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Stimulation of the immune system or experimental conditions (bacterial lipopolysaccharide (LPS) treatment) provoke a broad spectrum of physiological responses. It was recently shown that one of them is the activation of the hypothalamic-pituitary-adrenal (HPA) axis. The mechanism and the site or sites through which LPS stimulates the HPA axis are not well understood. To establish whether the effect of bacterial LPS is related in vivo to the presence of hypothalamic hypophysiotrophic peptides (corticotrophin-releasing factor-41, arginine vasopressin, etc.), plasma ACTH and corticosterone levels were monitored in intact and sham-operated rats, and in rats with paraventricular nucleus lesions in order to remove the main source of these neuropeptides. Evidence was obtained that 4 h after treatment, LPS was able to activate the hypophysial-adrenal system in the absence of hypophysiotrophic neuropeptides of paraventricular origin. It is suggested that, in vivo, LPS could have a direct effect on the pituitary gland or that it acts through an extrapituitary, non-paraventricular pathway to activate the HPA axis.

TUCHWEBER, AND L. BERT6K. Effect of lead acetate on susceptibility of rats to bacterial endotoxins. J. Bacteriol. 91:884-890. 1966.-A single, normally well-tolerated, intravenous injection of lead acetate increases the sensitivity of the rat to the endotoxins of various gram-negative bacteria about 100,000 times above normal. Under the conditions of these experiments, the mortality and organ changes normally produced by the intravenous injection of 100 ,ug of Escherichia coli endotoxin were essentially the same as those obtained by use of 1 nanogram in lead-sensitized rats. The sensitizing effect of lead acetate for E. coli endotoxin is greatest when the two agents are given simultaneously. However, considerable sensitization is still detectable when endotoxin is injected up to 1 hr before or 7 hr after sensitization with lead. No sensitization was noted when the endotoxin was administered 24 hr before or after lead acetate. Under our experimental conditions, the minimal dose of lead acetate which could still induce significant sensitization to E. coli endotoxin was 1 mg per 100 g of body weight. Although lead acetate induces a high degree of susceptibility to various endotoxins, other reticuloendothelial blocking agents did not acquire unusualtoxicity after pretreatment with lead. Finally, none of the other metals or reticuloendothelial blocking agents tested could duplicate the pronounced decrease in endotoxin resistance induced by lead acetate.

The plasma level of endotoxin was determined in 116 healthy blood donors. After a routine physical and laboratory investigations the endotoxin level was determined with Limulus amebocyte lysate assay (LAL-test) by the chromogenic kinetic method of Bio-Whittaker Co. (USA). Its sensitivity was 0.005-50 EU/ml. The plasma level of endotoxin in most of the healthy donors was less than 1 EU/ml (in the range of 0.01-1.0 EU/ml), but always measurable. The average +/- S.D. was 0.128 +/- 0.215 EU/ml. Because of the high standard deviation and high range of values, the data were distributed into two groups with the means of 0.05 +/- 0.022 EU/ml and 0.294 +/- 0.186 EU/ml. The difference between the groups was significant (p < 0.001). In conclusion, endotoxin can be measured in plasma of healthy individuals.

The absorption of tritium-labeled Escherichia coli O89 Westphal-type endotoxin from the peritoneal cavity of rats was diminished by bile by 23% and by sodium deoxycholate by 47%, respectively. Practically, there is no endotoxin absorption from the intestinal tract of normal rats. The bile duct of rats was chronically cannulated for experimental purposes. A significant amount of perorally administered endotoxin absorbed from the intestinal canal into the blood in the rats treated thus. Absorption was demonstrated by the lethal effect of endotoxin on rats previously hypersensitized by lead acetate, and by the radioactivities found in the blood samples. The intestinal absorption of endotoxin in rats, rendered bile-deficient, may be prevented by sodium deoxycholate. Supported by their experimental findings, we emphasize the important role of bile acids in the defense mechanism of the macroorganism against bacterial endotoxins.

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A BSTRACT : Innate resistance is mediated by non-immune defense and by natural immunity. Non-immune defense includes diverse mechanisms (e.g., physico-chemical defense by bile acids). Natural killer (NK) cells, ␥␦ T lymphocytes and CD5 + B lymphocytes are key mediators of natural immunity. These cells utilize germ-line coded receptors that recognize highly conserved, homologous epitopes (homotopes). Typically, it is not the antigen, but cytokines and hormones that regulate the level of NK-mediated cytotoxicity. These include interleukin-2, interferons, prolactin and growth hormone. Less is known about ␥␦ T lymphocytes. CD5 + B lymphocytes produce germ-line coded antibodies (predominantly IgM) that are polyspecific, and able to recognize a great variety of microorganisms, cancer cells and self-components. Antigen is not an effective stimulus for natural antibody (NAb), but bacterial lipopolysaccharide (LPS) is. During the acute phase response (febrile illness) the T-cell-regulated adaptive immune response is switched off and natural immune mechanisms are amplified several hundred to a thousand times within 24-48 hours (immunoconversion). This immunoconversion is initiated by immune-derived cytokines, and involves profound neuroendocrine and metabolic changes, all in the interest of host defense. Immune recognition is assured by natural antibodies and by some liver-derived acute phase proteins, such as C-reactive protein or endotoxin-binding protein, the level of which is elevated in the serum. Thus, natural immunity is essential for a first and last line of defense and the neuroendocrine system is an important promoter of this activity.

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