE M phi. Similarly, in vitro addition of ST 789 to the latter cultures significantly increased the production of interleukin 1 (IL-1) and tumour necrosis factor (TNF) induced by lipopolysaccharide (LPS). These studies demonstrate that ST 789 is a potent phagocyte activator for the induction of cytokine release, phagocytosis and cytotoxic activity against tumour cells in vitro.

Carnitine and congeners as regulators of tumour necrosis factor

In the past few years the steady increase in septic shock has been fuelled by the augmented use of invasive medical technology, immunosuppressive drug therapy, and increased longevity of patients with secondary immunodeficiencies. The septic shock syndrome probably represents the eects of many mediators on vasculature, myocardium and other systems. Endotoxin has been postulated to mediate the early stages of mediator cascade during septic shock, and inhibiting its eect has become an underlying principle of certain therapies. The presently available anti-endotoxin monoclonal antibodies seem effective only in patients with Gram-negative bacterial infections. However, there is usually no time to distinguish this sub-group of individuals from others with diEerent infections before the start of therapy and one of the central problems with antibody-based therapies--the lack of understanding of how they work--is still unsolved. Tumour necrosis factor might be a direct or indirect mediator of many of the cardiovascular responses associated with sepsis. Hypotension, hypothermia, hypoglycaemia, acidosis, focal hepatic necrosis, and acute interstitial pneumonitis with neutrophil trapping have been observed following experimental injections of high doses of TNF. As a mediator of inflammation, TNF triggers the release of a large body of cytokines, interleukin 1 included, and of arachidonic acid metabolites. Experimental data have suggested that TNF could be an appropriate target for the treatment of septic shock, but work in animals up to now has shown that anti-TNF antibodies are not very effective in focal sepsis. Recently, many investigators independently from each other reached the conclusion that carnitine and congeners can behave as modulators of TNF production. The results of their studies were the subject of a symposium held in Pomezia, Rome, on 28 January, 1993 and are published in Mediators of Inqammation. The information presented in this volume must be considered as an effort to stimulate scientists’ creative thought and clinicians’ awareness of the therapeutic potential of carnitine and carnitine congeners for the treatment of septic shock.

Behavioural and Immunological Changes in the Aging Rat

Main features of the aging process in the rat are marked changes in immunological activities and in behavioural performances.