Attenuated febrile response to lipopolysaccharide in rats with biliary obstruction

L. K. McCullough1, Y. Takahashi2, T. Le1, Q. J. Pittman2, and M. G. Swain1

1 Liver Unit, Department of Medicine, and 2 Neuroscience Research Group, Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada T2N 4N1


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Patients with biliary tract obstruction have unexplained, inordinately high rates of perioperative morbidity and mortality, whereas cholestatic animals display abnormal hypothalamic responses to pyrogenic stimuli. We asked if obstructive cholestasis was associated with abnormal fever generation. Male Sprague-Dawley rats (250 g) underwent laparotomy for implantation of thermistors and either bile duct resection (BDR) or sham operation. After recovery, temperatures were recorded by telemetry and conscious, unrestrained rats in each group were injected intraperitoneally with either interleukin-1beta (IL-1beta ;1 µg/kg) or Escherichia coli lipopolysaccharide (LPS; 50 µg/kg). Baseline temperatures in both groups were similar. Febrile responses after IL-1beta injection in BDR and sham groups were not significantly different. However, in response to LPS injection, BDR rats showed an initial hypothermia with a subsequently attenuated febrile response. Administration of anti-tumor necrosis factor-alpha (TNF-alpha ) antibody 2 h before LPS injection blocked the LPS-induced hypothermia seen in BDR animals. However, serum levels of TNF-alpha were not significantly different between sham and BDR animals after LPS injection at any time point measured (0, 1.5, and 3 h).

thermoregulation; cytokines; interleukin; tumor necrosis factor-alpha


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

FEVER MAY BE DEFINED AS AN elevation in body temperature in response to infection, injury, or inflammation. It is one of the most clinically important indicators of disease and is a critical part of the acute phase response, which is composed of a large spectrum of physiological alterations (3). Hypothermia, or the inability to generate fever in response to infection or inflammation, is a poor prognostic factor in certain disease states (11, 15, 33). Ectothermic animals that are infected with Gram-negative bacteria and are prevented from developing fever have markedly increased mortality compared with animals that generate a febrile response (21), and fever is now thought to be an important component of the acute phase response. It has been shown that various components of the immune response such as T cell activation, T cell helper function, and generation of cytotoxic T cells are augmented at higher temperatures (17).

Cholestatic patients have high rates of perioperative morbidity and mortality, but the pathophysiology behind these increases are unknown. Surgical mortality rates are much higher than expected, and this increase is seen independent of whether the biliary obstruction is secondary to benign or malignant causes (1, 31). A variety of physiological abnormalities are seen in obstructive cholestasis, including delayed wound healing with increased rates of wound infection, increased propensity to renal failure, increased plasma endotoxin levels, and biliary bacteremia (4, 9, 10, 14, 19, 20, 29). Many studies (8, 30, 31) have attempted to correlate preoperative factors to operative outcome; however, the underlying pathophysiology remains unclear.

Cytokine-mediated fever induction is in general felt to be prostaglandin dependent (27). Obstructive cholestasis in the rat is associated with decreased hypothalamic production of PGE2 in response to the cytokine interleukin-1beta , (IL-1beta ) (35). Furthermore, inflammatory mediator-induced central activation of the hypothalamic-pituitary-adrenal axis is defective in rats with obstructive cholestasis (35, 36).

The role of tumor necrosis factor-alpha (TNF-alpha ) in both cholestasis and thermoregulation is controversial. Some studies (6, 22, 28, 34) report increased levels of serum TNF-alpha in cholestasis, whereas others (5, 23, 31) report no difference. Whether TNF-alpha acts as a cyrogen or pyrogen is also controversial (13, 23), but the majority of studies (25) point to enhanced fever generation when the actions of TNF-alpha are blocked.

The possible presence of abnormalities in thermoregulatory mechanisms that may occur in obstructive cholestasis has not been studied. Given that it is already known that cholestatic animals have an attenuated activation of the hypothalamic-pituitary-adrenal axis in response to endogenous pyrogens (37), we hypothesized that cholestatic rats may have an abnormal thermoregulatory response to pyrogenic stimuli. The following experiments were undertaken to determine if indeed fever generation is altered in rats with early obstructive cholestasis.


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Male Sprague-Dawley rats (250 g; Charles River, Pointe Claire, QC, Canada) were housed in a light-controlled room with a 12:12-h light-dark cycle and given free access to food and water. All experiments were performed according to the University of Calgary Animal Care Committee guidelines. The animals were anesthetized with inhalational halothane, and a laparotomy was performed. In bile duct-resected (BDR) animals, the bile duct was identified, isolated, doubly ligated with silk suture, and then resected between the ligatures. Sham-resected animals had their bile ducts identified and dissected free, but not divided. A precalibrated temperature telemetry device (model VMHF, Mini-mitter, Sunriver, OR) was then implanted in the peritoneal cavity. The rats were given the antibiotic gentamycin (50 mg/kg; Schering Canada, Pointe Claire, QC, Canada) as a one-time intramuscular dose at the time of surgery. The animals were then allowed to recover for 5 days, at which point the BDR rats were overtly cholestatic. Table 1 shows serum bilirubin and aspartate aminotransferase levels from a separate cohort of eight rats (n = 4 each in BDR and sham-resected groups) at day 5.

                              
View this table:
[in this window]
[in a new window]
 
Table 1.   Serum biochemistries in BDR and sham-resected animals 5 days after surgery

Each of the radiotransmitters was calibrated before use and wax coated before implantation, as described previously (18). Temperature measurements were taken every 5 min for 1 h preinjection and 8 h postinjection. The transmitted radio frequencies representing the rats' temperatures were transduced via receiver plates placed under each cage and fed into an online data acquisition system (Dataquest II, Data Sciences, St. Paul, MN) On day 4, rats were brought to an environmentally controlled room (22°C;12:12-h light-dark cycle), handled, and given sham injections of PBS (200 µl) to accustom them to experimental protocol. The following day, separate groups of rats were injected either with recombinant human IL-1beta (1 µg/kg ip; Biosource, Camarillo, CA; dose found in preliminary experiments to be consistently pyrogenic in control rats), PBS (200 µl), or lipopolysaccharide (LPS; endotoxin) (Escherichia coli serotype 026:B6; 50 µg/kg; Sigma Chemical, St. Louis, MO; dose found in preliminary experiments to be consistently pyrogenic in control rats). As a control, and to estimate the magnitude of hyperthermia from the stress response to injection, sham injections of PBS were done 2 days later only in the group of rats that received LPS injection, on postoperative day 7 (i.e., these animals had received injection of LPS 2 days earlier). All injections were done between 9 and 11 AM to avoid effects due to circadian rhythm in temperature regulation.

A second set of experiments were carried out to measure serum TNF-alpha levels after LPS injection. A separate cohort of 36 animals underwent bile duct ligation and 36 underwent sham operation, as described above. On day 5 postsurgery, LPS was injected at 50 µg/kg ip, and the animals were then killed and serum was drawn by cardiac puncture. Serum TNF-alpha levels were measured at 0-, 1.5-, and 3-h time points, (n = 6 BDR and sham animals per group). A TNF-alpha ELISA kit (Biosource, Montreal, QC, Canada) was used to measure serum levels of TNF-alpha at each time point according to the manufacturer's instructions (assay lower limit of detection 4 pg/ml).

A third cohort of animals (n = 8 BDR; n = 6 sham) were injected with rabbit anti-TNF-alpha antibody (a kind gift from Dr. S. Kunkel) (0.5 ml/kg ip) 2 h before injection of LPS on day 5 postlaparotomy. This antibody has been well characterized, and this dose of antibody effectively neutralizes endogenous TNF-alpha production. (24, 34)

For all groups, baseline temperatures were calculated for each individual animal as the mean of the body temperature values taken during the 1-h interval before injection. The results were expressed as the change from this average above or below pretreatment values. Grouped scores were expressed as means ± SE. For statistical analysis, overall significance between groups was assessed by two-way ANOVA (time and treatment as variables), and differences were identified using a Student-Newman-Kuels post hoc test. P < 0.05 was used for all comparisons, at which level the null hypothesis was rejected.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Baseline temperatures were similar in all groups (P > 0.05). BDR animals had significantly less weight gain than sham animals and, on average, lost weight compared with sham animals (P < 0.001; data not shown). BDR rats showed similar fever generation in response to IL-1beta injection (1 µg/kg ip) compared with sham-operated animals (peak change in baseline temperature 0.7 ± 0.2°C for sham vs. 0.9 ± 0.2°C for BDR; Fig. 1). BDR rats (n = 8) generated a fever response profile almost identical to that of sham animals (n = 9, P > 0.05) (Fig. 1).


View larger version (25K):
[in this window]
[in a new window]
 
Fig. 1.   Febrile response of bile duct-resected (BDR) (n = 8) and sham (n = 9) rats when injected with 1 µg/kg interleukin-1beta (IL-1beta ) ip at time 0 as shown by arrow. No significant differences between groups occurred over the 9-h time course.

However, in response to LPS injection, BDR animals (n = 8) showed a significant postinjection hypothermic response initially and subsequently failed to generate as great a magnitude of a febrile response over an 8-h time course compared with sham-operated animals (n = 9, P <=  0.05) (Fig. 2). At 1.5 h postinjection, BDR rat temperatures had reached their lowest point, dropping an average of 0.9°C, and the animals remained hypothermic until the 2-h time point, at which time their temperatures began to recover. The BDR rats subsequently generated a small fever. In contrast, sham animals showed a typical fever response to LPS. At 1.5 h after injection, mean temperature in sham animals was 0.5°C above baseline, reaching a maximum febrile response 2.25 h after injection (1.3°C above baseline). Temperatures in BDR rats were significantly different from those in sham animals at all time points between 1.5 and 2.5 h after injection (P < 0.05). There was clearly a lesser magnitude of febrile response in the BDR animals throughout all subsequent time points, which intermittently attained significance (Fig. 2). There was no mortality in any group of animals treated with PBS, IL-1beta , LPS, or anti-TNF-alpha antibody.


View larger version (34K):
[in this window]
[in a new window]
 
Fig. 2.   Febrile response of BDR (n = 8) and sham (n = 9) rats when injected with 50 µg/kg lipopolysaccharide (LPS) ip at time 0 as shown by arrow. The initial hypothermic response of BDR rats was significantly different from that of sham animals from 1.5 to 2.75 h. Subsequent fever generation by BDR rats was of a lesser magnitude than that observed in shams, although only significantly different at 1 time point (* P < 0.05).

Sham injections of PBS (200 µl), done 48 h post-LPS injection (day 7 postlaparotomy), were not associated with a change in temperature in either BDR or sham-operated animals at any time point (Fig. 3).


View larger version (33K):
[in this window]
[in a new window]
 
Fig. 3.   Temperature response to 200 µl PBS at time 0 as shown by arrow. No significant difference was detected at any time point, and no significant temperature change from baseline was observed in either group. BDR, n = 8; sham, n = 9.

Injection of anti-TNF-alpha antibody 2 h before injection of LPS in BDR rats resulted in fevers that were significantly different from those of BDR rats not treated with the antibody (P < 0.05, Fig. 4). When responses were compared in anti-TNF-alpha antibody-treated sham and BDR rats, the fevers observed were identical. There were no significant differences in fever generation between the two groups given the anti-TNF-alpha antibody at all time points (P > 0.05; Fig. 5).


View larger version (34K):
[in this window]
[in a new window]
 
Fig. 4.   Temperature response of BDR animals given anti-tumor necrosis factor-alpha (TNF-alpha ) antibody (Ab) (n = 6/group) 2 h before LPS injection (50 µg/kg ip) compared with BDR animals receiving no anti-TNF-alpha antibody (n = 6/group). Attenuated hypothermia seen with injection of anti-TNF-alpha antibody, and significantly greater fever generation at 3-4 h postinjection. * P < 0.05.



View larger version (29K):
[in this window]
[in a new window]
 
Fig. 5.   Temperature response of BDR vs. sham animals in response to LPS (50 µg/kg). Both groups were given anti-TNF-alpha antibody (Ab) 2 h before LPS injection. No significant differences were seen between sham and BDR rats at any time point.

Serum levels of TNF-alpha did not differ significantly between BDR and sham animals at any of the three time points (0, 1.5, and 3 h) post-LPS injection (Table 2).

                              
View this table:
[in this window]
[in a new window]
 
Table 2.   Serum TNF-alpha levels in BDR vs. sham animals at 0, 1.5, and 3 h after LPS injection


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

The development of a febrile response has been shown to be a tightly regulated physiological phenomenon (21) that is highly conserved across a diverse range of mammals and is felt to be of critical importance for survival. A wide variety of derangements in homoeostatic physiology are associated with the development of obstructive cholestasis in both animal models and humans. Patients with obstructive cholestasis have an unexplained high rate of surgical mortality and morbidity; however, defects in thermoregulation and fever have not been assessed in this group of patients, although prior studies (34) have found abnormalities in the cytokines thought to be important for thermoregulation. In the current study, we have identified an altered febrile response to LPS in rats with obstructive cholestasis and, in addition, have found that this can be reversed by prior treatment with anti-TNF-alpha antibody. We suggest that this defect in fever generation in cholestasis may contribute, at least in part, to the increased surgical mortality identified in cholestatic patients.

In contrast to the reduced febrile response to LPS, the febrile response after administration of IL-1beta was identical in both BDR and sham animals. To understand why responses to these two pyrogens are different, it is instructive to examine differences in the mechanisms of action of LPS and IL-1beta . In animals and patients developing fever, it is thought that exogenous pyrogens such as LPS, derived from the cell coat of Gram-negative bacteria, induce the production of pyrogenic cytokines from macrophages and other cells of the immune system. Cytokines are immunoregulatory peptides that have a variety of functions in mediating the febrile and acute phase response. In the brain, prostaglandin production is induced by cytokines, and prostaglandins then mediate the fever response via their actions on hypothalamic neurons (21). From the above schema, it would seem that the febrile response to IL-1beta and LPS would be identical, but in fact the literature suggests that some of the mechanisms of fever induction may be different. For example, Bishai and Coceani (7) found increased PGE2 synthesis in isolated brain tissue in response to peripheral endotoxin injection, but not in response to IL-1beta . There may also be differences in the peripheral responses to IL-1beta and LPS; LPS causes the elaboration and secretion of many other substances in addition to IL-1beta . Significant among these is the production of the cytokine TNF-alpha (13).

The role of TNF-alpha in fever has been intensively investigated. Although under some conditions it may potentiate the effects of IL-1beta , there is also good evidence that it is cryogenic (12, 24). In keeping with this, animals becoming hypothermic during sepsis have elevated TNF-alpha levels, and interference with the actions of TNF-alpha mitigates the hypothermic response (12, 23, 24) and also attenuates the rise in plasma corticosterone in other models of inflammation (34). Indeed, there is considerable evidence that obstructive cholestasis is associated with augmented TNF-alpha release in response to LPS in cholestasis (6, 16, 22, 28), although other studies (5) contradict these findings.

Plasma TNF-alpha levels are also increased in patients with biliary tract obstruction (2, 37, 38), possibly due to elevations in plasma LPS levels (19, 29). In association with these elevations in serum TNF-alpha levels, cholestatic patients are predisposed to septic complications, which are often contributing factors to the high mortality seen in these patients. In neonates and the elderly, hypothermia, as opposed to fever, is often seen in response to infectious stimuli. The incidence of hypothermia accompanying sepsis has been reported to vary between 1% and 10% and approximately doubles the rate of mortality (11, 15, 33). Because of this evidence for both a role for TNF-alpha as a cryogen and elevated levels of TNF-alpha in obstructive cholestasis, we considered the possibility that the hypothermia after LPS in BDR rats could be due to elevated levels of TNF-alpha . To test this hypothesis, we pretreated BDR animals with an anti-TNF-alpha antibody to interfere with the actions of endogenously released TNF-alpha . In keeping with the possible involvement of TNF-alpha in the transient hypothermic response to LPS, rats pretreated with the anti-TNF-alpha antibody did not exhibit the atypical hypothermia. Indeed, these anti-TNF-alpha antibody-pretreated BDR animals displayed fevers that were identical to sham animals.

As an additional way to investigate a role for TNF-alpha in the atypical febrile response in BDR rats in response to LPS, we also measured serum TNF-alpha levels after LPS. However, although serum TNF-alpha levels were elevated after LPS administration in both groups of rats, there was no difference between levels observed in BDR and sham animals. The finding of no significant differences between BDR and sham animals in the absolute serum values of TNF-alpha after LPS administration is not necessarily surprising. Although some prior studies (6, 16, 22, 28) have found elevations in serum TNF-alpha levels after LPS in BDR compared with sham rats, often these studies had differences in experimental protocol, such as higher doses of LPS, longer duration of cholestasis, and different techniques of measurement of TNF-alpha . In addition, TNF-alpha may act as a cryogen in cholestasis due to an increased central TNF-alpha sensitivity as opposed to an increase in serum TNF-alpha levels. It has been suggested than elevations of TNF-alpha in biliary obstruction are rapidly inactivated by soluble plasma receptors. (6)

Overall, the literature seems to support the presence of enhanced immune function at higher temperatures with a decrease in the body's ability to resist infectious agents at lower temperatures. Although hypothermia in sepsis may merely be a marker of how ill the patient is, as opposed to an actual contributor to increased mortality, all evidence suggests that the body's capabilities in fighting infection are compromised in the absence of fever. This study has shown an abnormal thermoregulatory response in cholestatic rats, which is then blocked by administration of an anti-TNF-alpha antibody. Although it is difficult to ascribe a deleterious effect of the transient hypothermia seen in BDR rats in the present experiments, it should be noted that a single intraperitoneal injection of LPS is a transient stimulus, whereas sepsis in cholestatic patients is an ongoing process. If cholestatic patients were to show a similar abnormal thermoregulatory response to LPS, the reduction in fever and accompanying hypothermia could be one contributor to their increased morbidity and mortality. Further research is needed to further elucidate the roles of TNF-alpha and other cytokines in fever generation in cholestasis.


    ACKNOWLEDGEMENTS

This study was supported by the Medical Research Council of Canada (MRC) and the Alberta Heritage Foundation for Medical Research. Q. Pittman was also supported as an MRC Senior Scientist and M. Swain as an MRC Scholar.


    FOOTNOTES

Address for reprint requests and other correspondence: M. G. Swain, Liver Unit, Gastroenterology Research Group, Health Sciences Centre, Univ. of Calgary, 3330 Hospital Dr. NW, Calgary, Alberta, Canada T2N 4N1 (E-mail: swain{at}ucalgary.ca).

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. §1734 solely to indicate this fact.

Received 26 April 1999; accepted in final form 12 February 2000.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

1.   Armstrong, CP, Dixon JM, Taylor TV, and Davies GC. Surgical experience of deeply jaundiced patients with bile duct obstruction. Br J Surg 71: 234-238, 1984[ISI][Medline].

2.   Ballinger, AB, Woolley JA, Ahmed M, Mulcahy H, Alstead EM, Landon J, Clark ML, and Farthing MJR Persistent inflammatory response after stent insertion in patients with malignant bile duct obstruction. Gut 42: 555-559, 1998[Abstract/Free Full Text].

3.   Baumann, H, and Gauldie J. The acute phase response. Immunol Today 15: 74, 1994[ISI][Medline].

4.   Bayer, I, and Ellis H. Jaundice and wound healing: an experimental study. Br J Surg 63: 392-396, 1976[ISI][Medline].

5.   Beierle, EA, Vauthey JN, Moldawer LL, and Copeland EM. Hepatic tumor necrosis factor-alpha production and distant organ dysfunction in a murine model of obstructive jaundice. Am J Surg 171: 202-206, 1995[ISI].

6.   Bemelmans, MHA, Greve JWM, Gouma DJ, and Buurman WA. Increased concentrations of tumor necrosis factor (TNF) and soluble TNF receptors in biliary obstruction in mice: soluble TNF receptors as prognostic factors for mortality. Gut 38: 447-453, 1994[Abstract].

7.   Bishai, I, and Coceani F. Differential effects of endotoxin and cytokines on prostaglandin E2 formation in cerebral microvessels and brain parenchyma: implications for the pathogenesis of fever. Cytokine 8: 371-376, 1996[ISI][Medline].

8.   Blamey, SL, Fearon KCH, Gilmour WH, Osborne DH, and Carter DC. Prediction of risk in biliary surgery. Br J Surg 70: 535-538, 1983[ISI][Medline].

9.   Clements, B, Halliday I, Irwin P, McCaique M, and Rowlands BJ. Decreased Kupffer cell clearance capacity to endotoxemia seen in cholestasis (Abstract). Gut 33, Suppl: W78, 1992.

10.   Clements, WDB, Parks R, Erwin P, Halliday I, Barr J, and Rowlands BJ. Role of the gut in the pathophysiology of extrahepatic biliary obstruction. Gut 39: 587-593, 1996[Abstract].

11.   Clemmer, TP, Fisher CJ, Jr, Bone RC, Slotman GJ, Metz CA, and Thomas FO. Hypothermia in the sepsis syndrome and clinical outcome. The methylprednisolone severe sepsis study group. Crit Care Med 20: 1395-1401, 1992[ISI][Medline].

12.   Derijk, RH, and Berkenbosch F. Hypothermia to endotoxin involves the cytokine tumor necrosis factor and the neuropeptide vasopressin in rats. Am J Physiol Regulatory Integrative Comp Physiol 266: R9-R14, 1994[Abstract/Free Full Text].

13.   Dinarello, CA, Cannon JG, Wolff SM, Bernheim HA, Beutler B, Cerami A, Figari IS, Palladino MA, and O'Connor JV. Tumor necrosis factor (cachectin) is an endogenous pyrogen and induces production of interleukin 1. J Exp Med 163: 1433-1450, 1986[Abstract].

14.   Greve, JW, Maessen JG, Tiebosch T, Buurman WA, and Gouma DJ. Prevention of postoperative complications in jaundiced rats. Ann Surg 212: 221-227, 1989[ISI].

15.   Harris, RL, Musher DM, Bloom K, Rice L, Sugarman G, Williams TW, and Young EJ. Manifestations of sepsis. Arch Intern Med 147: 1895-1906, 1987[Abstract].

16.   Harry, D, Holt S, Davies S, Marley R, Fernando B, Goodier D, and Moore K. Increased sensitivity to endotoxemia in the bile duct-ligated cirrhotic rat. Hepatology 30: 1198-1205, 1999[ISI][Medline].

17.   Hasday, JD. The influence of temperature on host defenses. In: Fever: Basic Mechanisms and Management (2nd ed.), edited by Mackowiak PA.. Philadelphia: Lippincott-Raven, 1997, p. 177-196.

18.   Horn, T, Marshall FW, Landgraf R, and Pittman Q. Reduced febrile responses to pyrogens after lesions of the hypothalamic paraventricular nucleus. Am J Physiol Regulatory Integrative Comp Physiol 267: R230-R238, 1994.

19.   Hunt, DR, Allison MEM, Prentice CRM, and Blumgart LH. Endotoxemia, disturbance of coagulation, and obstructive jaundice. Am J Surg 144: 325-329, 1982[ISI][Medline].

20.   Keighley, MRB, Lister DM, Jacobs SI, and Giles GR. Hazards of surgical treatment due to microorgansims in the bile. Surgery 75: 578-583, 1974[ISI][Medline].

21.   Kluger, MJ, Ringler DH, and Anver MR. Fever and survival. Science 188: 166-168, 1975[ISI][Medline].

22.   Lechner, AJ, Velasquez A, Knudson KR, Johanns CA, Tracy TF, and Matuschak GM. Cholestatic liver injury increases circulating TNF-alpha and IL-6 and mortality after Escherichia coli endotoxemia. Am J Respir Crit Care Med 157: 1550-1558, 1998[Abstract/Free Full Text].

23.   Leon, LR, White AA, and Kluger MJ. Role of IL-6 and TNF in thermoregulation and survival during sepsis in mice. Am J Physiol Regulatory Integrative Comp Physiol 275: R269-R277, 1998[Abstract/Free Full Text].

24.   Long, NC, Kunkel SL, Vander AJ, and Kluger MJ. Antiserum against tumor necrosis factor enhances lipopolysaccharide fever in rats. Am J Physiol Regulatory Integrative Comp Physiol 258: R332-R337, 1990[Abstract/Free Full Text].

25.   Long, NC, Otterness I, Kunkel SL, Vander AJ, and Kluger MJ. Roles of interleukin 1beta and tumor necrosis factor in lipopolysaccharide in rats. Am J Physiol Regulatory Integrative Comp Physiol 259: R724-R728, 1990[Abstract/Free Full Text].

26.   Mackowiak, PA, and Boulant JA. Fever's glass ceiling. Clin Infect Dis 22: 525-536, 1996[ISI][Medline].

27.   Milton, AS. Thermoregulatory actions of eicosanoids in the central nervous system with particular regard to the pathogenesis of fever. Ann NY Acad Sci 559: 392-410, 1989[ISI][Medline].

28.   O'Neil, S, Hunt J, Filkins J, and Gammelli R. Obstructive jaundice in rats results in exaggerated hepatic production of tumor necrosis factor-alpha and systemic and tissue tumor necrosis factor-alpha levels after endotoxin. Surgery 122: 281-287, 1997[ISI][Medline].

29.   Pain, JA, and Bailey ME. Measurement of operative plasma endotoxin levels in jaundiced and non-jaundiced patients. Eur Surg Res 19: 207-216, 1997.

30.   Pitt, HA, Cameron JL, Postier RG, and Gadacz TR. Factors affecting mortality in biliary tract surgery. Am J Surg 141: 66-72, 1981[ISI][Medline].

31.   Reynolds, JV, Murchan P, Redmond HP, Watson RWG, Leonard N, Hill A, Clarke P, Marks P, Keane FBV, and Tanner WA. Failure of macrophage activation in experimental obstructive jaundice: association with bacterial translocation. Br J Surg 82: 534-538, 1995[ISI][Medline].

32.   Shirahatti, RG, Alphonso N, Joshi RM, Prasad KV, and Wagle PK. Palliative surgery in malignant obstructive jaundice: prognostic indicators of early mortality. J R Coll Surg Edinb 42: 238-243, 1997[ISI][Medline].

33.   Sprung, CL, Peduzzi PN, and Shatney CH. Impact of encephalopathy on mortality in the sepsis syndrome. Crit Care Med 18: 801-806, 1990[ISI][Medline].

34.   Swain, MG, Appleyard CB, Wallace JL, and Maric M. TNF-alpha facilitates inflammation-induced glucocorticoid secretion in rats with biliary obstruction. J Hepatol 26: 361-368, 1997[ISI][Medline].

35.   Swain, MG, Maric M, and Carter L. Defective interleukin-1-induced ACTH release in cholestatic rats: impaired hypothalamic PGE2 release. Am J Physiol Gastrointest Liver Physiol 268: G404-G409, 1995[Abstract/Free Full Text].

36.   Swain, MG, Patchev GV, Vergalla J, Chrousos G, and Jones EA. Suppression of hypothalamic-pituitary-axis responsiveness to stress in a rat model of acute cholestasis. J Clin Invest 91: 1903-1908, 1993[ISI][Medline].

37.   Tilg, H, Wilmer A, Vogel W, Herold M, Nolchen B, Judmaier G, and Huber C. Serum levels of cytokines in chronic liver diseases. Gastroenterology 103: 264-274, 1992[ISI][Medline].

38.   Wardle, EN, and Wright NA. Endotoxin and acute renal failure associated with obstructive jaundice. Br Med J 4: 472-474, 1970[ISI][Medline].


Am J Physiol Gastrointest Liver Physiol 279(1):G172-G177
0193-1857/00 $5.00 Copyright © 2000 the American Physiological Society