Quantitative Studies of Human Leukocytic and Febrile Response to Single and Repeated Doses of Purified Bacterial Endotoxin*

Comparison of agents producing a neutrophilic leukocytosis in man. Hydrocortisone, prednisone, endotoxin, and etiocholanolone.

“…It should be noted that these endotoxin responses are not normally distributed (Table II); two individuals gave particularly large responses. This individual variability in the PMN response to endotoxin has been noted previously (1,15). In fact, because of this variability, the minimum response after endotoxin considered as "normal" (an increase of at least 2,000 cells/mm3) has been based on the range of results in normal subjects rather than a calculated confidence interval.…”

“…Endotoxin, on the other hand, causes blood granulocytes to be transiently shifted from the circulating granulocyte pool to the marginal pool, which leads to an apparent granulocytopenia shortly after its administration (5). Endotoxin, in contrast to glucocorticosteroids and etiocholanolone, causes the release of progressively higher numbers of nonsegmented PMNs at progressively higher doses, with no apparent plateau to this dose-response curve in man (1). At the doses usually given, however, no shift to nonsegmented cells normally occurs (13,15).…”

“…administration of endotoxin (1,2), etiocholanolone (3), and glucocorticosteroids (4). The principal mechanism of the leukocytosis for each of these agents is release of PMNs from the bone marrow PMN reserves (5)(6)(7).…”

“…Most investigators have used endotoxin or etiocholanolone to study the marrow reserves (8)(9)(10)(11)(12)(13)(14)(15). Neither of these agents are widely available, and both cause fever, pain, and other significant symptoms (1)(2)(3). The few studies in which corticosteroids have been used to measure the capacity to develop a neutrophilic leukocytosis suggest that the response to corticosteroids may parallel the response to etiocholanolone and endotoxin (4,10,(16)(17)(18)(19)(20) Endotoxin from Salmonella abortuts-equi (Lipexal, Dorsey Laboratories, Lincoln, Nebr.)…”

Mechanisms of Endotoxin Tolerance

“…The responsiveness of rabbits to febrile phase plasma during the pyrogenic refractory state, as has been reported during pyrogenic tolerance (1), precludes exhaustion of the thermoregulatory mechanisms. The leukocytosis during the pyrogenic refractory state, and the absence of severe leukopenia during pyrogenic tolerance (15), precludes destruction of a major cell population implicated in the production of endotoxin/ever No reversal (17) Normal (15) (1). Two alternative mechanisms of desensitization to endotoxin to be considered are (a) elaboration of circulating antibody which accelerates the blood clearance and destruction of endotoxin by the RES, and (b) desensitization at the cellular level.…”