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INFLAMMATION, CYTOKINES, AND TEMPERATURE REGULATION
1Systemic Inflammation Laboratory, Trauma Research, St. Joseph's Hospital and Medical Center, Phoenix, Arizona 85013; 2Thermoregulation Laboratory, Legacy Clinical Research and Technology Center, Portland, Oregon 97140; and 3Department of Physiology, Southern Illinois University, Carbondale, Illinois 62901
Submitted 16 December 2002 ; accepted in final form 16 April 2003
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ABSTRACT |
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 TOP ABSTRACT MATERIAL AND METHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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2°C) and long-lasting (>3 wk) hyperthermia. Because the
hyperthermia was not accompanied by tail skin vasoconstriction, it likely
reflected increased thermogenesis. After the rats recovered from the acute
(but not chronic) side effects, their febrile response to IL-1
(500
ng/kg iv) was tested. The sham-operated rats developed typical monophasic
fevers (0.5°C), the lesioned rats did not. However, the absence of
the febrile response in the OVLT-lesioned rats likely resulted from the
untreatable side effects. For example, hyperthermia at the time of pyrogen
injection was high enough (39–40°C) to solely prevent fever from
developing. Hence, the changed febrile responsiveness of OVLT-lesioned animals
is given an alternative interpretation, unrelated to febrigenic signaling to
the brain. fever; adipsia; third ventricle; median preoptic nucleus
, access the CNS by carrier-mediated transport across the
blood-brain barrier (BBB) (2).
Second, circulating pyrogens bind to the cerebral vascular endothelium and
stimulate production of fever mediators, most importantly PGE2, by
endothelial cells; endotheliocytes release PGE2 into the brain
tissue (10). Third, pyrogens
act on neural terminals in peripheral tissues and convey febrigenic signals to
the CNS via sensory fibers, e.g., those of the vagus nerve
(7,
74). Fourth, peripheral immune
signals enter the brain through the organum vasculosum laminae terminalis
(OVLT) (4) and possibly other
periventricular organs (69),
in which capillaries are fenestrated resulting in a "leaky" BBB
(36). The significance of routes associated with a single neural structure (i.e., the vagus nerve or the OVLT) has been evaluated by assessing changes in febrile responsiveness after lesioning the respective structure. For the vagus nerve, experiments have involved surgical or chemical vagotomy (for review, see Ref. 48). For the OVLT, experiments have involved electrolytic, surgical (knife cuts), or thermal ablation of this structure (for review, see Ref. 40). However, a neural lesion may affect a physiological function not only by interrupting signaling along the corresponding route but also by causing undesired "side effects" that change the response of interest. For example, bilateral truncal vagotomy decreases fevers evoked by low doses of bacterial LPS (54), but it also leads to malnutrition, unless the animals are kept postoperatively on a liquid diet (1). Malnutrition itself attenuates febrile responsiveness (24, 62, 67). It was important, therefore, to determine that vagotomized animals have decreased febrile responsiveness even in the absence of malnutrition (51).
Lesions of the OVLT and its surrounding tissue in the anterior wall of the third ventricle also cause multiple side effects, including severe adipsia and emaciation (for review, see Ref. 8). In the fever literature, only a small number of studies (4, 6, 69) paid attention to these side effects. Blatteis et al. (4, 6) reported a tendency for polydipsia to develop in OVLT-lesioned guinea pigs in one study (4) and mentioned variable hypodipsia in another (6); the authors did not attempt to minimize these symptoms. Blatteis et al. (4, 6) also questioned whether lesions of the OVLT affect afebrile thermoregulation (6) or febrile responsiveness to intra-brain endogenous pyrogen (4), but found no gross deficiency. Takahashi et al. (69) tried to encourage resumption of normal drinking and eating patterns in lesioned rats by providing them with "palatable solutions," but the authors reported no data on the animals' eating, drinking, or body mass. In all other studies of fever in OVLT-lesioned animals (for references, see Table 1), side effects of the lesioning procedure were ignored altogether.
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The results of fever experiments in OVLT-lesioned animals are contradictory
(see Table 1). Electrolytic
lesions of the lamina terminalis blocked or attenuated intravenous IL-1-
or tumor necrosis factor (TNF)-
-induced fever in rabbits
(23) and peripheral
(intravenous, intraperitoneal, or intra-arterial) LPS-induced fevers in guinea
pigs (4,
6,
26) and rats
(9,
25). However, similar lesions
did not affect the febrile response of rats to intravenous LPS in a study by
Takahashi et al. (69) and
enhanced the responses of rats and rabbits to intravenous administration of a
crude preparation of IL-1 in a study by Stitt
(63). It cannot be excluded
that at least some of these results were "contaminated" by the
uncontrolled, variable side effects of brain tissue lesions in the lamina
terminalis. Therefore, we attempted to identify and minimize side effects of
OVLT lesioning and then studied the febrile response of the lesioned rats to
intravenous IL-1.
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MATERIAL AND METHODS |
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TOPABSTRACTMATERIAL AND METHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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180 g on receipt were housed individually
in the institutional animal care facility on a 12:12-h light/dark (lights on
from 7 AM to 7 PM) cycle and ambient temperature
(Ta) of 22°C. Standard laboratory rat pellets (Teklad
Rodent Diet "W" 8604, Harlan Teklad, Madison, WI) and tap water
were available ad libitum. The cage space was enriched with artificial
"rat holes" (cylindrical confiners made of stainless steel wire).
In addition to spending time in the confiners voluntarily, the rats were
systematically habituated to them (at least 5 training sessions, 4–5 h
each). During some training sessions, the rats were instrumented with colonic
thermocouples, and their colonic temperature (Tc) was recorded.
Rats easily learn to stay in the enclosures and often prefer them to the open
space of their home cages. Well-adapted, confined rats exhibit neither a
stress fever nor any other signs of stress
(52). The same confiners were
used later in experiments. To minimize the effect of circadian rhythms on the
experimental outcome, all experiments began at 9 AM. On
completion of the study, the animals were killed with a bolus intravenous
injection of ketamine-xylazine-acepromazine cocktail (22.2, 2.2, and 0.4
mg/kg, respectively). The protocol was approved by the institutional animal
care and use committee.
Electrolytic ablation of the OVLT. On the day of lesioning
(day 0), the rats were treated with the antibiotic enrofloxacin (12
mg/kg sc) and anesthetized with a ketamine-xylazineacepromazine cocktail
(55.6, 5.5, and 1.1 mg/kg ip). The skin of the head over the frontal and
parietal bones was shaved and scrubbed. The head was fixed in a stereotaxic
apparatus (David Kopf, Tujunga, CA) in the de Groot
(14) position, i.e., the
incisor bar set 5 mm dorsal to the interaural line. The skin was incised over
the sagittal suture, and the subcutaneous tissues were retracted and scraped
off the skull. Two miniature stainless steel screws (1 on each side of the
mid-line) were threaded into the bone 5 mm caudal to the bregma and
5 mm lateral to the sagittal suture. A 3-mm hole (centered on the
midline, 8.2 mm rostral to the interaural line) was drilled through the skull
to the dura mater. The dura was incised, and the underlying sinus was
retracted to the side. At the center of the hole, a tapered (100 µm)
tungsten electrode, insulated except for 0.5 mm at its tip, was inserted 8.4
mm below the dura (i.e., 1.8 mm below de Groot's horizontal zero plane). Thus
the de Groot coordinates of the electrode tip were as follows: rostral-caudal,
8.2 mm; medial-lateral, 0.0 mm; and dorsal-ventral, -1.8 mm. The coordinates
were based on the atlas by Pellegrino and Cushman
(45) and earlier work by
Hunter (25). For a sham
lesion, the first two coordinates remained the same, but the third was 0.6 mm
(i.e., 6.0 mm below the dura). A second electrode (an "alligator"
clip) was attached to the edge of the skin wound. The electrodes were
connected to a Precision Lesion instrument (Stoelting, Wood Dale, IL). To
lesion the brain tissue, constant anodal current (3 mA) was passed between the
electrodes for 15 s. No current was passed in sham-lesioned rats. The
electrodes were withdrawn, and the bone defect was filled with bone wax.
Dental acrylic was applied over the exposed skull surface and screws. The
acrylic was shaped to form a flat platform for later attachment of a plastic
screw-capped container to hold the exteriorized end of the jugular catheter.
When the acrylic hardened, the animal was released from the stereotaxic
apparatus.
Postlesion care. Because animals with lesions in the lamina terminalis typically become adipsic but often accept palatable liquids (8), tap water was substituted with 5% sucrose to stimulate drinking for 1 wk after the surgery. During the same week, all operated animals were examined twice a day for signs of dehydration and general malaise; their body mass and sucrose consumption were measured daily. If a rat lost body mass >15% at 24 h postlesion, continued losing body mass at 48 h, or did not drink (0 daily consumption of sucrose) at any time after the surgery, it was hydrated with an infusion of isotonic saline (50 ml/kg sc) containing enrofloxacin (12 mg/kg). Postlesion care was conducted under close supervision of the staff veterinarian.
Jugular catheterization. On day 10, each rat was anesthetized a second time, and a silicone catheter filled with heparinized (20 IU/ml) saline was implanted in the superior vena cava through the right jugular vein (for details, see Refs. 28, 29). In brief, the catheter was tunneled under the skin to exit at the caudal edge of the cranial acrylic platform. A small plastic screw cap container was slipped over the cannula and affixed to the platform with fresh dental acrylic. The catheter was then coiled inside, and the container was capped. The catheter was flushed with heparinized saline on the next day and every other day thereafter.
Fever test. On days 18 and 22, the rats were
placed in their enclosures and instrumented with copper-constantan
thermocouple probes to measure Tc (10 cm beyond the anus) and tail
skin temperature (Tsk). The thermocouples were fed to a data logger
(model TCA-Al-24; Dianachart, Rockaway, NJ) and then to a microcomputer. The
instrumented rats, in their confiners, were placed in an environment chamber
(Forma Scientific, Marietta, OH) set to 50% relative humidity and a
Ta of 30.0°C, which correspond to the midpoint of the rat's
thermoneutral zone in our setup
(50). The exteriorized portion
of the jugular catheter was passed through a wall port and connected to a
syringe. After a 1-h stabilization period, the measurements were begun, and
Tc, Tsk, and Ta were recorded every 2 min
from 30 min before to 180 min after an intravenous injection of either
IL-1 or saline. One-half of the rats received IL-1 on day
18 and saline on day 21; the other one-half received the drugs
in the opposite order. Recombinant mouse interleukin IL-1 (Endogen,
Boston, MA; 98% purity; LPS contamination <100 pg/µg) was freshly
dissolved in pyrogen-free saline and infused at a dose of 500 ng/kg (1 ml/kg
iv) over 1 min. Recalculated per body mass, LPS contamination was <50
pg/kg, which is substantially below the 1 µg/kg minimal pyrogenic dose for
the rat (54). The controls
received saline (1 ml/kg) containing the same trace amount (50 pg/kg) of
Escherichia coli 0111:B4 LPS (lot no. 35H4086; Sigma, St. Louis,
MO).
Measurements of water-electrolyte balance. In addition to monitoring fluid consumption and body mass (see Postlesion care), drinking responses to hypertonic (5%) saline (4 ml/kg iv) were measured on day 14; plasma sodium concentration and osmolality were measured on day 40. For sodium and osmolality measurements (which were performed by flame photometry and freezing-point osmometry, respectively, by the Legacy Clinical Laboratory), 3 ml of blood was withdrawn via cardiac puncture from ketamine-xylazine-acepromazine-anesthetized animals immediately before euthanasia.
Histological verification. The brains were removed from the euthanized animals, fixed in 10% neutral formalin, and dehydrated/cryoprotected in 20% sucrose. The hypothalami were sectioned (30 µm) with a cryotome. The sections were mounted, stained with thionine, examined by light microscopy, and photographed.
Data processing and analysis. The change in Tc
(deviation from the baseline) was used as a measure of the febrile response.
The heat loss index (HLI) was used as a measure of the skin vasomotor tone.
The HLI was calculated according to the formula: HLI = (Tsk -
Ta)/(Tc - Ta)
(50); the theoretical limits
for the HLI are 0 (maximal vasoconstriction) and 1 (maximal vasodilation).
Single-point quantitative measurements (body mass, change in body mass, water
consumption, plasma sodium and osmolality, basal Tc) were
statistically compared between OVLT-lesioned and sham-operated rats by using
Student's t-test. To compare the groups for the presence or absence
of adipsia and for requirements for rehydration therapy (see Postlesion
care), a nonparametric (Mann-Whitney U) test was used. As in the
past (27,
49), time-function
measurements (change in Tc, HLI) were converted into single numbers
by subtracting the control curve (saline) from the corresponding experimental
curve (IL-1) obtained in the same animal and integrating the resultant
curve over the observation period; these numbers were averaged across groups
(lesioned or sham) and for statistical comparisons treated as single-point
measurements. All analyses were performed using Statistica AX'99 (StatSoft,
Tulsa, OK). The data are presented as means ± SE.
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RESULTS |
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TOPABSTRACTMATERIAL AND METHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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During the acute postoperative period, eight of the nine lesioned animals consumed no sucrose solution for at least 1 day, whereas none of the eight sham-operated rats exhibited adipsia (P = 0.0002). During the first 24 h after the surgery, the lesioned animals lost as much as 60 g (23% of body mass). The mean loss of body mass in this group was 14 ± 2%, whereas the sham-operated group lost only 5 ± 2% (P = 0.0009; Fig. 2A). Despite access to a sucrose solution, eight of nine lesioned rats met the criteria for rehydration therapy on at least 1 day during days 1–3; five lesioned rats had to be treated with subcutaneous saline on 2 days. Rehydration therapy was indicated for none of the sham-operated rats (sham-lesion difference: P = 0.00003). None of sham-lesioned or lesioned rats died.
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After the acute period, the lesioned rats started to gain weight. At the time of the fever test, their body mass did not differ significantly from that of the sham-operated rats (324 ± 10 vs. 331 ± 10 g). However, rehydration therapy during the acute postoperative period did not prevent chronic impairments in the water-electrolyte balance. The lesioned rats were hyporesponsive to an osmotic stimulus. In a drinking test conducted on day 14, they consumed only 3.1 ± 0.7 ml of water over 1 h after a hypertonic saline load, whereas the sham-lesioned rats drank 5.5 ± 0.5 ml over the same period (P = 0.005; Fig. 2B). On day 40, the lesioned rats still showed hypernatremia (146.2 ± 0.7 vs. 144.0 ± 0.7 mmol/l in the sham-lesioned rats; P = 0.002) and hyperosmolality (313.8 ± 1.4 vs. 309.5 ± 1.3 mosmol/kgH20 in the sham-lesioned rats; P = 0.04) under nonstimulated conditions (Fig. 2C).
During training sessions (days 10–16 postlesion) and in both
IL-1 and saline experiments (days 18–21), the basal
Tc of the OVLT-lesioned rats was always 1.5–2°C higher
than that in the sham-operated animals. In the IL-1 experiment, the
initial Tc in the lesioned rats was 39.6 ± 0.4 compared with
37.7 ± 0.1°C in the sham-lesioned rats (P = 0.0003;
Fig. 2D). In the
saline experiment, these values were 39.3 ± 0.5 vs. 37.8 ±
0.1°C (P = 0.008). Extremely high values of Tc
(>40°C) were observed in several lesioned rats on several occasions.
Despite such high levels of basal Tc, the lesioned rats showed no
tail skin vasoconstriction. Their HLI (measured on days 18 and
21) was 0.6 and did not differ from that of the sham-operated
rats.
An intravenous injection of saline produced no thermal effects in either
lesioned or sham-lesioned animals. A low (500 ng/kg) dose of IL-1 caused
a fever in the sham-operated rats but had no effect on Tc of the
OVLT-lesioned rats (Fig. 3).
This difference was highly significant (P = 0.005). Simultaneously
with the onset of fever, the sham-lesioned rats developed a transient tail
skin vasoconstriction (the HLI decreased from 0.6 to 0.4), but the
magnitude of the response was not large enough to be significant. No
vasoconstriction was observed in the lesioned rats.
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DISCUSSION |
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TOPABSTRACTMATERIAL AND METHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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It is also unclear whether pronounced long-lasting hyperthermia is related to a certain location of the lesion within the lamina terminalis (many studies did not present a detailed anatomical description of the lesion) or whether it correlates with the presence or severity of any particular side effect. A potential role of intensive rehydration therapy should also be mentioned. The population of the lesioned rats in the present study likely included animals that would not have survived the procedure if they were not placed on rehydration therapy (8). Because such a therapy was not used in any thermoregulatory study in the past (Table 1), some animals were likely to die in those studies. Knowing that even mild hyperthermia strongly exaggerates neural damage and increases the related mortality rate (15), it is reasonable to suspect that hyperthermic animals were more likely to die after OVLT lesioning than normo- or hypothermic animals in the early studies.
The hyperthermia observed in the present experiments and the elevated body temperatures reported by Blatteis et al. (5, 6) and Hunter et al. (26) clearly differ from the acute fevers that often occur in response to preoptic hypothalamic tissue damage (13, 35, 53, 56). Such acute fevers are relatively short lasting and resolve within a few days (6, 35). They are thought to involve migration of leukocytes to the site of damage, local hemorrhage, and inflammation (13) and to be mediated by pyrogenic cytokines (35) and PGs (53, 56).
Although the exact genesis of the prolonged hyperthermia reported here is unknown, its duration is consistent with permanent damage to the thermoregulatory circuitry similar to the damage caused by knife cuts of brain tissue (21). That the lesioned rats had very high body temperatures but exhibited no tail skin vasoconstriction suggests an alteration in heat production, possibly a loss of warm-sensitive neurons that inhibit thermogenesis in the brown adipose tissue (BAT), the major source of heat production in the rat (19). The precise location of thermogenesis-inhibiting warm-sensitive neurons within the hypothalamus is unknown (41), but such neurons clearly exist (12, 76). Hypothalamic transections caudal to the presumed location of these neurons cause pronounced hyperthermia due to disinhibition of BAT thermogenesis (12, 72).
Several lines of evidence suggest that bodies of the thermogenesis-inhibiting neurons are located in the MnPO, a structure that was typically involved in the lesion in the present study (Fig. 1). Indeed, 20–30% of neurons in the MnPO are warm sensitive and have been proposed to play an important role in thermoregulation, including nonshivering thermogenesis (71). Efferent projections from the MnPO tend to be inhibitory (44), which is consistent with their GABAergic nature (43). Furthermore, MnPO neurons that project to the midbrain periaqueductal gray matter (which contains neurons generating excitatory signals for nonshivering thermogenesis) are activated by heat exposure (75), thus confirming their inhibitory role in the control of thermogenesis. Intriguingly, Nakamura et al. (43) recently identified projections from the MnPO to the rostral raphe pallidus nucleus (rRPa), a structure that also contains the excitatory efferent neurons for nonshivering thermogenesis. The authors have proposed that MnPO cells control BAT thermogenesis by tonically inhibiting rRPa neurons. Lesioning the MnPO would be consistent with disinhibition of thermogenesis and development of hyperthermia. Such a mechanism can also explain the very high values of body temperature observed in the present study. Indeed, disinhibition of BAT thermogenesis in the rat readily increases deep body temperature by several degrees, even under conditions of anesthesia and exposure to a subneutral Ta (61).
Other side effects of OVLT lesion. Lesions of the OVLT and its
adjacent structures are known to severely disturb water-electrolyte balance
and its hormonal regulation
(39). Lesioned animals often
become adipsic. When adipsia occurs, it is typically followed by anorexia. The
result is both dehydration and under-nourishment
(8). Consistent with the
literature, the lesioned animals in the present study exhibited acute adipsia
and gross emaciation (14% mean loss of body mass within 24 h of lesioning; see
Fig. 2A). Although
this side effect is not mentioned in fever studies
(Table 1), a higher degree of
emaciation, sometimes incompatible with life, is considered typical after
lesions of the anterior wall of the third ventricle
(8). For example, Johnson and
Buggy (30) observed severe
adipsia lasting as long as 6 days after electrolytic lesions of the lamina
terminalis; the mean weight loss of the adipsic rats on day 3 was 84
± 5 g (25%). The authors explained this loss by the rats' failure
to compensate for their attenuated water intake by an appropriate
antidiuresis. However, the magnitude of the postlesion emaciation recorded in
their study (and even in the current work) substantially exceeds normal daily
food and water consumption for rats; it also exceeds by several times the body
weight loss in starving rats
(65). Such a dramatic weight
loss, especially combined with the high body temperature, likely results from
intensive substrate "burning" caused by disinhibition of
nonshivering thermogenesis.
Although the intensive postlesion care in the present study was successful in minimizing the acute effects of the procedure and eliminating mortality, it was proved ineffective in preventing chronic impairments of water-electrolyte balance, including hypernatremia, hyperosmolality (Fig. 1C), and sluggish drinking responses to hypertonic stimuli (Fig. 1B). Interestingly, the latter three symptoms are consistent with a loss of inhibitory neurons in the MnPO, which play an important role in water-electrolyte homeostasis (71).
Effect of OVLT lesion on the febrile response: a reappraisal. That the OVLT is important for febrigenic signaling to the brain was proposed by Blatteis et al. (4), and their innovative hypothesis has dominated the field for almost two decades. However, the more recent analysis by Blatteis and Sehic reveals several shortcomings of this hypothesis (for review, see Ref. 7). Furthermore, some findings that are typically cited in support of the signaling hypothesis (e.g., that microinjection of pyrogens or antipyretic substances in the vicinity of the OVLT causes a fever or antipyresis, respectively; see Refs. 37, 57, 58, 64) do not actually support it. These findings show that the OVLT and/or other structures within the lamina terminalis are crucial for fever genesis, but they do not say by which of the four mechanisms (see Introduction) these structures are activated during systemic inflammation.
What is even more important in the context of the present work is that multiple studies designed to test the OVLT-signaling hypothesis produced contradictory results. Indeed, whereas several "lesion studies" (e.g., Ref. 4) and "nonlesion studies" (e.g., Refs. 22, 34, and 42) suggested an important role of the OVLT in immune-to-brain signaling, other lesion (e.g., Ref. 69) and nonlesion (e.g., Refs. 11 and 60) studies failed to support such a role, at least for the specific experimental conditions tested. In fact, lesion studies found all three possible effects on the fever response, namely, exaggeration, blockade, and no effect (see Table 1). When lesioning blocked the response, the blockade was attributed to interrupted pyrogenic signaling to the CNS (4–6, 9, 23, 25, 26). When a similar lesion exaggerated the response, the result was explained by stimulation of pyrogenic signaling (63). When lesioning produced no effect on fever in a study of Takahashi et al. (69), the authors did not eliminate the OVLT as a potential access point for circulating pyrogens and proposed that other routes of immune-to-brain communication (afferent nerves, the subfornical organ) may provide adequate access for circulating pyrogens, thus substituting for the role of the OVLT, in the lesioned animals. With the exception of two reports by Blatteis et al. (4, 6) and one by Takahashi et al. (69), all studies mentioned above failed to account for effects of the lesion unrelated to the processes of blood-to-brain pyrogenic signaling (side effects).
In the current study, OVLT-lesioned rats were found to have high basal body temperatures. After the original study of LPS fever in guinea pigs by Blatteis (3), it has been established for several pyrogens, including LPS (29, 66), yeast cells (33), PGE1 and E2 (18, 38, 68), and cholecystokinin-8 (68), that the maximal height of fever inversely correlates with basal body temperature. That is, animals readily respond to pyrogenic stimuli when their initial body temperature is low; no fever occurs when their basal body temperature is high. For example, rats do not respond to various pyrogens with fevers (68) and do not activate nonshivering thermogenesis in BAT (66) if basal Tc >39°. Clearly, the febrile response can be exaggerated, attenuated, or even blocked completely by simply changing basal body temperature (for review, see Ref. 29), and the present results show that tissue lesions in the lamina terminalis can produce a strong and long-lasting effect on body temperature. A putative mechanism for this effect in lesioned animals is the loss of thermogenesis-inhibiting neurons in the MnPO. If the MnPO was involved in the OVLT lesion to a variable extent in the earlier studies, it could explain the contradictory effects of the lesion on the febrile response (Table 1).
In addition to the MnPO, autonomic circuits involved in thermoregulation and fever include two other structures adjacent to the OVLT, i.e., the VMPO and AVPV. These structures show a sustained elevation of Fos-like immunoreactivity after intravenous challenge with LPS (17) and possess high sensitivity both to the pyrogenic action of locally administered PGE2 (57) and to the antipyretic action of a locally applied inhibitor of PGE synthesis, ketolar (58). Thus damage to these efferent structures would be consistent with a weakened ability of the OVLT-lesioned animals to respond to pyrogens with fever. In fact, this explanation has been proposed in two previous studies (59, 69).
Other side effects of OVLT lesion also affect febrile responsiveness. Indeed, severe hypernatremia and hyperosmolality attenuate the febrile response (31, 47, 55). Malnourished animals respond to pyrogens with low fevers, no fever, or even with hypothermia (24, 62, 67). Interestingly, in the only study in which lesioned animals were maintained postoperatively on palatable solutions (to attenuate the above side effects), the febrile response was normal (69); in eight other studies in which the animals were maintained on a regular diet, the febrile response was affected (see Table 1). Lesions of the anterior wall of the third ventricle also influence secretion of and/or responses to melanocortins (32), glucocorticoids, and several other hormones involved in the regulation of water-electrolyte balance (for review, see Refs. 8, 20, and 39). The same hormones are involved in febrile pathogenesis, most (melanocortins, glucocorticoids, arginine vasopressin) as antipyretics (40, 46, 70) but some (angiotensin II) as fever promoters (73). Therefore, lesions of the OVLT and its surrounding structures may affect febrile responsiveness by interfering with the complex balance of anti- and propyretic substances and not exclusively by modifying febrigenic signaling processes.
Conclusions and Perspectives
Lesions of the OVLT and neighboring structures cause severe side effects, such as acute dehydration, gross emaciation, and chronic impairments of water-electrolyte balance. The present work clearly shows that these side effects cannot be prevented by intensive rehydration therapy. This observation substantially limits the use of the electrolytic lesioning technique to study the physiological role of the OVLT.
This study also demonstrates a previously unrecognized phenomenon: high (> 39°C) and long-lasting (>3 wk) hyperthermia in the lesioned animals. The lesions performed in the present experiments appear to involve neurons that are crucial for the control of thermogenesis. On the basis of the recent studies by Yoshida et al. (75) and Nakamura et al. (43), we speculate that these neurons are located in the rostral MnPO, a structure that is adjacent to the OVLT and that was consistently damaged in our experiments. Further studies aimed at the identification of these neurons are required.
Starting with the pioneering works of Blatteis et al. (4–6), the fact that OVLT lesions can block the febrile response has been the most convincing argument favoring the physiological importance of the OVLT in febrigenic signaling to the CNS. We offer an alternative interpretation of this fact. We argue that lesions of the lamina terminalis may affect the febrile response via multiple mechanisms unrelated to the passage of the immune signal across the BBB. Clearly, nonlesion techniques, such as those used by Harré et al. (22) and possibly highly selective chemical lesioning techniques should be used to decisively prove or disprove the OVLT signaling hypothesis.
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DISCLOSURES |
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ACKNOWLEDGMENTS |
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N. Sugimoto was on leave from the Department of Physiology-2, Kanazawa University Medical School, Kanazawa 920, Japan.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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REFERENCES |
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TOPABSTRACTMATERIAL AND METHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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-induced ACTH
release. Am J Physiol Endocrinol Metab
258: E163–E171,
1990. on
PGE2 levels in several brain areas as determined by microdialysis.
Am J Physiol Endocrinol Metab
262: E246–E251,
1992. during fever. Brain Res
618: 155–159,
1993.[ISI][Medline]
- and prostaglandin E-induced fevers in rats:
possible involvement of brain angiotensin II receptor in fever induction.
J Pharmacol Exp Ther 282:
873–881, 1997.This article has been cited by other articles:
|
|
 |
|
  K. Nakamura and S. F. Morrison Preoptic mechanism for cold-defensive responses to skin cooling J. Physiol., May 15, 2008; 586(10): 2611 - 2620. [Abstract] [Full Text] [PDF]
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|
 Y. Ootsuka, W. W. Blessing, A. A. Steiner, and A. A. Romanovsky Fever response to intravenous prostaglandin E2 is mediated by the brain but does not require afferent vagal signaling Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2008; 294(4): R1294 - R1303. [Abstract] [Full Text] [PDF]
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 A. A. Steiner, V. F. Turek, M. C. Almeida, J. J. Burmeister, D. L. Oliveira, J. L. Roberts, A. W. Bannon, M. H. Norman, J.-C. Louis, J. J. S. Treanor, et al. Nonthermal Activation of Transient Receptor Potential Vanilloid-1 Channels in Abdominal Viscera Tonically Inhibits Autonomic Cold-Defense Effectors J. Neurosci., July 11, 2007; 27(28): 7459 - 7468. [Abstract] [Full Text] [PDF]
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D. G. Whyte and A. K. Johnson Lesions of the anteroventral third ventricle region exaggerate neuroendocrine and thermogenic but not behavioral responses to a novel environment Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2007; 292(1): R137 - R142. [Abstract] [Full Text] [PDF]
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 E. Tavares, F. J. Minano, R. Maldonado, and M. J. Dascombe Endotoxin fever in granulocytopenic rats: evidence that brain cyclooxygenase-2 is more important than circulating prostaglandin E2 J. Leukoc. Biol., December 1, 2006; 80(6): 1375 - 1387. [Abstract] [Full Text] [PDF]
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A. A. Steiner, S. Chakravarty, J. R. Robbins, A. S. Dragic, J. Pan, M. Herkenham, and A. A. Romanovsky Thermoregulatory responses of rats to conventional preparations of lipopolysaccharide are caused by lipopolysaccharide per se-- not by lipoprotein contaminants Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2005; 289(2): R348 - R352. [Abstract] [Full Text] [PDF]
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A. I. Ivanov, A. A. Steiner, S. Patel, A. Y. Rudaya, and A. A. Romanovsky Albumin is not an irreplaceable carrier for amphipathic mediators of thermoregulatory responses to LPS: compensatory role of {alpha}1-acid glycoprotein Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2005; 288(4): R872 - R878. [Abstract] [Full Text] [PDF]
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