ETA receptors are involved in the febrile response induced by high dose of bacterial endotoxin

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.

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PASSIVE TRANSFER OF TOLERANCE TO PYROGENICITY OF BACTERIAL ENDOTOXIN

Journal of Experimental Medicine ◽

10.1084/jem.111.4.453 ◽

1960 ◽

Vol 111 (4) ◽

pp. 453-463 ◽

Cited By ~ 27

Author(s):

Henry H. Freedman

Keyword(s):

Endotoxin Tolerance ◽

Passive Transfer ◽

Bacterial Endotoxin ◽

Febrile Response ◽

Highly Sensitive ◽

Altered Response ◽

Prior Administration

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.

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Cold defense mechanisms in vagotomized rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1997.273.2.r784 ◽

1997 ◽

Vol 273 (2) ◽

pp. R784-R789 ◽

Cited By ~ 2

Author(s):

A. A. Romanovsky ◽

V. A. Kulchitsky ◽

C. T. Simons ◽

N. Sugimoto ◽

M. Szekely

Keyword(s):

Defense Mechanisms ◽

Low Dose ◽

Jugular Vein ◽

High Dose ◽

Febrile Response ◽

Sharp Rise ◽

Tail Pinch ◽

External Cooling ◽

Brown Adipose ◽

The Common

Subdiaphragmatically vagotomized rats cannot mount a febrile response to pyrogens and are believed to have severe thermoregulatory deficiencies. We addressed the issue of thermoeffector competence of vagotomized rats by asking three questions. In Expt. 1 we asked, can vagotomized rats readily recruit tail skin vasoconstriction in the course of a moderate cold exposure? In Expt. 2 the question was, can brown adipose tissue (BAT) thermogenesis readily be activated in vagotomized rats (e.g., in response to a tail pinch)? In Expt. 3, we investigated the question: can vagotomized rats elevate their body temperature in response to ephedrine (a drug of high hyperthermizing potential) to the same extent as sham-operated controls? Rats were vagotomized or sham operated and implanted with a catheter into the jugular vein and a thermocouple into the interscapular BAT. To prevent the common complications of vagotomy, special perioperative care was given. During experiments, colonic, tail skin, and BAT temperatures (Tc, Tsk, and TBAT, respectively) were measured. The vagotomized animals were well nourished and had a body mass (325 +/- 6 g) similar to that of the controls (338 +/- 6 g). In Expt. 1, in response to external cooling (15 degrees C, 1 h), the vagotomized (n = 30) and sham-operated (n = 31) rats recruited tail skin vasoconstriction at close values of both Tc (37.84 +/- 0.08 and 37.97 +/- 0.07 degrees C) and Tsk (33.16 +/- 0.17 and 33.18 +/- 0.18 degrees C, respectively). In Expt. 2, tail pinch-associated stress in vagotomized rats resulted in a sharp rise in the TBAT-Tc gradient by 0.3-1.0 degree C. In Expt. 3, ephedrine administered intravenously (whether in a 5 or 35 mg/kg dose) evoked similar hyperthermic responses in the vagotomized and sham-operated rats: a moderate (approximately 2.5 degrees C) Tc rise in the low dose and a "supramaximal" (approximately 5.0 degrees C) rise in the high dose. In sum, the answer to all three questions asked is yes. Vagotomized rats, at least when well nourished, exhibit no signs of thermoeffector deficiency. It is, therefore, not effector incompetence but rather vagal deafferentation per se that can explain the febrile irresponsiveness of vagotomized rats.

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Absence of endotoxin fever but not prostaglandin E2 fever in the Brattleboro rat

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1982.242.1.r116 ◽

1982 ◽

Vol 242 (1) ◽

pp. R116-R120 ◽

Cited By ~ 1

Author(s):

P. C. Eagan ◽

N. W. Kasting ◽

W. L. Veale ◽

K. E. Cooper

Keyword(s):

Prostaglandin E2 ◽

Arginine Vasopressin ◽

Bacterial Endotoxin ◽

Cerebral Ventricle ◽

Intracerebroventricular Injection ◽

Brattleboro Rat ◽

Febrile Response ◽

Long Evans ◽

Colonic Temperature ◽

Lateral Cerebral Ventricle

Changes in colonic temperature following intracerebroventricular injection (icv) of bacterial endotoxin or prostaglandin E2 (PGE2) were measured in Long-Evans (LE) and Brattleboro (DI) rats. Indwelling cannulas were implanted into the brains of rats for subsequent microinjection into a lateral cerebral ventricle. Microinjection of 1 microgram of bacterial endotoxin into a lateral cerebral ventricle produced a fever in the LE rat but not in the DI rat. Daily injections of 1 microgram of endotoxin icv in the DI rat did not result in a fever. Intraperitoneal injections of 50 micrograms of bacterial endotoxin resulted in a fever in the LE rat, but the DI rat showed no such response. Both groups of animals did produce a fever in response to icv administration of 200 ng of PGE2. The lack of arginine vasopressin in the DI rat may be related to the animal's failure to show a febrile response to endotoxin.

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STUDIES ON THE PATHOGENESIS OF FEVER

Journal of Experimental Medicine ◽

10.1084/jem.106.6.787 ◽

1957 ◽

Vol 106 (6) ◽

pp. 787-809 ◽

Cited By ~ 23

Author(s):

Robert G. Petersdorf ◽

Willis R. Keene ◽

Ivan L. Bennett

Keyword(s):

Intravenous Injection ◽

Bacterial Endotoxin ◽

Endogenous Pyrogen ◽

Febrile Response ◽

Single Intravenous Injection ◽

Shwartzman Reaction ◽

Endogenous Serum Pyrogen ◽

Indirect Action ◽

Local Shwartzman Reaction ◽

Bacterial Products

The "endogenous serum pyrogen" that appears in the circulating blood after a single intravenous injection of endotoxin does not produce leukopenia in normal animals, fails to provoke the local Shwartzman reaction, and elicits no "tolerance" when injected daily. Suppression of the febrile response to endotoxin by prednisone does not prevent the appearance of pyrogen in the blood. Animals given large amounts of endotoxin daily continue to respond with high fevers despite failure of endogenous serum pyrogen to appear in detectable amounts after the first two or three injections. Analysis of the response to daily injections shows clearly that the fever during the first 2 hours after administration of endotoxin is unrelated to levels of endogenous serum pyrogen; in contrast, the magnitude of the fever after the 2nd hour correlates well with endogenous pyrogen in some instances. The leukopenic response to endotoxin could not be correlated with the appearance of endogenous serum pyrogen. The differences between endotoxin and endogenous pyrogen and the similarities between leukocyte extracts (sterile exudates) and endogenous pyrogen are summarized and discussed. Dissociation of the febrile response to bacterial endotoxin and levels of endogenous serum pyrogen are discussed and it is concluded that a mechanism involving both direct and indirect action of endotoxins offers the best explanation for the pyrogenic action of these bacterial products.

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IL-6 is essential in TNF-α-induced fever

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1998.275.6.r2028 ◽

1998 ◽

Vol 275 (6) ◽

pp. R2028-R2034 ◽

Cited By ~ 16

Author(s):

Anna K. Sundgren-Andersson ◽

Pernilla Östlund ◽

Tamas Bartfai

Keyword(s):

Tumor Necrosis ◽

Prostaglandin E ◽

High Dose ◽

Central Administration ◽

Wild Type ◽

Febrile Response ◽

Tnf Α ◽

Factor Α ◽

Deficient Mice ◽

Necrosis Factor

Tumor necrosis factor-α (TNF-α) is a pleiotropic cytokine that orchestrates an array of local and systemic effects. For instance, acute exposure to a high dose of TNF-α results in septic shock and fever. We have used interleukin-1β (IL-1β)- and interleukin-6 (IL-6)-deficient mice, along with their wild-type equivalents, to define a role for TNF-α in fever. Briefly, the mice produced prostaglandin E2-dependent fevers in response to recombinant murine TNF-α (rmTNF-α). Furthermore, rmTNF-α (12 μg/mouse ip) triggered a febrile response in IL-1β-deficient mice as well as in their corresponding wild-type controls. In contrast, the IL-6-deficient mice were resistant to rmTNF-α (4.5 μg/mouse ip), although their wild-type counterparts readily mounted a fever. In the IL-6-deficient mice, moreover, the febrile response to rmTNF-α could be restored by a central administration of rat recombinant IL-6 (500 ng/mouse icv). We thus conclude that TNF-α can trigger fever independent of IL-1β but dependent on IL-6. We also suggest that central, rather than peripheral, IL-6 (plasma IL-6 was measured 2 h after pyrogenic challenge) is essential in TNF-α-induced fever.

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Development of fever in the newborn lamb

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1979.236.3.r184 ◽

1979 ◽

Vol 236 (3) ◽

pp. R184-R187

Author(s):

N. W. Kasting ◽

W. L. Veale ◽

K. E. Cooper

Keyword(s):

Onset Time ◽

Bacterial Endotoxin ◽

Endogenous Pyrogen ◽

Febrile Response ◽

Newborn Lamb

Newborn lambs do not become febrile in response to intravenous (iv) bacterial endotoxin in moderate doses. Newborn lambs were tested to see if they could become febrile to large doses of endotoxin or to endogenous pyrogen. At 5 h of age lambs do not become febrile to relatively large doses of endotoxin or to endogenous pyrogen, but rather become hypothermic. At 32 h and all subsequent times, fevers could be elicited. Onset time of fevers in lambs was short initially and gradually lengthened over 9 days, at which time it was similar to the onset time of the adult fever. With respect to the febrile response, newborn lambs showed varying degrees of tolerance after 10 days of daily injections of endotoxin, as compared to the ewe which becomes tolerant in 2 or 3 days.

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Age-related differences in the febrile response of the New Zealand White rabbit to endotoxin

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y81-093 ◽

1981 ◽

Vol 59 (6) ◽

pp. 613-614 ◽

Cited By ~ 11

Author(s):

A. V. Ferguson ◽

W. L. Veale ◽

K. E. Cooper

Keyword(s):

New Zealand ◽

Age Groups ◽

Zealand White Rabbit ◽

Bacterial Endotoxin ◽

Febrile Response ◽

New Zealand White Rabbit ◽

Age Related ◽

New Zealand White Rabbits ◽

Effect Of Age ◽

Second Peak

The effect of age on the febrile response of New Zealand White rabbits was investigated by administering bacterial endotoxin intravenously to animals from two different age groups. Rabbits greater than 2.0 years of age developed significantly smaller fevers than did animals that were less than 1.0 year old (p < 0.001). The deficit in the febrile response of older animals was specifically related to an absence of the second peak of fever.

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