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PubMed1955

Studies on the antipyretic action of cortisone in pyrogen-induced fever.

The mode of action of cortisone as an antipyretic has been studied in rabbits challenged with intravenous injections of bacterial pyrogens. The fever induced by pyromen or dextran was found to be markedly suppressed when cortisone was administered in liberal amounts (25 mg. twice daily) for 3 days prior to the challenge. Although the cortisone effectively blocked the febrile response to both pyrogens, it failed to influence the transient but marked leucopenia which characteristically precedes the onset of fever. The antipyretic action of the drug also was shown to bear no relation to the activity of the serum factor recently demonstrated by Farr, Grant, and others to be involved in the production of pyrogen-induced fever. In preliminary experiments with typhoid vaccine as the inciting pyrogen, the presence of serum factor activity in normal blood and its absence in the blood of pyrogen-tolerant rabbits was confirmed. Subsequently the blood of rabbits treated with antipyretically effective doses of cortisone was shown to contain just as much serum factor activity as that of normal rabbits. In addition, previous incubation of the pyrogen with serum factor failed to influence the antipyretic effect of the drug. It is concluded from these findings that in suppressing pyrogen fever, cortisone acts neither upon the leucopenic reaction nor upon the fever-accelerating factor of the serum. By exclusion it would appear that the drug must influence some later stage of the fever-producing process. The mechanisms involved in the later stages of the response to exogenous pyrogen remain undefined, and the need for determining whether they are related to the prefebrile leucopenia is emphasized.

Animals↗
PubMed1955

Studies on the pathogenesis of fever. I. The presence of transferable pyrogen in the blood stream following the injection of typhoid vaccine.

The rate of clearance of intravenously injected typhoid vaccine was studied in unsensitized, sensitized, and pyrogen-tolerant rabbits by means of a passive transfer technique. The blood of unsensitized rabbits which had not been previously exposed to bacterial pyrogen remained pyrogenic for normal recipients throughout a period of 2 hours following the injection. In contrast, rabbits sensitized by having received either one or two injections of the vaccine at least 3 weeks prior to the experiment cleared their blood of the test vaccine within 30 minutes despite the fact that they exhibit the same febrile response as unsensitized rabbits. After 1 hour, however, a transferable pyrogenic substance was again demonstrable in the sera of this group. Reasons are discussed for believing that this newly appearing substance may be of endogenous origin and may be the factor which directly affects the thermoregulatory centers of the brain. Rabbits which are made tolerant by repeated daily injections of vaccine have a characteristically depressed febrile response. Not only were the blood streams of such animals cleared of the injected vaccine within less than 5 minutes, but samples of their sera obtained 1 and 2 hours after the injection also failed to contain demonstrable quantities of the secondary pyrogen observed in sensitized animals. The latter observation is in keeping with the suggestion that the secondary pyrogen may play a critical role in the production of fever.

Animals↗
PubMed1955

Studies on the pathogenesis of fever. II. Identification of an endogenous pyrogen in the blood stream following the injection of typhoid vaccine.

Further studies have been made of a pyrogenic substance which appears in the circulation of rabbits during the course of experimental fever induced by injection of typhoid vaccine. With the use of a passive transfer method and pyrogen-tolerant recipients, the biological properties of this substance have been differentiated from those of the uncleared vaccine in the circulation. The newly identified factor resembles leucocytic pyrogen in the rapidity with which it produces fever and in its failure to exhibit cross-tolerance with bacterial pyrogen. This striking similarity of properties suggests that the circulating factor is of endogenous origin and may arise from cell injury. A close correlation between its presence in the circulation and the existence of fever has been demonstrated. The possible relationship of these findings to the pathogenesis of fever is evident.

Animals↗
PubMed1959

The presence of plasma inhibitors during the crisis phenomenon in experimental relapsing fever (Borrelia novyi).

The intensity and duration of Borrelia novyi infection in rats depends upon the dose of spirochetes administered. The spirochetemia in response to an inoculum of 1 x 10(8) spirochetes/kg. characteristically reaches a peak of 4 to 5 million organisms per c.mm. of blood at about 72 hours. Resolution of the primary infection occurs within 48 hours after the peak counts have been observed, with crisis ending at 100 to 120 hours after inoculation. Treatment of the acute infection, so standardized, by 10 ml./kg. of crisis plasma intraperitoneally delays the onset of the spirochetemia 76 to 140 hours, and reduces the maximal spirochetal count 10(-3) to 10(-6) that of the unmodified controls. This is evidence that inhibitor is present in the plasma at the time of crisis and plays a role in limiting the primary infection and subsequent relapses. The activity of crisis plasma is not destroyed by freezing, or after storage at 4 degrees C. for 4 days. Fractions I + II + III and IV + V+ VI from crisis plasma, obtained by method 10 of Cohn et al., were also effective in suppressing the acute spirochetemia, but differed in duration and effectiveness. The first of these was about as potent as the undiluted whole plasma, and the second about as potent as plasma diluted 1:4.

Animals↗
PubMed1960

Passive transfer of tolerance to pyrogenicity of bacterial endotoxin.

The typical febrile response of normal rabbits given bacterial endotoxin intravenously may be modified by prior administration of plasma or, less effectively, serum of endotoxin-tolerant donors. This altered response is characterized by disappearance of the second rise in fever and by a striking reduction in fever index. It thus resembles the course of fever shown by rabbits made tolerant to endotoxin by one or more previous daily doses. This transfer of tolerance by plasma or serum depends critically upon the manner in which tolerance is induced in the donors. The plasma of donor rabbits made tolerant, then given an RES-blocking dose of carbon, still confers tolerance upon normal recipient rabbits. Such donors have lost their tolerance and are highly sensitive to endotoxin at the time their blood is taken. The implications of these findings for endotoxin tolerance and for transfer of this phenomenon are discussed. The evidence is consistent with the hypothesis that both tolerance and its transfer are based upon RES function and are independent of antibody.

Animals↗
PubMed1960

Studies on the pathogenesis of fever. VII. Preliminary chemical characterization of leucocytic pyrogen.

Study of the chemical properties of the pyrogenic component of rabbit polymorphonuclear leucocytes reveals it to contain an essential, non-dialyzable protein which: (a) is precipitated by perchloric acid, (b) is removed by extraction with phenol, (c) is soluble in 50 per cent methanol and 33 per cent saturated ammonium sulfate, and (d) is destroyed by the proteolytic action of both trypsin and pepsin. By combined chemical and chromatographic techniques the leucocytic pyrogen has been purified approximately 50-fold. The partially purified material contains less than 1 per cent carbohydrate, is resistant to periodate oxidation, is unaffected by extraction with butanol and contains at least two immunologically active components when tested by the Ouchterlony gel-diffusion technique. Its chemical properties distinguish it from other known pyrogenic substances which have been implicated in the pathogenesis of fever.

Animals↗
PubMed1960

Further studies on passive transfer of tolerance to pyrogenicity of bacterial endotoxin. The febrile and leucopenic responses.

The effect of various schedules for inducing tolerance to bacterial endotoxin in donor rabbits upon suitability for demonstration of passive transfer of tolerance to pyrogenicity in normal recipients has been investigated. Long-term treatment of donors, through 5 weeks, is no more effective than a brief series of injections, adding further evidence that tolerance is not attributable to specific antibody to the endotoxin. Qualitative differentiation of the febrile pattern of passively tolerant recipients from that seen in control animals depends upon the magnitude of the test dose of pyrogen. Passively tolerant rabbits respond to endotoxin with an acute leucopenia equivalent to that seen in controls suffering a full biphasic fever. Animals given daily injections of endotoxin continue to show the acute leucopenia, despite the early modification of the course of fever characteristic of endotoxin tolerance. The assumption that the leucopenia reflects damage to the leucocytes, with release of endogenous pyrogen, is not consistent with these findings. Rabbits rendered leucopenic by nitrogen mustard and then given endotoxin exhibit a rapidly developing fever of greater than normal intensity, the exaggeration of the febrile response being proportional to the severity of the induced leucopenia. The implications of these findings for the pathogenesis of endotoxin-induced fever are discussed. The evidence supports the hypothesis that endotoxin produces fever by direct action rather than by release of endogenous leucocytic pyrogen. It is postulated that the lesser fever, in animals having normal numbers of circulating leucocytes, reflects a limitation of available endotoxin by the known rapid sequestration in the white blood cells at the time of the acute leucopenia. It is further suggested that the biphasic febrile response of the normal rabbit results from reinoculation of the blood stream by the temporarily sequestered endotoxin, the RES of the tolerant animal clearing the released endotoxin at a rate sufficient to prevent triggering the second phase of fever.

Animals↗
PubMed1960

Pathogenesis of fever: effects of various endogenous pyrogens upon the level of circulating granulocytes in normal rabbits.

The endogenous pyrogen in the serum or plasma of rabbits 2 hours after the intravenous injection of typhoid vaccine had a marked effect on the circulating leucocytes of normal rabbits. Immediately following intravenous injection there was a brief, but marked, granulocytopenia which was quickly followed by a granulocytosis. Under the same circumstances pooled heterologous serum or plasma from normal rabbits produced no fever or significant change in the level of circulating leucocytes. The cell-free fluid of sterile peritoneal exudates produced a marked leucocytosis without a preceding leucopenia when injected intravenously into normal rabbits. When comparably pyrogenic doses of typhoid vaccine were injected in the same manner no significant change in the level of circulating leucocytes occurred. The relevance of these findings to the pathogenesis of fever is discussed.

Agranulocytosis↗
PubMed1961

Endotoxin fever in granulocytopenic animals.

The febrile response to bacterial endotoxin was measured in rabbits made leukopenic with nitrogen mustard. A striking increase in susceptibility to the lethal effects of endotoxin occurred in severely leukopenic animals. Animals without circulating granulocytes, or with only basophils, developed no significant fever after endotoxin injection. Animals with circulating granulocytes other than basophils exhibited a biphasic febrile response to endotoxin; this response was significantly less in magnitude than that of control animals. Control animals, severely granulocytopenic animals, and animals with no circulating granulocytes other than basophils showed comparable febrile responses to serum pyrogen. These results suggest that granulocytes inactivate endotoxin in vivo and support the hypothesis that leukocyte pyrogen is a necessary intermediate in endotoxin fever. Basophils do not appear to participate in this process. These observations also contradict previous studies that were taken to indicate a normal febrile response to endotoxin in leukopenic animals and suggest that those results are related to the persistence of granulocytes.

Agranulocytosis↗