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Research in Nursing & Health, 1992, 15, 13 1 137
The Effects of Noise Stress on Leukocyte Function in Rats Donna 0. McCarthy, Mary E. Ouimet, and Jane M. Daun
It has been reported that exposure to increased noise levels impairs wound healing in surgical patients and in rats. The purpose of the present study was to determine if exposure to noise stress would alter the biological function of neutrophils, macrophages, and lymphocytes, leukocytes that are involved in wound healing. Rats were exposed to 80 db of "rock" music for 24 hr, during which time the control animals were maintained in their usual environment. Leukocyte subpopulations were obtained and stimulated in vitro. Neutrophils and macrophages from noise-exposed animals secreted significantly less superoxide anion and interleukin-1 than cells from control animals. Lymphocyte function was not altered following noise stress. We conclude that short-term exposure of rats to noise stress alters some of the biological functions of leukocytes.
Noise has long been recognized as an environmental stressor that causes physiological, psychological, and behavioral changes in healthy subjects (Fruhstorfer, Pritsch, Pritsch, Clement, & Wesemann, 1988). Noise and its potential effects on patient recovery and well-being are of special concern to nurses in hospital settings where noise levels often exceed 70 decibels (db) (Redding, Hargest, & Minsky, 1977; Soutar & Wilson, 1986). The effects of noise on patient sleep, cognitive function, and postoperative pain have been well documented in the literature (Hansel], 1984; Minckley, 1968; Snyder-Halpem, 1985). However, there are few studies on the effects of noise on physiological measures of patient recovery or wellbeing. There are some data to suggest that increased environmental noise prolongs wound healing. Billewicz-Stankiewicz and Krepinska-Urban (1974) reported that exposure of rats to 85 db of noise for 2 hr altered the normal inflammatory response to skin wounds. Wysocki (1987) reported that exposure of rats to 85 db of broadband noise for 15 min of every hour for 24 hr over 19 days altered healing of surgical wounds made on their backs. Photographs of the wounds were taken
every other day and compared by computerized digital analysis of surface area and color. There was a significant delay in wound healing in noiseexposed animals throughout the 19-day period of study. Finally, Fife and Rappaport (1976) reported that the length of patient stay following cataract surgery was significantly increased during a period of hospital construction compared to the length of stay before and after the period of construction. These authors questioned if the increased length of stay was related to physiological effects of increased noise on healing of the surgical wounds. Wound healing is the result of an orderly series of cellular processes that lead to restoration of tissue integrity. These processes take place in three interdependent phases: inflammation, cell proliferation, and collagen remodeling (Cooper, 1990). Neutrophils are the predominate cell type in the wound for the first 24 hr. Activated neutrophils release superoxide (02-) anions that play a major role in protecting the wound from infection. Monocytes are slower to migrate into the tissue and are the predominate cell type in the wound for 2 to 3 days. Monocyte secretion of peptides such as interleukin-I (IL- I ) stimulate neovascularization and the chemotaxis of lymphocytes and
Donna 0. McCarthy, PhD, AN, is an assistant professor, Mary E. Ouimet, MSN, RN, is a graduate student, Jane M. Daun, BS, is a research scientist, at the School of Nursing, University of Wisconsin-Madison. The study was supported by a grant from the Wisconsin Alumni Research Fund. This article was received on May 3, 1991, was revised, and accepted for publication October 4, 1991. Requests for reprints can be addressed to Dr. Donna 0. McCarthy, University of Wisconsin-Madison, School of Nursing K6/326, 600 Highland Avenue, Madison, WI 53792. 0 1992 John Wiley & Sons, Inc. CCC 0160-6891/92/020131-07 $04.00
RESEARCH IN NURSING & HEALTH
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fibroblasts into the wound (Herrod, 1989). The second phase of healing involves proliferation of epithelial cells and fibroblasts. Lymphocytes contribute to this process by secreting a factor that promotes proliferation of fibroblasts (Wahl & Gately, 1983). The purpose of the present study was to determine if exposure to noise stress alters the biological function of neutrophils, monocyteshnacrophages, and lymphocytes in vitro. The study was conducted using an animal model in order to control for inherent differences in nutritional status, age, or genetic endowment of subjects that could affect leukocyte function. Given the documented effects of stressful life events on leukocyte function in vitro, the use of an animal model in a laboratory setting permitted the investigators to control the amount, duration, and nature of the stress experienced by all subjects.
METHOD
Animal Model Male Sprague-Dawley rats weighing 180 to 200 grams were housed individually in two adjoining rooms in the animal care facility on a 12-hr light/ dark cycle with free access to food and water. The animals were allowed 7 days to adapt to the housing conditions prior to the start of the experiment. The noise level in this facility ranges between 30 and 60 db of equipment and voice noise, and is highest when employees are present. On the day of the experiment, baseline levels of body temperature and activity were recorded for 2 hr as described below. Beginning at 8 a.m., the six experimental animals were subjected to 60 to 80 db of “rock” music delivered via stereo speakers placed within 4 ft of the cages. In order to prevent habituation to the noise, we selected a radio station with varied programming and used electronic timers to turn on the noise for 90 min every 2 hr for the next 22 hr. The noise level was checked every 6 to 8 hr using a battery-operated decibel meter (AMF Electrical Products, Alexandria, VA) held within 12 in. of the cages. The six control animals were maintained in their ‘‘usual” environment during the same time period and noise levels were checked every 6 to 8 hr as described above. Stress induces an acute rise in body temperature in rats referred to as stress-induced hyperrhermia (Singer, Harker, Vander, & Kluger, 1986). To verify that exposure to 60 to 80 db of “rock” radio
programming was stressful, that is, would induce stress hyperthermia, the animals were surgically implanted with temperature-sensitive miniature battery-operated transmitters (Minimitter Company, SunRiver, OR) in the peritoneal cavity 5 days prior to the start of the experiment as described by Singer et al. (1986). The calibrations of the transmitters (output frequency in Hz) were checked in a temperature-controlled circulating waterbath (Fischer, Chicago IL) that maintains the temperature within 0.02 “C. The temperature of the waterbath was constantly monitored using a digital thermometer (VWR, Chicago IL)accurate to .1”C. Transmitters that deviated more than 5 Hz or .1”C from the manufacturer’s original calibrations were not used for this experiment. Following implantation of the transmitters, the individual cages were placed over antenna boards that were connected via a signal processor (Dataquest III, Minimitter, Inc.) to an IBM-Compatible PC computer. Body temperature was recorded every 2 min and the 30 two-min readings were averaged every 60 rnin to obtain an hourly measure of body temperature for each animal. To differentiate the effects of noise stress versus sleep deprivation due to the noise, activity of the rats was measured using the same biotelemetry system described above. As the animal moves, the orientation of the transmitter changes with respect to the antenna board under the cage, creating a change in signal strength, which is recorded as one “pulse” or one activity count. Activity was recorded very 2 min and averaged every 60 min to obtain mean 2-min activity counts each hour for each animal. Because rats are noctumal animals, the hourly 2-min activity counts during lights-on (6 a.m. to 5 p.m.) and lights-off (6 p.m. to 5 a.m.) were averaged to obtain mean 2-min activity counts during both the dark and the light phases of the 24-hr period of data collection. Data were analyzed using Student’s t test to compare the group means for each phase. At the end of the 22-hr period of noise exposure, the control and experimental animals were lightly anesthetized with ether fumes and exsanguinated by cardiac puncture. All reagents and media used in the preparation and assays of leukocytes were obtained from Sigma Chemical Co. (St. Louis, MO), unless otherwise noted. The heparinized blood was diluted 1:1 in phosphate buffered saline (PBS) and separated by density centrifugation as described by McCarthy, Domurat, Nichols, and Roberts (1989). An aliquot of plasma was removed from the top fraction and the lower fraction containing neutrophils was mixed 1 :1 with 4.5% dextran to remove red blood cells by sedimentation.
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Macrophages were obtained by sterile lavage of the peritoneal cavity with warmed PBS. To obtain a single cell suspension of mononuclear leukocytes, the spleen was removed and gently pressed through a fine wire mesh into a centrifuge tube containing PBS. Tissue debris was allowed to settle for 10 min and the supernatant cell suspension was gently removed using a sterile pipette.
reduction measured every 10 min as the increase in absorbance at 550 nM read vertically through the individual wells using a microplate spectrophotometer (Biotek Instruments, Winooski, VT). Results are expressed as mean nanomoles (nM) of 0 2 - released and data were analyzed using Student's t test to compare overall group means for each phase.
Lymphocyte Proliferation
Interleukin-1 (IL-1) Secretion
Lymphocyte proliferation in response to mitogen stimulation is a general measure of immune responsivenessand a specific measure of lymphocyte function (Monjan & Collector, 1977). Mitogeninduced lymphocyte proliferation was measured as described by McCarthy et al. (1989). Briefly, the mononuclear leukocytes from each animal were suspended at lo6 cells/mL of RPMI 1640 supplemented with 2 p M glutamine, 10 nM HEPES buffer, 100 U/mL penicillin, and 100 pg/mL streptomycin and 2 pg/mL of concanavalin-A. Aliquots of lo5 cells (0.1 mL) from each animal were placed in flat bottom 96 well microtitre plates. Pooled plasma from control or experimental animals was diluted I : ] with medium and . I mL added to triplicate cultures in a crossover design. The cultures were incubated for 72 hr at 37 "C in humidified air with 5% COz and pulsed with .5 uCi/well of tritiated thymidine (Amersham) during the final 6 hr of culture. The cells were harvested onto glass filter paper, dried, and counted for 4 min in a liquid scintillationcounter (Packard Instruments). Results are expressed as mean counts per minute (cpm) and data were analyzed using Student's t test to compare group means.
IL-1 is a small peptide secreted by activated monocytes/macrophages that plays a major role in inflammation and immunity (Herrod, 1989). To induce IL-I secretion, the peritoneal macrophages were suspended at lo6 cells/ml of medium and incubated overnight in medium alone or in medium containing 10 p,g/mL of E. coli endotoxin as described by McCarthy et al. (1989). The cultures were centrifuged and the cell-free supernatant fluids were gently removed using a sterile pipette. IL-1 activity in the culture fluids was measured using the mouse thymocyte comitogen assay as described by McCarthy et al. (1989). Each fluid was serially diluted 10 fold in medium and added to triplicate cultures of mitogen-stimulatedmouse thymocytes. Serial dilution of the fluids was done to demonstrate that proliferation varies with the concentration of factors contained in the added fluids. As a control, an aliquot of thymocytes was incubated in the presence of medium alone with no added cell-derived fluids and a second aliquot of thymocytes was incubated in the presence of medium containing serial dilutions (. 1 to .OOOl%) of recombinant human IL-1(Genzyme, Cambridge MA). The cultures were incubated for 72 hr and proliferation measured as cell uptake of tritiated thymidine as described above. Data were analyzed using oneway ANOVA and the Tukey procedure for paired comparisons of proliferation at the highest concentration of added supernatant fluids.
Superoxide Release Neutrophil activation is associated with the generation of superoxide (Oz-) anions (Fantone & Ward, 1982). Oz- release was measured based on the reduction of cytochrome C using a semiautomated microassay as described by Pick and Mizel(l98 1). Briefly, neutrophils from each animal were suspended at lo6cells/mL of Hanks balanced salt solution without phenol red and 6 m /mL cytochromeC. Quadruplicate samples of 10 cells were placed in flat-bottom 96 well plates with and without 5 mg/mL opsonized zymosan to stimulate the cells. As a control, parallel cultures of stimulated and unstimulated cells were incubated in the presence of 20 p/mL superoxide dismutase to inhibit the reduction of cytochrome C. Cells were incubated for 90 min at 37 "C and cytochrome C
B
RESULTS Temperature and Activity As shown in Figure 1, initiation of the noise exposure induced an abrupt 1 "C rise in body temperature of the noise-exposed animals. Body temperature returned to control levels within 3 hr, after which the noise-exposed animals resumed a circadian temperature pattern similar to that of control animals with the normal diurnal trough and nocturnal rise in temperature.
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Mean 2-min activity counts during the lightson phase of the experiment (6 a.m. to 5 p.m.) were 5.5 f 4.5 versus 4.0 2.6 for the control animals exposed to the usual noises of the animal care facility during the same time period, t = 2 . 1 5 , ~< .05. During the lights-off phase (6 p.m. to 5 a.m.), mean 2-min activity counts of noiseexposed animals were significantly greater than control animals, 10.3 & 3.2 versus 8.1 1.5 (t = 4 , p < .001).
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i HOURS OF NOISE EXPOSURE
FIGURE 1. Mean hourly body temperature of noiseexposed and control animals during the 24-hr period of study. Arrow indicates when 60 to 85 db of noise was initiated and the dark bar indicates when lights were turned off. Note: missing values resulted when electrical interference from the radio interrupted signal reception.
As shown in Figure 2, the hourly mean 2-min activity counts of noise-exposed animals frequently exceeded that of control animals during both the light and dark phases of the 24-hr experimental period. The sharpest increase in activity of the noise-exposed animals occurred during the first 3 hr of noise exposure, after which the activity counts returned to control levels. During the second half of the lights-off period, activity counts in the two groups were again similar, dropping to 2.4 and 2.1 by the end of the 24-hr experimental period.
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Mitogen-inducedproliferation of lymphocytes from noise-exposed animals was similar to that of lymphocytes from control animals (7558 & 740 and 7309 745 cpm respectively) when the cells were incubated in the presence of plasma from control animals. However, when the cells from either noise-exposed or control animals were incubated in the presence of plasma from noiseexposed animals, proliferation was significantly less than when the cells were incubated in the presence of control plasma (4413 766 and 1046 cpm respectively; p < .OW1 for 4392 each comparison).
*
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*
Superoxide Release The time course for zymosan-stimulated release of 02- from neutrophils of noise-exposed and control animals is shown in Figure 3. Cells from control animals showed the expected kinetics of zymosan-stimulated02-release, rising slowly and leveling off after 60 min. Cumulative 02-production by neutrophils of noise-exposed animals
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FIGURE 2. Mean hourly 2-min activity counts for noise-exposed and control animals during the 24 hr period of study. Arrow indicates when 60 to 85 db of noise was initiated and the dark bar indicates when lights were turned off. Note: missing values resulted when electrical interference from the radio interrupted signal reception.
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FIGURE 3. Cumulative nM superoxide ? s.8.m. released by 1O5 zymosan-stimulated neutrophils from noise-exposed and control animals. ' p < .01.
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NOISE STRESS I McCARTHY ET AL.
was significantly less than controls at 40 min after stimulation (2.0 2 1.5 vs. 4.9 2 9 nM; p < .001).
IL-1 Secretion
Y
2
Using the mouse thymocyte comitogen assay, no IL-1 activity was detected in the supernatant fluids from cultures of control macrophages incubated in medium alone; proliferation of thymocytes incubated in the presence of fluids from macrophages of control animals was not different from thymocytes incubated in the absence of any added supematant fluids. However, as shown in Figure 4, addition of supematant fluids from macrophages of noise-exposed animals significantly suppressed thymocyte proliferation below control levels. Thymocyte proliferation approached control levels when the supernatant fluids were serially diluted before being added to the thymocyte cultures, suggestingthe presence of an antiproliferativefactor that could be diluted out in a dose-dependent fashion. When the macrophages from control and noiseexposed animals had been incubated in the presence of endotoxin to induce IL-1 secretion, significantly more IL-1 activity was detected in the fluids from control macrophages than in fluids from macrophages of noise-exposed animals. As shown in Figure 5 , the IL-1 like activity in control fluids was similar to .5 ng/mL of recombinant human IL-1 and could be serially diluted in a dose-de-
b4-
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pendent fashion. However, serial dilution of fluids from macrophages of noise-exposed animals did not show a dose-response effect for either IL-1like or antiproliferative factors in the fluids.
DISCUSSION
CONTROL
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RECIPROCAL DILUTION
FlGURE4. Mean cpm ? s.e.m. of tritiated thymidine incorporated by mitogen-stimulated thymocytes incubated in the presence of culture fluids of macrophages from noise-exposed or control animals. 0 = cpm of mitogen-stimulated thymocytes incubated in the absence of any macrophage-derivedculture fluids. Data points with different letters are significantly different, p c .05.
500
FIGURE 5. Mean cpm ? s.8.m. of tritiated thymidine incorporated by mitogen-stimulated thymocytes incubated in the presence of culture fluids of macrophages from noise-exposed or control animals that had been stimulated with endotoxin to induce IL-1 secretion. = cpm of mitogen-stimulatedthymocytes incubated in the presence of .0001% (.5 ng/mL) of recombinant human IL-1. Data points with different letters are significantly different, p < .05.
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The present study was undertaken to determine if exposure to increased levels of environmental noise would alter the biological function of leukocytes in v i m . Exposure of rats to 60 to 80 db of "rock" radio programming for 90 min of every 2 hr for 24 hr was associated with significant reductions in macrophage secretion of IL-1 and neutrophil release of 02-anion. In contrast, mitogen-induced proliferation of lymphocytes was not altered when the animals were exposed to noise. We conclude that exposure of rats to increased environmental noise alters some of the biological functions of macrophages and neutrophils in v i m . The conventional bioassay for IL-1 is its capacity to potentiate proliferation of mitogen-stimulated murine thymocytes. While this assay is not specific for IL- 1, it does permit bioassay of IL- 1-like activity where specific immunological reagents are not available. In the present study, addition of supematant fluids from macrophages of noiseexposed animals incubated in medium alone significantly suppressed mitogen-stimulated thymo-
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cyte proliferation below control levels. The antiproliferative activity of the fluids was reduced as the fluids were serially diluted in a dose-dependent fashion. These data suggest the presence of an antiproliferativeof IL-1 inhibitory factor in these fluids. There are several reports of IL- 1 inhibitory factors produced by human monocytes/macrophages in response to immune complexes (Hannum et al., 1990), E. coli endotoxin (Berman, Sandborg, Calabia, Andrews, & Friou, 1986) or exposure to infectious virus (Roberts, Prill, & Mann, 1986). Such a factor has also been detected in supernatant fluids of a murine macrophage cell line (Isono & Kumagai, 1989; Nishihara, Koga, & Hamada, 1988). We know of no other reports of an inhibitory or antiproliferative factor secreted by rat macrophages, nor such a factor(s) secreted in response to stress. Macrophage secretion of an IL- 1 inhibitory factor in response to stress may contribute in part to the frequently reported immunosuppressive effects of acute stress (Kiecolt-Glaser & Glaser, 1986) and therefore warrants further investigation. In the present study, we did not find that exposure of rats to 60 to 80 db of noise for 24 hr affected lymphocyte proliferation responses to mitogen. In contrast, Monjan and Collector (1977) reported that exposure to 100 db of noise for 1 min every hour for 3 hr for at least three nights suppressed mitogen-induced proliferation of lymphocytes in mice. Our conflicting results may be due to differences in timing and duration of the noise exposure. Thus, further study is needed to determine whether a longer period of noise stress would affect mitogen-induced lymphocyte proliferation in rats. It is interesting to note that while lymphocyte proliferation responses to mitogen were not affected by the noise exposure in the present study, proliferation was suppressed if the lymphocytes were incubated in the presence of plasma from noiseexposed animals. These data suggest the presence of an antiproliferative factor in the plasma of the noise-exposed animals. While the identity of this purported antiproliferative factor is unknown, exposure to noise stress has been shown to increase plasma levels of ACTH and corticosterone in mice (Amario, Lopez-Calderon, Jolin, 8i Balasch, 1986; Monjan & Collector, 1977) and glucocorticoids are known to suppress mitogen-induced proliferation of lymphocytes. The release of 0 2 - anion reflects the respiratory burst that occurs with neutrophil activation. The SO- and other oxygen radicals generated by this reaction are bactericidal and play an important
role in resistance to infection. There are very few reports of metabolic insufficiency in neutrophils related to stress, although Peavery, Lawlis, and Goven (1985) found a significant relationship between self-reported stress and phagocytic capacity of neutrophils. The data from the present study suggest that noise shress could alter the bactericidal function of neutrophils. Given the important role of neutrophils in wound healing and resistance to infection, the impact of stressors found in the patient care environment on selected aspects of neutrophil function warrants further study by nurses. The theoretical linkages that can be made between noise stress, endocrine responses to stress, and leukocyte function in noise-stressed animals suggest a possible mechanism by which noise stress might impair wound healing in rats as described by Wysocki (1987). However, in the study by Wysocki, rats were exposed to noise stress for 15 min of every hour, 24 hr a day for 19 days. Therefore, the relationship between noise stress and wound healing might be due to alterations in the sleep/wake cycle of the noise-exposed animals. In the present study, we found that activity of the noise-exposed animals was significantly increased above control levels during the first half of the lights-on phase, when rats are normally quiescent. However, the activity counts of the noise-exposed animals returned to control levels during the second half of the lights-on phase. A similar pattern was noted during the lights-off phase of the experiment, when rats are normally more active. While our data would suggest that it is unlikely that the relationship between noise stress and leukocyte function is due to gross changes in the sleep/wake cycles of the animals, that possibility cannot be ruled out.
REFERENCES Amario, A . , Lopez-Calderon, A . , Jolin, T., & Balasch, J . (1986). Responses of anterior pituitary hormones to chronic stress. Neuroscience and Biobehavior Reviews, 10, 245-250. Berman, M . A . , Sandborg, C . I . , Calabia, B . S . , Andrews, B . S . , & Friou, G.J. (1986). Studies of an interleukin 1 inhibitor: Characterization and clinical significance. Clinical and Experimental Immunology, 6 4 , 136- 145. Billewicz-Stankiewicz, J . , & Krepinska-Urban, A. (1974). The effect of vibration and noise on development of inflammatory reaction in rats. Acta Physiologica Poland, 25, 235-240. Cooper, D.M.(1990). Optimizing wound healing:
NOISE STRESS I McCARTHY ET AL.
A practice within nursing’s domain. Nursing Clinics of North America, 25, 165- 180. Fantone, J.C., &Ward, P.A. (1982). Roleofoxygenderived free radicals and metabolites in leukocytedependent inflammatory reactions. American Journal of Pathology, 107, 397-418. Fife, D., & Rappaport, E. (1976). Noiseand hospital stay. American Journal of Public Health, 6 6 , 680-681. Fruhstorfer, B., Pritsch, M.G., Pritsch, M.B., Clement, H.W., & Wesemann, W. (1988). Effects of daytime noise load on the sleep-wake cycle and endocrine patterns in man. International Journal of Neuroscience, 43, 53-62. Hannum, C.H., Wilcox, C. J., Arend, W.P., J o s h , F.G., Dripps, D.J., Heimdal, P.L., Armes, L.G., Sommer, A., Eisenberg, S.P., & Thompson, R.C. ( 1990). Interleukin- 1 receptor antagonist activity of a human interleukin-1 inhibitor. Nature, 343, 336- 340. Hansel], H.N. (1984). The behavioral effects of noise on man: The patient with “intensive care unit psychosis.” Heart and Lung, 13, 59-65. Herrod, H.G. (1989). Interleukins in immunologic and allergic diseases. Annals of Allergy, 6 3 , 269-272. Isono, N., & Kumagai, K. (1989). Production of interleukin- 1 inhibitors by the murine macrophage cell line P388DI which produces interleukin-1. Microbiology & Immunology, 33, 43-51. Kiecolt-Glaser, J.K., & Glaser, R. (1986). Psychological influences on immunity. Psychosomatics, 27, 621 -624. McCarthy, D.O., Domurat, F.M., Nichols, J.E., & Roberts, N.J., Jr. (1989). Interleukin-1 inhibitor production by human mononuclear leukocytes and leukocyte subpopulations exposed to respiratory syncytial virus: Analysis and comparison with the response to influenza virus. Journal of Leukocyte Biology, 4 6 , 189- 198. Minckley, B.B. (1968). A study of noise and its relationship to patient discomfort in the recovery room. Nursing Research, 17, 247-251. Monjan, A.A., & Collector, M.J. (1977). Stressinduced modulation of the immune response. Science, 196, 307-308.
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Nishihara, T., Koga, T., & Hamada, S. (1988). Production of an interleukin-1 inhibitor by cell line P388DI murine macrophages stimulated with haemophilus actinomycetemcomitans lipopolysaccharide. Infection and Immunity, 56, 2801 2801. Peavey, B.S., Lawlis, G.F., & Goven, A. (1985). Biofeedback-assisted relaxation: Effects on phagocytic capacity. Biofeedback and Self-Regulation, 10,33-47. Pick, E . , & Mizel, D. (1981). Rapid microassays for the measurement of superoxide and hydrogen peroxide production by macrophages in culture using an automatic enzyme immunoassay reader. Journal of Immunological Methods, 4 6 , 2 1 I - 226. Redding, J.S., Hargest, T.S., & Minsky, S.H. (1977). How noisy is intensive care? Critical Care Medicine, 5 , 215. Roberts, N.J., Jr., Prill, A.H., & Mann, T.N. (1986). Interleukin 1 and interleukin 1 inhibitor production by human macrophages exposed to influenza virus or respiratory syncytial virus: Respiratory syncytial virus is a potent inducer of inhibitor activity. Journal of Experimental Medicine, 163, 511-518. Singer, R., Harker, C.T., Vander, A.J., & Kluger, M .J . ( 1986). Hyperthermia induced by open-field stress is blocked by salicylate. Physiology & Behavior, 3 6 , 1179- 1182. Snyder-Halpern, R. (1985). The effect of critical care unit noise on patient sleep cycles. Critical Care Quarterly, 7 , 41-50. Soutar, R.L., & Wilson, J.A. (1986). Does hospital noise disturb patients? British Medical Journal, 292, 305. Wahl, S.M., & Gately, C.L. (1983). Modulation of fibroblast growth by a lympholine of human T cell and continuous T cell line origin. Journal of Immunology, 130, 1226- 1230. Wysocki, A.B. (1987). The effect of intermittent noise exposure on excisional wound healing in albino rats. 1987 International Nursing Research Conference, Abstracts, 459. Kansas City, MO: American Nurses Association.
Research in Nursing & Health, 1992, 15, 13 1 137
The Effects of Noise Stress on Leukocyte Function in Rats Donna 0. McCarthy, Mary E. Ouimet, and Jane M. Daun
It has been reported that exposure to increased noise levels impairs wound healing in surgical patients and in rats. The purpose of the present study was to determine if exposure to noise stress would alter the biological function of neutrophils, macrophages, and lymphocytes, leukocytes that are involved in wound healing. Rats were exposed to 80 db of "rock" music for 24 hr, during which time the control animals were maintained in their usual environment. Leukocyte subpopulations were obtained and stimulated in vitro. Neutrophils and macrophages from noise-exposed animals secreted significantly less superoxide anion and interleukin-1 than cells from control animals. Lymphocyte function was not altered following noise stress. We conclude that short-term exposure of rats to noise stress alters some of the biological functions of leukocytes.
Noise has long been recognized as an environmental stressor that causes physiological, psychological, and behavioral changes in healthy subjects (Fruhstorfer, Pritsch, Pritsch, Clement, & Wesemann, 1988). Noise and its potential effects on patient recovery and well-being are of special concern to nurses in hospital settings where noise levels often exceed 70 decibels (db) (Redding, Hargest, & Minsky, 1977; Soutar & Wilson, 1986). The effects of noise on patient sleep, cognitive function, and postoperative pain have been well documented in the literature (Hansel], 1984; Minckley, 1968; Snyder-Halpem, 1985). However, there are few studies on the effects of noise on physiological measures of patient recovery or wellbeing. There are some data to suggest that increased environmental noise prolongs wound healing. Billewicz-Stankiewicz and Krepinska-Urban (1974) reported that exposure of rats to 85 db of noise for 2 hr altered the normal inflammatory response to skin wounds. Wysocki (1987) reported that exposure of rats to 85 db of broadband noise for 15 min of every hour for 24 hr over 19 days altered healing of surgical wounds made on their backs. Photographs of the wounds were taken
every other day and compared by computerized digital analysis of surface area and color. There was a significant delay in wound healing in noiseexposed animals throughout the 19-day period of study. Finally, Fife and Rappaport (1976) reported that the length of patient stay following cataract surgery was significantly increased during a period of hospital construction compared to the length of stay before and after the period of construction. These authors questioned if the increased length of stay was related to physiological effects of increased noise on healing of the surgical wounds. Wound healing is the result of an orderly series of cellular processes that lead to restoration of tissue integrity. These processes take place in three interdependent phases: inflammation, cell proliferation, and collagen remodeling (Cooper, 1990). Neutrophils are the predominate cell type in the wound for the first 24 hr. Activated neutrophils release superoxide (02-) anions that play a major role in protecting the wound from infection. Monocytes are slower to migrate into the tissue and are the predominate cell type in the wound for 2 to 3 days. Monocyte secretion of peptides such as interleukin-I (IL- I ) stimulate neovascularization and the chemotaxis of lymphocytes and
Donna 0. McCarthy, PhD, AN, is an assistant professor, Mary E. Ouimet, MSN, RN, is a graduate student, Jane M. Daun, BS, is a research scientist, at the School of Nursing, University of Wisconsin-Madison. The study was supported by a grant from the Wisconsin Alumni Research Fund. This article was received on May 3, 1991, was revised, and accepted for publication October 4, 1991. Requests for reprints can be addressed to Dr. Donna 0. McCarthy, University of Wisconsin-Madison, School of Nursing K6/326, 600 Highland Avenue, Madison, WI 53792. 0 1992 John Wiley & Sons, Inc. CCC 0160-6891/92/020131-07 $04.00
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fibroblasts into the wound (Herrod, 1989). The second phase of healing involves proliferation of epithelial cells and fibroblasts. Lymphocytes contribute to this process by secreting a factor that promotes proliferation of fibroblasts (Wahl & Gately, 1983). The purpose of the present study was to determine if exposure to noise stress alters the biological function of neutrophils, monocyteshnacrophages, and lymphocytes in vitro. The study was conducted using an animal model in order to control for inherent differences in nutritional status, age, or genetic endowment of subjects that could affect leukocyte function. Given the documented effects of stressful life events on leukocyte function in vitro, the use of an animal model in a laboratory setting permitted the investigators to control the amount, duration, and nature of the stress experienced by all subjects.
METHOD
Animal Model Male Sprague-Dawley rats weighing 180 to 200 grams were housed individually in two adjoining rooms in the animal care facility on a 12-hr light/ dark cycle with free access to food and water. The animals were allowed 7 days to adapt to the housing conditions prior to the start of the experiment. The noise level in this facility ranges between 30 and 60 db of equipment and voice noise, and is highest when employees are present. On the day of the experiment, baseline levels of body temperature and activity were recorded for 2 hr as described below. Beginning at 8 a.m., the six experimental animals were subjected to 60 to 80 db of “rock” music delivered via stereo speakers placed within 4 ft of the cages. In order to prevent habituation to the noise, we selected a radio station with varied programming and used electronic timers to turn on the noise for 90 min every 2 hr for the next 22 hr. The noise level was checked every 6 to 8 hr using a battery-operated decibel meter (AMF Electrical Products, Alexandria, VA) held within 12 in. of the cages. The six control animals were maintained in their ‘‘usual” environment during the same time period and noise levels were checked every 6 to 8 hr as described above. Stress induces an acute rise in body temperature in rats referred to as stress-induced hyperrhermia (Singer, Harker, Vander, & Kluger, 1986). To verify that exposure to 60 to 80 db of “rock” radio
programming was stressful, that is, would induce stress hyperthermia, the animals were surgically implanted with temperature-sensitive miniature battery-operated transmitters (Minimitter Company, SunRiver, OR) in the peritoneal cavity 5 days prior to the start of the experiment as described by Singer et al. (1986). The calibrations of the transmitters (output frequency in Hz) were checked in a temperature-controlled circulating waterbath (Fischer, Chicago IL) that maintains the temperature within 0.02 “C. The temperature of the waterbath was constantly monitored using a digital thermometer (VWR, Chicago IL)accurate to .1”C. Transmitters that deviated more than 5 Hz or .1”C from the manufacturer’s original calibrations were not used for this experiment. Following implantation of the transmitters, the individual cages were placed over antenna boards that were connected via a signal processor (Dataquest III, Minimitter, Inc.) to an IBM-Compatible PC computer. Body temperature was recorded every 2 min and the 30 two-min readings were averaged every 60 rnin to obtain an hourly measure of body temperature for each animal. To differentiate the effects of noise stress versus sleep deprivation due to the noise, activity of the rats was measured using the same biotelemetry system described above. As the animal moves, the orientation of the transmitter changes with respect to the antenna board under the cage, creating a change in signal strength, which is recorded as one “pulse” or one activity count. Activity was recorded very 2 min and averaged every 60 min to obtain mean 2-min activity counts each hour for each animal. Because rats are noctumal animals, the hourly 2-min activity counts during lights-on (6 a.m. to 5 p.m.) and lights-off (6 p.m. to 5 a.m.) were averaged to obtain mean 2-min activity counts during both the dark and the light phases of the 24-hr period of data collection. Data were analyzed using Student’s t test to compare the group means for each phase. At the end of the 22-hr period of noise exposure, the control and experimental animals were lightly anesthetized with ether fumes and exsanguinated by cardiac puncture. All reagents and media used in the preparation and assays of leukocytes were obtained from Sigma Chemical Co. (St. Louis, MO), unless otherwise noted. The heparinized blood was diluted 1:1 in phosphate buffered saline (PBS) and separated by density centrifugation as described by McCarthy, Domurat, Nichols, and Roberts (1989). An aliquot of plasma was removed from the top fraction and the lower fraction containing neutrophils was mixed 1 :1 with 4.5% dextran to remove red blood cells by sedimentation.
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NOISE STRESS / McCARTHY ET AL.
Macrophages were obtained by sterile lavage of the peritoneal cavity with warmed PBS. To obtain a single cell suspension of mononuclear leukocytes, the spleen was removed and gently pressed through a fine wire mesh into a centrifuge tube containing PBS. Tissue debris was allowed to settle for 10 min and the supernatant cell suspension was gently removed using a sterile pipette.
reduction measured every 10 min as the increase in absorbance at 550 nM read vertically through the individual wells using a microplate spectrophotometer (Biotek Instruments, Winooski, VT). Results are expressed as mean nanomoles (nM) of 0 2 - released and data were analyzed using Student's t test to compare overall group means for each phase.
Lymphocyte Proliferation
Interleukin-1 (IL-1) Secretion
Lymphocyte proliferation in response to mitogen stimulation is a general measure of immune responsivenessand a specific measure of lymphocyte function (Monjan & Collector, 1977). Mitogeninduced lymphocyte proliferation was measured as described by McCarthy et al. (1989). Briefly, the mononuclear leukocytes from each animal were suspended at lo6 cells/mL of RPMI 1640 supplemented with 2 p M glutamine, 10 nM HEPES buffer, 100 U/mL penicillin, and 100 pg/mL streptomycin and 2 pg/mL of concanavalin-A. Aliquots of lo5 cells (0.1 mL) from each animal were placed in flat bottom 96 well microtitre plates. Pooled plasma from control or experimental animals was diluted I : ] with medium and . I mL added to triplicate cultures in a crossover design. The cultures were incubated for 72 hr at 37 "C in humidified air with 5% COz and pulsed with .5 uCi/well of tritiated thymidine (Amersham) during the final 6 hr of culture. The cells were harvested onto glass filter paper, dried, and counted for 4 min in a liquid scintillationcounter (Packard Instruments). Results are expressed as mean counts per minute (cpm) and data were analyzed using Student's t test to compare group means.
IL-1 is a small peptide secreted by activated monocytes/macrophages that plays a major role in inflammation and immunity (Herrod, 1989). To induce IL-I secretion, the peritoneal macrophages were suspended at lo6 cells/ml of medium and incubated overnight in medium alone or in medium containing 10 p,g/mL of E. coli endotoxin as described by McCarthy et al. (1989). The cultures were centrifuged and the cell-free supernatant fluids were gently removed using a sterile pipette. IL-1 activity in the culture fluids was measured using the mouse thymocyte comitogen assay as described by McCarthy et al. (1989). Each fluid was serially diluted 10 fold in medium and added to triplicate cultures of mitogen-stimulatedmouse thymocytes. Serial dilution of the fluids was done to demonstrate that proliferation varies with the concentration of factors contained in the added fluids. As a control, an aliquot of thymocytes was incubated in the presence of medium alone with no added cell-derived fluids and a second aliquot of thymocytes was incubated in the presence of medium containing serial dilutions (. 1 to .OOOl%) of recombinant human IL-1(Genzyme, Cambridge MA). The cultures were incubated for 72 hr and proliferation measured as cell uptake of tritiated thymidine as described above. Data were analyzed using oneway ANOVA and the Tukey procedure for paired comparisons of proliferation at the highest concentration of added supernatant fluids.
Superoxide Release Neutrophil activation is associated with the generation of superoxide (Oz-) anions (Fantone & Ward, 1982). Oz- release was measured based on the reduction of cytochrome C using a semiautomated microassay as described by Pick and Mizel(l98 1). Briefly, neutrophils from each animal were suspended at lo6cells/mL of Hanks balanced salt solution without phenol red and 6 m /mL cytochromeC. Quadruplicate samples of 10 cells were placed in flat-bottom 96 well plates with and without 5 mg/mL opsonized zymosan to stimulate the cells. As a control, parallel cultures of stimulated and unstimulated cells were incubated in the presence of 20 p/mL superoxide dismutase to inhibit the reduction of cytochrome C. Cells were incubated for 90 min at 37 "C and cytochrome C
B
RESULTS Temperature and Activity As shown in Figure 1, initiation of the noise exposure induced an abrupt 1 "C rise in body temperature of the noise-exposed animals. Body temperature returned to control levels within 3 hr, after which the noise-exposed animals resumed a circadian temperature pattern similar to that of control animals with the normal diurnal trough and nocturnal rise in temperature.
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Mean 2-min activity counts during the lightson phase of the experiment (6 a.m. to 5 p.m.) were 5.5 f 4.5 versus 4.0 2.6 for the control animals exposed to the usual noises of the animal care facility during the same time period, t = 2 . 1 5 , ~< .05. During the lights-off phase (6 p.m. to 5 a.m.), mean 2-min activity counts of noiseexposed animals were significantly greater than control animals, 10.3 & 3.2 versus 8.1 1.5 (t = 4 , p < .001).
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a HEALTH
RESEARCH IN NURSING
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6
6
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18
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24
Lymphocyte Proliferation
i HOURS OF NOISE EXPOSURE
FIGURE 1. Mean hourly body temperature of noiseexposed and control animals during the 24-hr period of study. Arrow indicates when 60 to 85 db of noise was initiated and the dark bar indicates when lights were turned off. Note: missing values resulted when electrical interference from the radio interrupted signal reception.
As shown in Figure 2, the hourly mean 2-min activity counts of noise-exposed animals frequently exceeded that of control animals during both the light and dark phases of the 24-hr experimental period. The sharpest increase in activity of the noise-exposed animals occurred during the first 3 hr of noise exposure, after which the activity counts returned to control levels. During the second half of the lights-off period, activity counts in the two groups were again similar, dropping to 2.4 and 2.1 by the end of the 24-hr experimental period.
f + NMSEEXPOSED
I
Mitogen-inducedproliferation of lymphocytes from noise-exposed animals was similar to that of lymphocytes from control animals (7558 & 740 and 7309 745 cpm respectively) when the cells were incubated in the presence of plasma from control animals. However, when the cells from either noise-exposed or control animals were incubated in the presence of plasma from noiseexposed animals, proliferation was significantly less than when the cells were incubated in the presence of control plasma (4413 766 and 1046 cpm respectively; p < .OW1 for 4392 each comparison).
*
*
*
Superoxide Release The time course for zymosan-stimulated release of 02- from neutrophils of noise-exposed and control animals is shown in Figure 3. Cells from control animals showed the expected kinetics of zymosan-stimulated02-release, rising slowly and leveling off after 60 min. Cumulative 02-production by neutrophils of noise-exposed animals
NOISE-EXPOSED C m O L
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16
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A HOURS OF NOISE EXPOSURE
FIGURE 2. Mean hourly 2-min activity counts for noise-exposed and control animals during the 24 hr period of study. Arrow indicates when 60 to 85 db of noise was initiated and the dark bar indicates when lights were turned off. Note: missing values resulted when electrical interference from the radio interrupted signal reception.
0
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40
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TIME FROM STIMULATION(MINUTES)
FIGURE 3. Cumulative nM superoxide ? s.8.m. released by 1O5 zymosan-stimulated neutrophils from noise-exposed and control animals. ' p < .01.
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NOISE STRESS I McCARTHY ET AL.
was significantly less than controls at 40 min after stimulation (2.0 2 1.5 vs. 4.9 2 9 nM; p < .001).
IL-1 Secretion
Y
2
Using the mouse thymocyte comitogen assay, no IL-1 activity was detected in the supernatant fluids from cultures of control macrophages incubated in medium alone; proliferation of thymocytes incubated in the presence of fluids from macrophages of control animals was not different from thymocytes incubated in the absence of any added supematant fluids. However, as shown in Figure 4, addition of supematant fluids from macrophages of noise-exposed animals significantly suppressed thymocyte proliferation below control levels. Thymocyte proliferation approached control levels when the supernatant fluids were serially diluted before being added to the thymocyte cultures, suggestingthe presence of an antiproliferativefactor that could be diluted out in a dose-dependent fashion. When the macrophages from control and noiseexposed animals had been incubated in the presence of endotoxin to induce IL-1 secretion, significantly more IL-1 activity was detected in the fluids from control macrophages than in fluids from macrophages of noise-exposed animals. As shown in Figure 5 , the IL-1 like activity in control fluids was similar to .5 ng/mL of recombinant human IL-1 and could be serially diluted in a dose-de-
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pendent fashion. However, serial dilution of fluids from macrophages of noise-exposed animals did not show a dose-response effect for either IL-1like or antiproliferative factors in the fluids.
DISCUSSION
CONTROL
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RECIPROCAL DILUTION
FlGURE4. Mean cpm ? s.e.m. of tritiated thymidine incorporated by mitogen-stimulated thymocytes incubated in the presence of culture fluids of macrophages from noise-exposed or control animals. 0 = cpm of mitogen-stimulated thymocytes incubated in the absence of any macrophage-derivedculture fluids. Data points with different letters are significantly different, p c .05.
500
FIGURE 5. Mean cpm ? s.8.m. of tritiated thymidine incorporated by mitogen-stimulated thymocytes incubated in the presence of culture fluids of macrophages from noise-exposed or control animals that had been stimulated with endotoxin to induce IL-1 secretion. = cpm of mitogen-stimulatedthymocytes incubated in the presence of .0001% (.5 ng/mL) of recombinant human IL-1. Data points with different letters are significantly different, p < .05.
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50 RECIPROCAL DILUTION
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The present study was undertaken to determine if exposure to increased levels of environmental noise would alter the biological function of leukocytes in v i m . Exposure of rats to 60 to 80 db of "rock" radio programming for 90 min of every 2 hr for 24 hr was associated with significant reductions in macrophage secretion of IL-1 and neutrophil release of 02-anion. In contrast, mitogen-induced proliferation of lymphocytes was not altered when the animals were exposed to noise. We conclude that exposure of rats to increased environmental noise alters some of the biological functions of macrophages and neutrophils in v i m . The conventional bioassay for IL-1 is its capacity to potentiate proliferation of mitogen-stimulated murine thymocytes. While this assay is not specific for IL- 1, it does permit bioassay of IL- 1-like activity where specific immunological reagents are not available. In the present study, addition of supematant fluids from macrophages of noiseexposed animals incubated in medium alone significantly suppressed mitogen-stimulated thymo-
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RESEARCH IN NURSING & HEALTH
cyte proliferation below control levels. The antiproliferative activity of the fluids was reduced as the fluids were serially diluted in a dose-dependent fashion. These data suggest the presence of an antiproliferativeof IL-1 inhibitory factor in these fluids. There are several reports of IL- 1 inhibitory factors produced by human monocytes/macrophages in response to immune complexes (Hannum et al., 1990), E. coli endotoxin (Berman, Sandborg, Calabia, Andrews, & Friou, 1986) or exposure to infectious virus (Roberts, Prill, & Mann, 1986). Such a factor has also been detected in supernatant fluids of a murine macrophage cell line (Isono & Kumagai, 1989; Nishihara, Koga, & Hamada, 1988). We know of no other reports of an inhibitory or antiproliferative factor secreted by rat macrophages, nor such a factor(s) secreted in response to stress. Macrophage secretion of an IL- 1 inhibitory factor in response to stress may contribute in part to the frequently reported immunosuppressive effects of acute stress (Kiecolt-Glaser & Glaser, 1986) and therefore warrants further investigation. In the present study, we did not find that exposure of rats to 60 to 80 db of noise for 24 hr affected lymphocyte proliferation responses to mitogen. In contrast, Monjan and Collector (1977) reported that exposure to 100 db of noise for 1 min every hour for 3 hr for at least three nights suppressed mitogen-induced proliferation of lymphocytes in mice. Our conflicting results may be due to differences in timing and duration of the noise exposure. Thus, further study is needed to determine whether a longer period of noise stress would affect mitogen-induced lymphocyte proliferation in rats. It is interesting to note that while lymphocyte proliferation responses to mitogen were not affected by the noise exposure in the present study, proliferation was suppressed if the lymphocytes were incubated in the presence of plasma from noiseexposed animals. These data suggest the presence of an antiproliferative factor in the plasma of the noise-exposed animals. While the identity of this purported antiproliferative factor is unknown, exposure to noise stress has been shown to increase plasma levels of ACTH and corticosterone in mice (Amario, Lopez-Calderon, Jolin, 8i Balasch, 1986; Monjan & Collector, 1977) and glucocorticoids are known to suppress mitogen-induced proliferation of lymphocytes. The release of 0 2 - anion reflects the respiratory burst that occurs with neutrophil activation. The SO- and other oxygen radicals generated by this reaction are bactericidal and play an important
role in resistance to infection. There are very few reports of metabolic insufficiency in neutrophils related to stress, although Peavery, Lawlis, and Goven (1985) found a significant relationship between self-reported stress and phagocytic capacity of neutrophils. The data from the present study suggest that noise shress could alter the bactericidal function of neutrophils. Given the important role of neutrophils in wound healing and resistance to infection, the impact of stressors found in the patient care environment on selected aspects of neutrophil function warrants further study by nurses. The theoretical linkages that can be made between noise stress, endocrine responses to stress, and leukocyte function in noise-stressed animals suggest a possible mechanism by which noise stress might impair wound healing in rats as described by Wysocki (1987). However, in the study by Wysocki, rats were exposed to noise stress for 15 min of every hour, 24 hr a day for 19 days. Therefore, the relationship between noise stress and wound healing might be due to alterations in the sleep/wake cycle of the noise-exposed animals. In the present study, we found that activity of the noise-exposed animals was significantly increased above control levels during the first half of the lights-on phase, when rats are normally quiescent. However, the activity counts of the noise-exposed animals returned to control levels during the second half of the lights-on phase. A similar pattern was noted during the lights-off phase of the experiment, when rats are normally more active. While our data would suggest that it is unlikely that the relationship between noise stress and leukocyte function is due to gross changes in the sleep/wake cycles of the animals, that possibility cannot be ruled out.
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NOISE STRESS I McCARTHY ET AL.
A practice within nursing’s domain. Nursing Clinics of North America, 25, 165- 180. Fantone, J.C., &Ward, P.A. (1982). Roleofoxygenderived free radicals and metabolites in leukocytedependent inflammatory reactions. American Journal of Pathology, 107, 397-418. Fife, D., & Rappaport, E. (1976). Noiseand hospital stay. American Journal of Public Health, 6 6 , 680-681. Fruhstorfer, B., Pritsch, M.G., Pritsch, M.B., Clement, H.W., & Wesemann, W. (1988). Effects of daytime noise load on the sleep-wake cycle and endocrine patterns in man. International Journal of Neuroscience, 43, 53-62. Hannum, C.H., Wilcox, C. J., Arend, W.P., J o s h , F.G., Dripps, D.J., Heimdal, P.L., Armes, L.G., Sommer, A., Eisenberg, S.P., & Thompson, R.C. ( 1990). Interleukin- 1 receptor antagonist activity of a human interleukin-1 inhibitor. Nature, 343, 336- 340. Hansel], H.N. (1984). The behavioral effects of noise on man: The patient with “intensive care unit psychosis.” Heart and Lung, 13, 59-65. Herrod, H.G. (1989). Interleukins in immunologic and allergic diseases. Annals of Allergy, 6 3 , 269-272. Isono, N., & Kumagai, K. (1989). Production of interleukin- 1 inhibitors by the murine macrophage cell line P388DI which produces interleukin-1. Microbiology & Immunology, 33, 43-51. Kiecolt-Glaser, J.K., & Glaser, R. (1986). Psychological influences on immunity. Psychosomatics, 27, 621 -624. McCarthy, D.O., Domurat, F.M., Nichols, J.E., & Roberts, N.J., Jr. (1989). Interleukin-1 inhibitor production by human mononuclear leukocytes and leukocyte subpopulations exposed to respiratory syncytial virus: Analysis and comparison with the response to influenza virus. Journal of Leukocyte Biology, 4 6 , 189- 198. Minckley, B.B. (1968). A study of noise and its relationship to patient discomfort in the recovery room. Nursing Research, 17, 247-251. Monjan, A.A., & Collector, M.J. (1977). Stressinduced modulation of the immune response. Science, 196, 307-308.
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Nishihara, T., Koga, T., & Hamada, S. (1988). Production of an interleukin-1 inhibitor by cell line P388DI murine macrophages stimulated with haemophilus actinomycetemcomitans lipopolysaccharide. Infection and Immunity, 56, 2801 2801. Peavey, B.S., Lawlis, G.F., & Goven, A. (1985). Biofeedback-assisted relaxation: Effects on phagocytic capacity. Biofeedback and Self-Regulation, 10,33-47. Pick, E . , & Mizel, D. (1981). Rapid microassays for the measurement of superoxide and hydrogen peroxide production by macrophages in culture using an automatic enzyme immunoassay reader. Journal of Immunological Methods, 4 6 , 2 1 I - 226. Redding, J.S., Hargest, T.S., & Minsky, S.H. (1977). How noisy is intensive care? Critical Care Medicine, 5 , 215. Roberts, N.J., Jr., Prill, A.H., & Mann, T.N. (1986). Interleukin 1 and interleukin 1 inhibitor production by human macrophages exposed to influenza virus or respiratory syncytial virus: Respiratory syncytial virus is a potent inducer of inhibitor activity. Journal of Experimental Medicine, 163, 511-518. Singer, R., Harker, C.T., Vander, A.J., & Kluger, M .J . ( 1986). Hyperthermia induced by open-field stress is blocked by salicylate. Physiology & Behavior, 3 6 , 1179- 1182. Snyder-Halpern, R. (1985). The effect of critical care unit noise on patient sleep cycles. Critical Care Quarterly, 7 , 41-50. Soutar, R.L., & Wilson, J.A. (1986). Does hospital noise disturb patients? British Medical Journal, 292, 305. Wahl, S.M., & Gately, C.L. (1983). Modulation of fibroblast growth by a lympholine of human T cell and continuous T cell line origin. Journal of Immunology, 130, 1226- 1230. Wysocki, A.B. (1987). The effect of intermittent noise exposure on excisional wound healing in albino rats. 1987 International Nursing Research Conference, Abstracts, 459. Kansas City, MO: American Nurses Association.
