Graves Db

Humoral versus neural pathways for fever production in rats after administration of lipopolysaccharide.

BACKGROUND These studies address the question of the relative roles of humoral and neural pathways in the genesis and control of the fever component of the acute phase response. METHODS Two experiments were performed to examine the effect of vagotomy (VagX) on the febrile response to intraperitoneal (i.p.) and intra-arterial (i.a.) lipopolysaccharide (LPS), and plasma cytokine and LPS concentrations after intravenous (i.v.) or i.p. injections of LPS. In experiment 1, body temperature (T(B)) was obtained from unperturbed animals by using radio transmitters and telemetry after injection of LPS i.a. or i.p. In the second study, serial blood samples were obtained for cytokine and LPS assay after injection of LPS either i.v. or i.p. Colonic temperatures (T(C)) were obtained from indwelling thermistors. RESULTS The maximal increments in T(B) for animals receiving LPS i.a. and i.p. with or without VagX were not different from one another: sham vagotomy (Sham-VagX) + LPS i.a., 1.20 +/- 0.26 degrees C; VagX + LPS i.a., 1.23 +/- 0.64 degrees C; Sham-VagX + LPS i.p., 1.45 +/- 0.27 degrees C; VagX + LPS i.p., 1.50 +/- 0.35 degrees C (F = 1.12, p = 0.36). Neither were the four resulting response curves for T(B) different from one another. Plasma levels of LPS, tumor necrosis factor-alpha, and interleukin-6 were significantly elevated at 45 minutes after LPS injection by either the i.v. or i.p. routes, preceding any increments in T(B), and were not effected by VagX. CONCLUSION Fever development for animals receiving LPS in experiment 1 demonstrates a temporal relationship -- with increments in plasma levels of LPS and pyrogenic cytokines obtained in experiment 2 after administration of LPS either i.p. or i.v. Vagotomy had no discernible effect on the responses regardless of the route of administration of LPS.

Pathogenesis of fever in a rat burn model : The role of cytokines and lipopolysaccharide

We investigated the possible causal relationship between interleukin-6 (IL-6) and increased body temperature (T(B)) in a rat burn model. Transmitters for measuring core temperature and estimating activity were implanted in the abdominal cavity. Animals in the burn group were clipped and received full-thickness scald burns to 45% to 55% of the body surface area, and control animals were clipped. T(B) and activity were measured continuously through the tenth postburn day. Carotid lines were placed, and serial blood samples obtained for lipopolysaccharide, IL-6, and tumor necrosis factor-alpha assay. From the third through the tenth postburn day, the burn group had a consistently significantly higher T(B) during light hours than the control group did (average, 0.45 degrees C +/- 10 degrees C, p = 0.0001). Differences in activity during light hours were not significant between the two groups, therefore, do not account for the observed significant difference in T(B). The average IL-6 serum levels were 3.5-fold higher for the burned animals. In this study, burn and control serum levels of IL-6 demonstrated positive correlation with T(B). These data suggest, but do not prove, a causal relationship between IL-6 and fever in the rat burn model, and make it unlikely that circulating systemic lipopolysaccharide is the cause.We investigated the possible causal relationship between interleukin-6 (IL-6) and increased body temperature (T(B)) in a rat burn model. Transmitters for measuring core temperature and estimating activity were implanted in the abdominal cavity. Animals in the burn group were clipped and received full-thickness scald burns to 45% to 55% of the body surface area, and control animals were clipped. T(B) and activity were measured continuously through the tenth postburn day. Carotid lines were placed, and serial blood samples obtained for lipopolysaccharide, IL-6, and tumor necrosis factor-alpha assay. From the third through the tenth postburn day, the burn group had a consistently significantly higher T(B) during light hours than the control group did (average, 0.45 degrees C +/- 10 degrees C, p = 0.0001). Differences in activity during light hours were not significant between the two groups, therefore, do not account for the observed significant difference in T(B). The average IL-6 serum levels were 3.5-fold higher for the burned animals. In this study, burn and control serum levels of IL-6 demonstrated positive correlation with T(B). These data suggest, but do not prove, a causal relationship between IL-6 and fever in the rat burn model, and make it unlikely that circulating systemic lipopolysaccharide is the cause.

Studies on the mechanism of fever after intravenous administration of endotoxin

BACKGROUND The sequential events in fever production after intravenous administration of lipopolysaccharide (LPS) remain unsettled and controversial. Vessels of the organum vasculosum laminae terminalis (OVLT) lack the tight junctions of the blood-brain barrier and allow substances of high molecular weight to enter the interstitium but not the neuropil. The present studies investigate the hypothesis that the OVLT is needed for fever production after intravenous administration of LPS in the rat. METHODS Electrolytic lesions were produced in the OVLT of rats. After recovery, left carotid and right atrial catheters were inserted, and 24 hours later calorimetry was performed. Blood was drawn for baseline assay for cytokines and LPS after which LPS was given intravenously, with studies continued for 5 hours, and additional blood samples were drawn at 90 and 300 minutes. RESULTS The maximal increment in rectal temperature for the sham lesion LPS group (1.25 +/- 0.44 degrees C) was significantly greater than for the sham-saline (-0.05 +/- 0.46 degrees C) and the lesion-LPS groups (0.35 +/- 0.45 degrees C) for minutes 120 to 300. Ninety minutes after LPS administration, serum levels of interleukin (IL)-6, tumor necrosis factor-alpha, and LPS were significantly elevated (p < 0.0001) above baseline for the sham-LPS and lesion-LPS groups. IL-1beta serum levels remained below detection levels. CONCLUSION Large lesions of the OVLT prevent and/or attenuate fever due to LPS even though tumor necrosis factor-alpha and IL-6 are greatly increased in serum. IL-1beta does not seem to be an endogenous humoral mediator in this model.

An epidemiological profile and trend analysis of wound flora in burned children: 7 years' experience

A retrospective chart review was conducted of 5418 culture and sensitivity reports from 93 paediatric burn patients to determine profiles of wound flora and invasive organisms, trend analysis and patterns of antibiotic resistance. Coagulase-positive Staphylococcus was the predominant burn wound pathogenic isolate and the predominant invasive organism for burns less than 60 per cent BSA. Pseudomonads were the predominant invasive organism for burn wounds greater than or equal to 60 per cent BSA. Only 7 per cent of all pathogenic isolates were fungi. A significant association was demonstrated between increasing burn size and an increasing incidence of Gram-negative and invasive organisms. Silver sulphadiazine remains a very effective topical agent for the control of bacterial and fungal growth in burn wounds after 10 years of intensive use in this burn unit. Pseudomonad isolates were routinely multi-drug resistant. Pseudomonad isolates from wounds treated topically with a silver sulphadiazine-cerium nitrate mixture were frequently resistant to aminoglycosides, colistin and carbenicillin. It is concluded from this review that severe restrictions on antibiotic usage within burn units, and strict internal environmental control within burn units may help to decrease the incidence of nosocomial resistant strains and cross infection. Regular monitoring of burn wound flora, and the protocol for wound care used in treating these patients have been effective in preventing septic episodes and death due to sepsis.

Alteration in temperature regulation induced by burn injury in the rat.

The preoptic anterior hypothalamus (POAH) of rats housed at three ambient temperatures was implanted with perfusion apparatuses. Response of heat production to displacement of POAH temperature was determined for control animals and animals with burns (31% +/- 3% total body surface area). At an ambient temperature of 22 degrees C there was a significant increase in thermosensitivity of the POAH for both control rats and rats with burns compared with thermosensitivity at 32 degrees C. Within ambient temperatures there was no effect on thermosensitivity detected for rats with burns compared with control rats. The threshold temperature for heat production was shifted significantly upward (p less than 0.05) both by a lower ambient temperature and by burn injury. The reference temperature for heat production was also shifted to the right by burn injury (p less than 0.05). The significant shifts to the right for threshold temperature and reference temperature for heat production enhance the organismss ability to meet the stress of the hypermetabolic response. At a warm ambient temperature (32 degrees C) there are no significant differences in thermoregulation detected in animals with burns or control animals.The preoptic anterior hypothalamus (POAH) of rats housed at three ambient temperatures was implanted with perfusion apparatuses. Response of heat production to displacement of POAH temperature was determined for control animals and animals with burns (31% +/- 3% total body surface area). At an ambient temperature of 22 degrees C there was a significant increase in thermosensitivity of the POAH for both control rats and rats with burns compared with thermosensitivity at 32 degrees C. Within ambient temperatures there was no effect on thermosensitivity detected for rats with burns compared with control rats. The threshold temperature for heat production was shifted significantly upward (p less than 0.05) both by a lower ambient temperature and by burn injury. The reference temperature for heat production was also shifted to the right by burn injury (p less than 0.05). The significant shifts to the right for threshold temperature and reference temperature for heat production enhance the organismss ability to meet the stress of the hypermetabolic response. At a warm ambient temperature (32 degrees C) there are no significant differences in thermoregulation detected in animals with burns or control animals.

Intraperitoneal blood exacerbates the remote inflammatory response to murine peritonitis.

BACKGROUND This study investigated the effects of intra-abdominal blood on the systemic response to peritonitis using a murine model of hemorrhage, peritonitis, and multiple organ dysfunction syndrome. METHODS The model used male ICR mice subjected to hemorrhage and intraperitoneal zymosan. Half of the mice received intraperitoneal blood. Outcome measures included lung myeloperoxidase, lung edema, lung injury score, and plasma and lung tissue chemokine production. RESULTS Peritoneal blood (in association with peritoneal inflammation) increased lung neutrophil sequestration (myeloperoxidase) (2.56 +/- 1.42 vs. 1.45 +/- 0.49 U/left lung, p = 0.04) and lung weight (0.11 +/- 0.04 vs. 0.07 +/- 0.02 g/left lung, p = 0.02), and was associated with significantly higher chemokine levels in plasma (KC and MCP-1) and lung tissue (KC, MIP-2, and MCP-1). Both plasma and lung tissue neutrophil chemoattractants KC and MIP-2 were significantly linearly correlated with myeloperoxidase (p < 0.009), and lung tissue KC (a neutrophil chemokine) and MCP-1 and MIP-1alpha (mononuclear cell chemokines) correlated with lung injury score (p < 0.003). CONCLUSION Although blood alone in the peritoneal cavity was well tolerated, in conjunction with inflammation, it was synergistic in amplifying the systemic inflammatory response. The amplified lung injury in this model was associated with significant increases in circulating and lung tissue chemokine concentrations.

Relationships between heat production, heat loss, and body temperature for rats with burn injuries between 26% and 63% of the body surface area.

Burn injury in man is characterized by increased body temperature proportional to burn wound size and may represent fever and/or hyperthermia. A nonseptic animal model used to study this phenomena has not been described. To test the hypothesis that large burn injuries in rats would produce increased body temperature, the rectal, skin, and body temperatures were sequentially measured and were calculated for rats in the control group and rats with burn injuries covering 26% to 63% of the body surface area [< or = 35%, 36% to 45%, and > or = 46% body surface area]. The group with burns covering > or = 46% of the body surface area had significantly higher rectal temperatures than did at least one other group on postburn days 7, 9, 11, 13, 18, and 20. On postburn days 7 and 11 this increase was significantly higher than that of all burn and control groups. Animals did not demonstrate any overt evidence of wound infection. These data do not establish a cause for increased body temperature after burn injury but suggest that a reproducible animal model may be possible for the study of the cause of increased body temperature after burn injury.

The effect of ablation of the preoptic anterior hypothalamus on energy metabolism and plasma catecholamines after burn injury in the rat.

Rats with burn injuries demonstrate changes in thermoregulation including an upward shift of the set-point and reference temperatures with no change in sensitivity of the response in heat production to displacement of the temperature of the preoptic anterior hypothalamus. In the present studies, the response in plasma and urinary catecholamines to burn injury after destruction of the preoptic anterior hypothalamus was examined in the rat. Preoptic anterior hypothalamic lesioning impaired the hypermetabolic response to burn injury, and at 22 degrees C, burned lesioned rats were hypothermic. Furthermore, plasma levels and urinary excretion rates for catecholamines were not decreased in burned lesioned rats, but rather showed an inverse relationship with heat production. Burned lesioned rats were capable of maintaining body temperature at an ambient temperature of 28 degrees C. This suggests that a less precise thermoregulation is present in lesioned animals. Rats in which the preoptic anterior hypothalamus has been destroyed have reduced tolerance to burn injury.

The response in heat production, plasma catecholamines, and body temperature of burned rats to hypothalamic temperature displacement

Rats, with the preoptic anterior hypothalamus implanted with two thermodes and a thermocouple reentry tube, had simultaneous direct and indirect calorimetry performed [during the ninth to eleventh postburn day interval] at ambient temperatures of 22 degrees and 28 degrees C. During calorimetry, blood was drawn at baseline and near the end of each period of displacement of the preoptic anterior hypothalamus temperature for catecholamine assay. Cooling the preoptic anterior hypothalamus resulted in a significant increase in heat production and plasma epinephrine and norepinephrine concentrations for both burn and control groups at 22 degrees C and 28 degrees C (p < 0.05 for all comparisons). Heat production demonstrated consistent negative linear correlation with preoptic anterior hypothalamic temperature. Plasma epinephrine values correlated with preoptic anterior hypothalamic temperature for only the controls at 28 degrees C ambient, whereas norepinephrine had significant linear correlation with heat production for all groups and significant negative linear correlation with preoptic anterior hypothalamic temperature. These data indicate norepinephrine may be more important than epinephrine in the maintenance of postburn hypermetabolism in this rat burn model while demonstrating that the hypermetabolism is appropriately responsive to perturbation of preoptic anterior hypothalamic temperature.Rats, with the preoptic anterior hypothalamus implanted with two thermodes and a thermocouple reentry tube, had simultaneous direct and indirect calorimetry performed [during the ninth to eleventh postburn day interval] at ambient temperatures of 22 degrees and 28 degrees C. During calorimetry, blood was drawn at baseline and near the end of each period of displacement of the preoptic anterior hypothalamus temperature for catecholamine assay. Cooling the preoptic anterior hypothalamus resulted in a significant increase in heat production and plasma epinephrine and norepinephrine concentrations for both burn and control groups at 22 degrees C and 28 degrees C (p < 0.05 for all comparisons). Heat production demonstrated consistent negative linear correlation with preoptic anterior hypothalamic temperature. Plasma epinephrine values correlated with preoptic anterior hypothalamic temperature for only the controls at 28 degrees C ambient, whereas norepinephrine had significant linear correlation with heat production for all groups and significant negative linear correlation with preoptic anterior hypothalamic temperature. These data indicate norepinephrine may be more important than epinephrine in the maintenance of postburn hypermetabolism in this rat burn model while demonstrating that the hypermetabolism is appropriately responsive to perturbation of preoptic anterior hypothalamic temperature.

Polyclonal antibodies to rat interleukin-6 attenuate fever in rats after burn injuries: a preliminary report.

Rats with 50% total body surface area full-thickness burn injuries have sustained increases in body temperature without evidence of sepsis. In this animal model, the only known endogenous pyrogen consistently present in plasma is interleukin-6 (IL-6). We investigated the hypothesis that IL-6 acts as an endogenous pyrogen and produces the observed increase in body temperature. Body temperature and activity index were recorded every 5 minutes for control rats and rats with burns (50% total body surface area scald burns) for a period before the burn injuries and through the eighth day after the burn injuries. On the fifth day after the burn injuries, between 8 and 9 AM, control animals and animals with burns were given an intra-arterial dose of IL-6 polyclonal neutralizing antibody (IL-6 pAb) that was equivalent to one half of the neutralizing dose of IL-6 pAb. This calculation was based on plasma levels of IL-6 obtained from rats with burns in previous studies and on the neutralizing capability of the IL-6 used. On the sixth and seventh days after the burn injuries, a full neutralizing dose of IL-6 pAb was given. Blood samples were obtained for IL-6 assays at baseline and after treatment with IL-6 pAb but were lost because of the failure of an ultracold freezer. A one half neutralizing dose of IL-6 pAb produced no discernible effect on the body temperature of the control animals or of the animals with burns. On the sixth and seventh days after the burn injury, IL-6 pAb produced 45% and 34% respective decreases in body temperature compared with the animals with burns that received saline solution (P < .05 for both comparisons). On the eighth day after the burn injuries, the effect had completely dissipated. We concluded that our results support the idea that increased circulating levels of IL-6 may be causally related to fever that occurs in nonseptic rats with large burn wounds.