Biomedical subjects

C A Conn

Publications and source records attributed to C A Conn.

At least 37 records · Page 2Linked to original sources

PubMed1995

Cytokines and the acute phase response to influenza virus in mice.

This study characterized selected aspects of the acute phase response after intranasal inoculation of mice with two doses of mouse-adapted influenza virus differing in lethality. Mice given 140 plaque-forming units (PFU) of virus (58% survival) gradually decreased food and water intake to nearly zero over 6 days; survivors then slowly increased intakes. Declines in these behaviors were parallel to decreases in body temperature and general locomotor activity and were associated with elevated activities of interleukin-6 (IL-6), tumor necrosis factor-alpha, and interferons in lung lavage fluid. Circulating levels of these cytokines were not increased. After 55,000 PFU of virus (100% mortality), food and water intake fell to near zero within 48 h, temperature and locomotor activity decreased significantly, and activities of IL-1 and IL-6 were elevated in lung lavage fluid. These data show that cytokine activities in the lungs are elevated in a time frame that supports the hypothesis that cytokines could mediate behavioral and physiological changes in mice during acute influenza infections.

Animals↗

PubMed1995

TNF soluble receptor and antiserum against TNF enhance lipopolysaccharide fever in mice.

We tested the effects of tumor necrosis factor (TNF) soluble receptor (sTNFR) and anti-TNF serum (anti-TNF) administered intraperitoneally on fever induced by lipopolysaccharide (LPS) in mice. Both agents have been shown to block bioactivity of mouse TNF-alpha. Core temperature (Tb) and locomotor activity in unrestrained mice were measured by biotelemetry. Within 1 h from the LPS injection (2.5 mg/kg ip) Tb decreased below normal for 5-6 h and motor activity was depressed for the following 48 h. After this initial reduction, Tb increased and reached a peak at approximately 24 h postinjection. Anti-TNF and sTNFR blocked this "hypothermic phase" after LPS, and the fevers started sooner; however, the levels and time of peak temperature did not change markedly. In addition, a human recombinant TNF-alpha given intraperitoneally abolished fever and prolonged the fall of Tb in mice after LPS. We conclude that the reduction of Tb soon after injection of LPS in mice is dependent on TNF-alpha.

Animals↗

PubMed1995

Thermal and behavioral effects of lipopolysaccharide and influenza in interleukin-1 beta-deficient mice.

This study characterized body temperature (Tb), locomotor activity (Act), and feeding behavior under normal conditions and following injection with lipopolysaccharide (LPS) or inoculation with live influenza virus of transgenic C57/black mice deficient in interleukin-1 beta (IL-1 beta). Tb and Act in freely moving mice were measured by biotelemetry. Mice deficient in IL-1 beta had normal circadian rhythm of Tb but were less active than their control counterparts. Mice injected with LPS (2.5 mg/kg i.p.) responded with a prompt decrease of Tb, which lasted approximately 10 h, followed by a fever in which Tb reached a peak at approximately 24 h postinjection. There was no difference between groups in the early drop of Tb after the LPS; however, the 24-h peak of Tb was lower in IL-1 beta-deficient mice. The anorexic effects of LPS and influenza infection were similar in both groups of mice. In mice given influenza virus (17.5 plaque-forming units, median lethal dose), Tb and Act gradually decreased. The fall of Tb was smaller in the transgenic mice. The mice deficient in IL-1 beta displayed a higher mortality rate due to influenza infection than the control mice. We conclude that deficiency in IL-1 beta results in lower fever following the LPS injection and in impairment of the defense response to infection with influenza.

Animals↗

PubMed1995

Effect of exercise and food restriction on selected markers of the acute phase response in hamsters.

Acute aerobic exercise has been shown to elicit physiological changes characteristic of the acute phase response (APR), a nonspecific host defense response. Regular evocation of these changes may prime the immune system to improve resistance to disease. Because food deprivation is associated with an impaired APR, food restriction may prevent these beneficial changes. We tested the hypotheses that voluntary exercise elicits an APR and that food restriction modifies this response in four groups of hamsters: ad libitum-fed sedentary, ad libitum-fed exercised, food-restricted sedentary, and food-restricted exercised. Five variables altered during an APR were examined: core temperature, serum iron, serum interleukin-6, serum amyloid A, and serum glucocorticoids measured by biotelemetry, colorimetric analysis, B-9 cell growth assay, indirect enzyme-linked immunosorbent assay, and radioimmunoassay, respectively. Blood was drawn during the hamsters' inactive period after 19-20 days of access to running wheels. Resting core temperature was elevated by exercise and depressed by food restriction (P < 0.01). Iron was depressed by food restriction (P < 0.01). Cortisol, but not corticosterone, was elevated by food restriction (P < 0.001). There were no significant differences among groups in interleukin-6 (P > 0.49) or serum amyloid A (P > 0.29). We conclude that there is little evidence that voluntary exercise or exercise combined with food restriction causes an APR in hamsters.

Acute-Phase Reaction↗

PubMed1995

Effect of voluntary exercise and food restriction in response to lipopolysaccharide in hamsters.

We tested the hypothesis that voluntary running and moderate food restriction alter the acute phase response (APR), one index of nonspecific immune function. Hamsters were kept sedentary or permitted to run and were fed ad libitum or had food restricted for 20 days and were then injected intraperitoneally with saline or lipopolysaccharide (LPS). Fever and circulating interleukin-6, serum amyloid A (SAA), serum iron, and cortisol were measured by biotelemetry, B-9 cell growth assay, indirect enzyme-linked immunosorbent assay, colorimetric analysis, and radioimmunoassay, respectively. The febrile temperature; hypoferremia; and elevation of circulating interleukin-6, SAA, and cortisol after LPS injection were not altered by exercise. Because baseline temperatures were elevated in the exercised hamsters, the change in temperature in response to LPS was less than it was in the sedentary hamsters. Food restriction significantly decreased SAA and elevated cortisol after LPS injection and depressed the absolute temperature to which the core temperature rose in response to LPS in one trial but not in another. Because food restriction depressed baseline temperatures, it also affected the change in temperature after LPS injection. The hypoferremic response to LPS was inhibited in hamsters that were both food restricted and permitted to run. We conclude that exercise does not enhance the APR to a low dose of LPS, whereas food restriction and the combination of exercise and food restriction depress some portions of the APR in hamsters.

Acute-Phase Reaction↗

PubMed1994

Lipopolysaccharide induces fever and depresses locomotor activity in unrestrained mice.

The purpose of this study was to characterize the basic biology of fever to lipopolysaccharide (LPS) in unrestrained mice. Although LPS has been shown to induce fevers in many laboratory animals (e.g., rats, guinea pigs, rabbits), there is some question of whether LPS causes a fall or rise in body temperature (Tb) in mice. Tb was measured by biotelemetry in unrestrained mice maintained at an ambient temperature of 30 degrees C. Intraperitoneal injections of LPS at doses of 1.0, 2.5, and 3.0 mg/kg induced dose-independent prompt decreases of Tb for 5.7 h. After this postinjection reduction, Tb increased and reached a peak at approximately 24 h postinjection. The peak rises in Tb were dose dependent. Changes in Tb due to LPS were accompanied by suppression of locomotor activity. Indomethacin, at a dose that did not affect normal Tb, enhanced the temperature-lowering effect of LPS as well as inhibited the febrile rise of Tb after LPS. Indomethacin did not modify the reduction in activity caused by the injections of LPS. Food intake of the mice was decreased by LPS in a dose-dependent manner, and tolerance developed to a second injection of LPS. We conclude that freely moving mice can develop pronounced and reproducible fevers in response to LPS, which is different in time course, dose-dependent profile, induction of pyrogenic tolerance profile, and mode of inhibition by indomethacin from those responses that have been observed in other species studied so far.

Animals↗

PubMed1994

Tumor necrosis factor and interleukin-6 are not elevated in venous blood from ischemic canine myocardium.

To test the hypothesis that cytokines play a role in ischemic or reperfusion injury, we measured tumor necrosis factor (TNF) and interleukin-6 (IL-6) in pentobarbital-anesthetized dogs before, during, and after coronary occlusion lasting 60 min. Epicardial venous samples from the ischemic (IS) area were compared with nonischemic (NIS) and systemic (SYS) samples. Baseline IS TNF levels were low (2.2 +/- 1.2 U/ml) and not significantly different from NIS and SYS levels. After 50 min of coronary occlusion and at 40 min postreperfusion, IS, NIS, and SYS TNF levels were unchanged. At baseline, IS IL-6 levels were also relatively low (806 +/- 255 U/ml) and not significantly different from NIS and SYS IL-6. Although IS IL-6 increased significantly during coronary occlusion (5682 +/- 1495 U/ml) and reperfusion (10309 +/- 3708 U/ml), NIS and SYS levels were also elevated and did not differ significantly from IS values. The data indicate that TNF and IL-6 are not uniquely elevated in blood from ischemic or reperfused myocardium.

Animals↗

PubMed1993

Glucocorticoids alter fever and IL-6 responses to psychological stress and to lipopolysaccharide.

The purpose of this study was to determine whether glucocorticoids exert inhibitory feedback on lipopolysaccharide (LPS)-induced fever, stress-induced fever (exposure to an open field), and plasma concentrations of interleukin-6 (IL-6)-like and tumor necrosis factor-alpha (TNF)-like activity in biotelemetered rats. Injections of LPS (50 micrograms/kg) or exposure to an open field (30 min) led to significantly higher fevers in adrenalectomized (ADX) rats than in sham-ADX rats. To test the hypothesis that higher fevers were specifically the result of an absence of glucocorticoids, the glucocorticoid antagonist RU 38486 (20 mg/kg) was administered orally to rats with intact adrenal glands. The RU 38486-treated rats had higher plasma concentrations of IL-6-like activity and developed significantly higher fevers than did vehicle-treated rats. Rats injected intracerebroventricularly with 10 ng RU 38486 also developed higher fevers. Other ADX animals were implanted subcutaneously with replacement corticosterone pellets before exposure to an open field or injection with LPS. In response to an open field or injection with LPS, ADX animals implanted with replacement pellets that mimic plasma concentrations of corticosterone observed in stressed animals (100-mg pellets) developed fevers that were significantly lower than those observed in ADX rats given placebo pellets, but that were not different from fevers in sham-ADX rats given placebo pellets. ADX animals implanted with replacement pellets that mimic plasma concentrations of corticosterone observed in unstressed animals (25-mg pellets) developed fevers that were significantly higher than those observed in sham-ADX rats given placebo pellets, but that were not different from fevers in ADX rats given placebo pellets.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenalectomy↗

PubMed1993

Experimental cachexia: effects of MCA sarcoma in the Fischer rat.

Temporal patterns of the cachectic effects of tumor growth and their relation to systemic levels of tumor necrosis factor (TNF) and IL-6 (interleukin-6) were examined in a rat model of experimental cancer cachexia employing the methylcholanthrene (MCA) sarcoma. Fischer 344 rats, implanted with biotelemeters for measuring temperature and activity, were implanted subdermally with tumor tissue fragments. Ad libitum-fed and pair-fed controls were sham incised. Bioassays for TNF and IL-6 were performed on serial plasma samples, obtained via jugular vein at 3- to 6-day intervals throughout the experimental period. Tumor growth induced significant anorexia, weight loss, and a decline in motor activity corresponding to an increase in mean plasma IL-6 levels, independent of reduced food intake or weight loss alone as shown in pair-fed controls. A significant lowering of body temperature then developed, followed by a two- to threefold increase in water consumption. The patterns of weight loss and temperature reduction differed in rate and degree from those seen with pair feeding.

Animals↗

PubMed1993

Kinetics of systemic and intrahypothalamic IL-6 and tumor necrosis factor during endotoxin fever in guinea pigs.

The time course of activity of interleukin-6 (IL-6) and tumor necrosis factor (TNF) was measured in blood plasma and hypothalamic push-pull perfusates during the febrile response to intramuscular injection of bacterial endotoxin (Escherichia coli, 20 micrograms/kg) in 24 guinea pigs. Injection of endotoxin caused a dramatic increase of IL-6 activity in plasma. The logarithmic values of plasma IL-6 activities showed a linear correlation to the febrile change in body temperature (r = 0.898) during the whole time course of fever. IL-6 activity in hypothalamic perfusates increased 12-fold in the first hour after pyrogen application and declined slowly despite the further increase in body temperature. Hypothalamic IL-6 activity did not correlate with the febrile increase in body temperature (r = -0.048). TNF activity in plasma, not detectable before pyrogen application, had its peak in the first hour after endotoxin injection and rapidly declined to 15-20% of the peak activity within the next 2 h and to an undetectable value 5 h after injection. In the hypothalamus TNF was not detectable before endotoxin injection, but it could be monitored in most animals after pyrogen application without a clear correlation to the fever response. These results taken together indicate that endotoxin fever represents a physiological situation in which production and release of cytokines in the peripheral immune system and in the hypothalamus are regulated and stimulated in independent patterns.

Animals↗

PubMed1993

Food restriction postpones, not prevents, exercise-induced growth in hamsters.

Voluntary exercise during ad libitum feeding accelerates growth in mature female hamsters. If food is restricted during the exercise period, growth is suppressed, but ad libitum access to food at the cessation of exercise permits rapid catch-up growth in length and weight during retirement. To see whether the exercise-induced stimulus to grow persists when food-restriction is continued during retirement, female golden hamsters were matched by weight and assigned to exercise (EX) and sedentary (SED) groups fed ad libitum and to corresponding activity groups (REST-EX, REST-SED) food-restricted to 80% of starting weight. At the end of each week for 3 weeks following retirement, one REST-EX and one REST-SED group were fed ad libitum. At 21-35 days post-refeeding, mean gains in length and weight of each exercise group were greater (p < 0.05) than the gains of the corresponding sedentary group. Thus, exercise under food restriction remained an effective stimulus for acceleration of growth throughout three weeks of continued food restriction beyond termination of exercise, and ad libitum feeding permitted the delayed expression of exercise-induced catch-up growth in hamsters.

Animals↗

PubMed1992

Behavioral thermoregulation in mice inoculated with influenza virus.

Mice housed at 30 degrees C and inoculated with a mouse-adapted influenza virus show a fall in body temperature (Tb) and a decrease in food intake to almost 0 grams per day. This study tested whether the fall in Tb could be accounted for by the decreased food intake and whether the fall in Tb was due to a decrease of thermoregulatory set point or to an inability to maintain Tb at set point level. The fall in Tb of influenza-infected mice was greater than that of food-deprived mice. When food deprived, mice given access to a thermal gradient increased their preference for warmer areas in the gradient and, as a result, Tb did not fall as much as Tb of starved mice not given access to a thermal gradient. When infected with influenza virus, mice given a thermal gradient decreased Tb less and at a slower rate than mice not given a gradient. However, this fall in Tb of influenza-infected mice was greater than that of food-deprived mice given a thermal gradient. Mice given a thermal gradient increased their preference for the warmer temperatures after inoculation; this returned to preinoculation preference for cooler temperatures during the later days of infection despite a continuous fall in Tb. Influenza-infected mice given a thermal gradient survived significantly fewer days than infected mice not given a thermal gradient. We conclude that the influenza-induced fall of Tb in mice cannot be explained solely by the decrease in food intake, and is partially due to a decrease in thermoregulatory set point.

Animals↗

PubMed1992

Fever, tumor necrosis factor, and interleukin-6 in young, mature, and aged Fischer 344 rats.

The purpose of this study was to compare the febrile responses of Fischer 344 rats of different ages [young (3-5 mo), mature (12-15 mo), and aged (24-27 mo; n = 8)] to two psychological stress paradigms, cage switch and exposure to an open field, as well as to injection of lipopolysaccharide (LPS). In addition, the cytokines tumor necrosis factor-alpha (TNF) and interleukin-6 were also measured in the plasma of these rats at 90 min postinjection with LPS. There was no significant difference among groups in febrile responses to switching their cages. Exposure to an open field for 30 min resulted in a smaller rise in temperature in the aged rats (0.62 degree C) than in the young rats (1.26 degrees C). This difference disappeared if rats were exposed to an open field for 60 min. Injection of LPS led to fevers that developed at a slower rate in aged rats than in the mature groups. The peak fevers, however, were not different. The activity of interleukin-6 90 min after injection of LPS was higher in aged rats (297,858 U/ml) than in young (17,462 U/ml) and mature rats (28,819 U/ml). TNF levels were also higher in aged rats (16,380 U/ml) compared with young (574 U/ml) and mature rats (36 U/ml). We conclude that although the magnitude of the febrile response is not different among rats of different ages, the rise in body temperature occurs slower in aged rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗

PubMed1991

Role of gram-negative and gram-positive gastrointestinal flora in temperature regulation of mice.

An earlier study showed that the presence of gut flora elevates body temperature of mice and rats. In these experiments, we questioned whether the signal coming from the gut was endotoxin from gram-negative (Gm-) bacteria or some signal derived from gram-positive (Gm+) microorganisms. To test the idea that endotoxin is responsible for the effects of flora, we compared the temperature of the endotoxin-resistant mouse (C3H/HeJ) with that of endotoxin-sensitive strains of mice (C3H/SnJ and C3H/HeN). Temperature of C3H/HeJ was not different from that of C3H/SnJ or C3H/HeN during the light period but was significantly lower during the later hours of the dark period. We speculated that, if endotoxin leaking across the gut wall were responsible for elevating temperature, then reduction of gut flora with nonabsorbable antibiotics would depress the temperature of the endotoxin-sensitive mice more than that of the endotoxin-resistant mice. Because antibiotics lowered the temperature of both strains of mice to the same extent, the signal coming from the gut is unlikely to be endotoxin. To test whether Gm+ flora can be responsible for elevating temperature, we inoculated one group of germfree mice with Gm+ organisms. Their mean temperature was significantly higher than that of mice that remained germfree. Cecectomy had no effect on temperature, indicating that the special properties of the germfree cecum were not involved in lowering the temperature of germfree mice. These data support the hypotheses that Gm+ organisms are a major source of the stimulatory effect of flora on normal body temperature and that the presence of Gm- organisms is unnecessary.

Animals↗

PubMed1990

Effect of gastrointestinal flora on body temperature of rats and mice.

The purpose of these experiments was to test the hypothesis that gut flora influences the body temperature of rodents. Rats and mice were implanted with biotelemetry transmitters that enabled us to record both abdominal temperature and activity for long periods of time. Rats given nonabsorbable antibiotics in their drinking water, which reduced their gut flora, had a marked decrease in both their daytime and nighttime temperatures. Similar results were found with germfree mice. The circadian rhythms in body temperature of germfree and conventionalized mice were not different. However, the body temperatures of the germfree mice were lower than those of the conventionalized mice during both the daytime and nighttime. The decrease in body temperature in the germfree mice was not related to changes in activity. These results support the hypothesis that gut flora has a tonic stimulatory effect on both the daytime and nighttime body temperature of rodents.

Abdomen↗

PubMed1990

Temperature regulation in biotelemetered spontaneously hypertensive rats.

Core temperature of the spontaneously hypertensive rat (SHR) was not found to be different from the core temperature of the control rat, the Wistar-Kyoto rat (WKY), when the rats were left undisturbed in their home cages. When the rats were exposed to a variety of stressful environments, including cage switching, exposure to an open field, and handling, both SHR and WKY rats showed an increase in temperature. For the set of rats supplied by Charles River, the SHR temperature response to the stress was identical to the WKY rats' temperature response. For the set of rats supplied by Taconic Farms, the SHR was found to have a greater temperature response to the acute stress and the open-field stress. The Taconic Farms rats were also exposed to restraint stress, which resulted in a rise in temperature that was greater for the SHR when compared with the WKY. Because we have observed the increased lability in body temperature of the SHR compared with the WKY rats during restraint, we believe that it is important that studies with these strains of rat be done using minimal or no restraint.

Abdomen↗

PubMed1990

Body temperature rhythm and response to pyrogen in exercising and sedentary hamsters.

In this study, we tested the hypothesis that daily voluntary exercise results in a chronic elevation in core temperature in the female golden hamster. Temperature and activity were measured by biotelemetry. Hamsters ran 6-7 km per night (12:12 L:D) when permitted access to wheels. No running occurred during the light periods. During the 3rd wk of running, temperatures of exercising hamsters were significantly elevated by 0.5 degree C (P less than 0.001) during the dark period and by 0.3 degree C (P less than 0.003) during the light period compared with sedentary hamsters. Cessation of running removed the difference between groups, and resumption of running restored it. Both the injection of endotoxin and the psychological stress of cage switch resulted in similar peak temperatures in exercising and sedentary hamsters despite higher pre-treatment temperatures in the exercise group. We interpret these results to support the hypothesis that regular exercise may cause an upward resetting of the set-point for body temperature.

Animals↗

PubMed1989

Anorexic effects of interleukin 1 in the rat.

Interleukin 1 (IL-1) administration produces anorexia. Among unanswered questions about this effect are 1) whether it plays a role in the cachexia associated with chronic infection and cancer, and 2) whether IL-1 acts directly on food intake or indirectly by first lowering the set point for body weight. To investigate these questions, rats were infused with recombinant IL-1 continuously for 14 days through osmotic minipumps. Tolerance to the anorexic effects of the infusion developed within a few days. Control experiments showed that neither loss of IL-1 potency nor failure in the delivery system were responsible for recovery of food intake. Prior weight reduction completely overrode the anorexic effects of IL-1; previously food-restricted rats were hyperphagic initially despite receiving IL-1. This result is consistent with the view that IL-1 lowers the set point for body weight, but the development of tolerance prevented the full evaluation of this interpretation.

Animals↗