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Biomedical subjects

S M Coyle

Publications and source records attributed to S M Coyle.

33 records · Page 2Linked to original sources
PubMed1995

Endotoxin induces downregulation of tumor necrosis factor receptors on circulating monocytes and granulocytes in humans.

Leukocytes rapidly lose their surface receptors for tumor necrosis factor (TNF) after exposure to various stimuli in vitro. To assess the effect of endotoxin on cellular TNF receptors in humans in vivo, binding of biotinylated TNF to circulating monocytes and granulocytes was determined by fluorescence-activated cell sorter analysis in six healthy subjects after intravenous injection of endotoxin (lot EC-5, 20 U/kg). Endotoxin administration was associated with a transient decrease in monocyte TNF receptors, reaching a nadir after 2 hours (P < .0001), and a more sustained decrease in granulocyte TNF receptors (P < .001). Although the decrease in cellular TNF receptors coincided with increases in soluble TNF receptors types I and II, no correlations were observed between trough monocyte or granulocyte TNF receptors and peak plasma concentrations of soluble TNF receptors. Stimulation of human whole blood with endotoxin resulted in reduced expression of both type I and type II TNF receptors on monocytes and granulocytes. Endotoxin induces downmodulation of monocyte and granulocyte TNF surface receptors in humans in vivo, which may represent a mechanism to reduce excessive activity of TNF during systemic infection.

Adult↗
PubMed1995

Influence of IL-1 receptor blockade on the human response to endotoxemia.

Although the experimental administration of IL-1 induces several aspects of the inflammatory response, such as fever, tachycardia, and acute phase proteinemia, the contribution of IL-1 to the human responses to injury or infection remains unclear. A specific IL-1R antagonist (IL-1ra), which effectively blocks the actions of IL-1, was utilized to evaluate the influence of endogenous IL-1 during experimental human endotoxemia. Eighteen healthy volunteers each underwent one control study day, followed 3 days later by one of three randomly chosen treatments: a 6-h infusion of IL-1ra alone (133 mg/h), 20 U/kg national reference endotoxin alone, or both endotoxin and IL-1ra infusion. IL-1ra administration alone was not associated with any observable response. Despite achieving high circulating levels of IL-1ra (34 +/- 3 micrograms/ml), there were no significant differences in hemodynamic parameters, core temperature, or resting energy expenditure in those endotoxemic volunteers receiving IL-1ra when compared with those who did not. Furthermore, leukocyte kinetic and circulating cytokine, acute phase protein, and endocrine responses were similar in both endotoxemic groups. However, IL-1 blockade did significantly reduce the subjective severity of symptoms experienced by the endotoxemic volunteers (p < 0.05). This study demonstrates that an endogenous IL-1 response does not play a significant role in the hemodynamic, immunologic, and metabolic responses to mild endotoxemia in humans.

Adrenocorticotropic Hormone↗
PubMed1995

Interleukin-1 blockade attenuates mediator release and dysregulation of the hemostatic mechanism during human sepsis.

OBJECTIVE: To define the influence of interleukin-1 activity on coagulation and fibrinolytic system activation and the release of proinflammatory mediators in the early human response to severe infection. STUDY DESIGN: All patients with severe sepsis syndrome who were enrolled from two surgical centers that were participating in a randomized, double-blind, placebo controlled, multicenter, multinational trial of recombinant human interleukin-1 receptor antagonist in the treatment of sepsis syndrome. POPULATION: Twenty-six patients with sepsis syndrome received an intravenous loading dose of recombinant human interleukin-1 receptor antagonist (100 mg) or placebo followed by a continuous 72-hour infusion of recombinant human interleukin-1 receptor antagonist (1.0 [n = 9] or 2.0 [n = 8] mg/kg per hour) or placebo (n = 9). OUTCOME MEASURE: Responses up to 72 hours after initiation of treatment. RESULTS: Plasma levels of the anaphylatoxin C3a and thrombin-antithrombin III complexes were reduced in the high-dose recombinant human interleukin-1 receptor antagonist treatment group after 72 hours (P < .05). Similarly, parameters of fibrinolysis, tissue-type plasminogen activator, and plasminogen activator inhibitor type 1 but not plasmin-alpha 2-antiplasmin complexes, were also significantly reduced (P < .05) after 72 hours of treatment with a high dose of recombinant human interleukin-1 receptor antagonist. Neutrophil elastase-alpha 1-antitrypsin complexes and phospholipase A2 levels were also significantly reduced in the high-dose recombinant human interleukin-1 receptor antagonist treatment group after 72 hours. CONCLUSIONS: The results confirm that activation of the coagulation and fibrinolytic systems and release of soluble inflammatory mediators are consistently observed in patients with severe sepsis syndrome. Interleukin-1 activity contributes to activation of these processes as documented by the reduction in surrogate activation markers during recombinant human interleukin-1 receptor antagonist treatment.

Adult↗
PubMed1995

Parenteral nutrition alters monocyte TNF receptor activity.

The route of nutrient provision has been reported to influence some aspects of the host inflammatory response in both patient populations and normal subjects. The tumor necrosis factor receptor system is a complex regulatory mechanism that modulates the bioavailability of tumor necrosis factor (TNF). We sought to determine whether maintenance on total parenteral nutrition (TPN) can alter host response to endotoxin challenge, specifically as it relates to the TNF receptor system. Seventeen healthy men were randomized to receive either TPN (n = 8) or a defined formula enteral diet (ENT, n = 9) prior to intravenous infusion of endotoxin (Lot EC-5, 20 U/kg). The subjects that received 1 week of antecedent TPN exhibited an increased heart rate and temperature and decreased mean arterial pressure post-LPS compared to those subjects maintained on enteral nutritional support. The TPN subjects also exhibited comparatively higher TNF and interleukin-6 levels in response to endotoxin. Monocyte TNF receptor levels decreased in both groups post-LPS, but TPN subjects exhibited consistently greater expression of this functional membrane-associated TNF receptor. After LPS, soluble tumor necrosis factor receptor II (sTNFr II, p75) peaked three times higher in TPN subjects than in ENT subjects. Conversely, sTNFr I (p55) was higher in the enterally fed group. From these studies it appears that antecedent TPN not only influences clinical manifestations of endotoxin but also modulates the regulation of all associated TNF receptors and shedding of soluble receptors.

Adolescent↗
PubMed1995

Influence of hypercortisolemia on soluble tumor necrosis factor receptor II and interleukin-1 receptor antagonist responses to endotoxin in human beings.

BACKGROUND: We have previously reported that the antecedent administration of glucocorticoids altered both the hormonal and proinflammatory cytokine responses to lipopolysaccharide (LPS) when administered to human volunteers. In that study, subjects with vastly exaggerated levels of tumor necrosis factor (TNF) and interleukin (IL)-6 12 and 144 hours after cortisol infusion exhibited hemodynamic and hormonal responses no different from those of untreated subjects after endotoxin. The current study examined levels of the antiinflammatory cytokines interleukin-1 receptor antagonist (IL-1ra) and soluble receptors to tumor necrosis factor (sTNF-R) in the same setting of the previous report. METHODS: Hydrocortisone succinate was infused into healthy volunteers. LPS was then injected immediately or was delayed by 6, 12, or 144 hours (C, C-6, C-12, and C-144, respectively). Subjects receiving LPS alone served as controls. Plasma was analyzed to determine levels of TNF, sTNF-R and IL-1ra by enzyme-linked immunosorbent assay before administration of LPS and at 30-minute intervals after administration of LPS for 6 hours. RESULTS: Levels of sTNF-R increased after LPS administration in all groups (p < 0.05 versus baseline) with a significantly higher level recorded in the subjects having received hydrocortisone 144 hours before (C-144, p < 0.05 versus all other groups). TNF levels remained undetectable in association with immediate infusion of LPS (C) and the relatively short delay group (C6). This cytokine peaked 90 minutes after LPS in all other groups, with a significantly higher peak in the C-144 subjects when compared with controls. IL-1ra levels rose in all groups but to a lesser extent in the C group (p < 0.05). CONCLUSIONS: These data confirm that glucocorticoids influence the production of both sTNF-R and IL-1ra. The potential for an exaggerated response of sTNF-R exists for an extended period of time after exposure to glucocorticoids.

Adult↗
PubMed1995

Interleukin-1 contributes to increased concentrations of soluble tumor necrosis factor receptor type I in sepsis.

Studies were done in baboons and humans to assess the role of interleukin (IL)-1 on the release of soluble tumor necrosis factor receptors (sTNFRs) during sepsis. In baboons, IL-1 alpha induced increased levels of sTNFR types I and II. Infusion of Escherichia coli into baboons also led to higher sTNFR levels. Treatment with IL-1 receptor antagonist (ra) attenuated the rise in sTNFR-I, which was positively correlated with a partial preservation of renal function by IL-1ra. In patients with sepsis, treatment with IL-1ra also was associated with lower levels of sTNFR-1 but did not influence plasma creatinine levels. IL-1ra did not affect sTNFR-II in baboons or humans. These data suggest that IL-1 produced during sepsis is involved in increases in sTNFR-I. Such increases during rapidly fatal septic shock may in part be explained by an effect on the renal clearance of sTNFR-I.

Aged↗
PubMed1995

Effect of hypertriglyceridemia on endotoxin responsiveness in humans.

Triglyceride-rich lipoproteins can inhibit endotoxin activity in vitro and in rodents. We sought to determine whether Intralipid, a triglyceride-rich fat emulsion which in contact with plasma functions similarly to endogenous lipoproteins, can alter the human response to endotoxin. Intralipid inhibited endotoxin-induced cytokine production in human whole blood in vitro in a dose-dependent manner, with maximal inhibition (up to 70%) being achieved at a concentration of 10 g/liter. In healthy men, a bolus intravenous injection of endotoxin (lot EC-5; 20 U/kg of body weight) was given midway through a 4-h infusion (125 ml/h) of either 5% glucose (n = 5) or 20% Intralipid (n = 5). The infusion of Intralipid led to an increase in triglyceride levels in serum from 95 +/- 16 to 818 +/- 135 mg/dl prior to endotoxin administration, i.e., levels that importantly reduced cytokine production in endotoxin-stimulated whole blood. However, in vivo hypertriglyceridemia did not influence inflammatory responses to endotoxin (fever, release of tumor necrosis factor and soluble tumor necrosis factor receptors, and leukocytosis) or even potentiated endotoxin responses (release of interleukins 6 and 8 and neutrophil degranulation). Hypertriglyceridemia does not inhibit the in vivo responses to endotoxin in humans.

Adult↗
PubMed1995

Interleukin-1 receptor blockade does not affect endotoxin-induced changes in plasma thyroid hormone and thyrotropin concentrations in man.

Interleukin-1 (IL-1) has been implicated as a mediator of the euthyroid sick syndrome. The effects of IL-1 can be blocked by the naturally occurring IL-1 receptor antagonist (IL-1ra). In the present study, iv administration of endotoxin was used as a human model of the euthyroid sick syndrome. To assess the role of endogenous IL-1 in endotoxin-induced changes in plasma thyroid hormone and TSH concentrations, 18 healthy postabsorptive humans were studied on a control study day, followed 3 days later by a study day on which they were randomly assigned to one of three treatments: a 6-h infusion of recombinant human IL-1ra alone (133 mg/h), endotoxin alone (lot EC-5; 20 U/kg), or both endotoxin and IL-1ra. Administration of IL-1ra alone did not affect the plasma concentrations of thyroid hormones or TSH compared with those on the control day. Endotoxin injection was associated with decreases in T4 (P = 0.06 vs. the control day), free T4 (P = 0.02), T3 (P < 0.001), and TSH (P < 0.0001) and a rise in rT3 (P < 0.001), reproducing the major features of the euthyroid sick syndrome. Coinfusion of IL-1ra did not influence these endotoxin-induced changes. Our results suggest that endogenous IL-1 does not play an important role in the alterations in plasma thyroid hormone and TSH concentrations induced by mild endotoxemia in healthy humans.

Adult↗
PubMed1994

Changes in polymorphonuclear leukocyte surface and plasma bactericidal/permeability-increasing protein and plasma lipopolysaccharide binding protein during endotoxemia or sepsis.

OBJECTIVE: To evaluate changes in levels of polymorphonuclear leukocyte surface bactericidal/permeability-increasing protein (BPI), plasma BPI, and plasma lipopolysaccharide (LPS) binding protein (LBP) in normal human volunteers administered Escherichia coli LPS and in patients with sepsis and gram-negative infections. DESIGN: Survey; case series. SETTING: Clinical research center and surgical intensive care unit of a medical school and an associated tertiary care hospital. PATIENTS OR OTHER PARTICIPANTS: Volunteers (n = 10) screened prior to study by history and physical examination to exclude those with underlying diseases or hematologic abnormalities. Consecutive sample of surgical intensive care unit patients (n = 10) meeting criteria for sepsis syndrome with gram-negative infection. An additional patient with systemic inflammatory response syndrome but no gram-negative infection. All patients were studied on meeting the criteria. Three of the patients with sepsis syndrome and the patient with systemic inflammatory response syndrome were evaluated on recovery (approximately 25 days after initial study). Because these studies in volunteers and patients overlapped temporally, the control values were those of volunteers evaluated prior to LPS administration. No matching was employed. MEASUREMENTS AND RESULTS: Compared with controls, LPS-challenged volunteers and patients with sepsis both exhibited significant granulocytosis (P < .01) and increased concentrations of polymorphonuclear leukocyte surface BPI (P < .01) and of plasma LBP (P < .01). Plasma BPI concentrations were increased (P < .01) in volunteers following LPS administration. There was a trend toward increased concentrations of plasma BPI in patients, but this was not significant relative to controls. Maximum concentrations of plasma LBP were approximately 250- and 3000-fold higher than plasma BPI concentrations in endotoxemic volunteers and in patients, respectively. CONCLUSIONS: Circulating polymorphonuclear leukocytes increase expression of BPI in response to LPS or gram-negative sepsis. Subsequently, concentrations of plasma BPI and LBP increase. Because both LBP and BPI bind to LPS, it is suggested that endogenously derived plasma levels of BPI are likely to be inadequate to compete for LPS binding to the much more abundant LBP in the circulation.

Acute-Phase Proteins↗
PubMed1994

Persistently elevated soluble tumor necrosis factor receptor and interleukin-1 receptor antagonist levels in critically ill patients.

The appearance of endogenously produced inhibitors against tumor necrosis factor (TNF) (soluble TNF-receptor type I, sTNFR-I) and interleukin-1 (IL-1 receptor antagonist, IL-1ra) was evaluated acutely in five normal patients after experimental endotoxemia lipopolysaccharide (LPS) and prospectively during a one to 11 week period in 12 septic, critically ill patients. Increased levels of both factors remained detectable in the circulation for up to 24 hours after LPS (2 nanograms per kilogram body weight) administration in normal patients. Despite free TNF-a activity being detected only sporadically (3 percent of the samples) and that IL-1 beta was never detectable in the patients in the intensive care unit, IL-6 bioactivity was present in 90 percent of initial samples. Circulating sTNFR-I levels up to 62,000 picograms per milliliter and IL-1ra levels of 14,800 picograms per milliliter were noted in the critically ill patients and remained consistently detectable throughout the extended period of evaluation. While there was no difference in IL-1ra levels between patients who survived or ultimately died, sTNFR-I levels were significantly (p < 0.001) lower in survivors compared with nonsurvivors. A correlation between circulating sTNFR-I and concurrent cortisol levels (r = 0.64; p < 0.002) was also noted. Furthermore, a correlation between sTNFR-I and the severity of initial insult, as assessed by APACHE II scores (r = 0.54; p < 0.01) was demonstrable. These naturally occurring cytokine antagonists likely represent additional indicators of the presence of an infectious or other inflammatory process and seem to persist in the circulation even during conditions in which their respective proinflammatory cytokines are not demonstrable.

Adolescent↗
PubMed1993

Glucocorticoid therapy alters hormonal and cytokine responses to endotoxin in man.

Previous experimental data have demonstrated that steroid pretreatment regulates endotoxin-elicited cytokine production. The timing of such hypercortisolemia also appears to be a major determinant of both the systemic and the cytokine response to infectious stimuli. Our study was undertaken to further study the in vivo influence of glucocorticoid infusion concurrent with and before endotoxin exposure in man. A total of 23 normal human subjects were given endotoxin (LPS) alone or pretreated with hydrocortisone infusion for 6 h immediately before and concomitant to LPS administration; or rendered hypercortisolemic for a 6-h period waiting 6, 12, or 144 h before LPS administration. LPS administration was followed by significant elevations in temperature (1.9 +/- 0.3 degrees C), pulse (29 +/- 6 bpm), and resting energy expenditure (26.2 +/- 0.4 kcal/kg/day) as well as epinephrine (236 +/- 59 pg/ml), cortisol (296 +/- 29), and C-reactive protein (4.2 +/- .03 mg/dl) as compared with base-line values. Levels of TNF and IL-6 that were not detectable before LPS administration, peaked, respectively, at 90 and 120 min after LPS (155 +/- 4 pg/ml, 12 +/- 1 U/ml). Glucocorticoids when given immediately before and concomitant with LPS significantly attenuated the temperature (0.8 +/- 0.01 degrees C) and pulse rate response (10 +/- 3 bpm) seen after LPS alone as well as suppressing peak levels of epinephrine (78 +/- 14 pg/ml) and C-reactive protein (undetected). TNF remained undetectable in this group although the IL-6 response (14 +/- 1 U/ml) was unchanged. With a 6-h interval between hydrocortisone infusion and LPS challenge, changes in temperature, pulse, resting energy expenditure, and hormone levels were similar to those seen after LPS alone whereas TNF remained undetectable and IL-6 levels were similar to subjects receiving LPS alone. Subjects receiving LPS after 12 or 144 h after hydrocortisone infusion displayed hemodynamic and hormonal responses similar to the LPS alone group, yet mounted significantly greater circulating levels of both IL-6 (117 +/- 14 U/ml, 160 +/- 51 U/ml at 12 and 144 h) and TNF (609 +/- 173, 671 +/- 132 pg/ml at 12 and 144 h) to those observed after LPS alone. We conclude that antecedent periods of hypercortisolemia participate in regulation of the hemodynamic, hormonal, and cytokine responses to endotoxin and that a complex temporal relationship between hypercortisolemia and LPS induced cytokine and systemic responses exists.

Adult↗
PubMed1992

Effect of combined cortisol-endotoxin administration on peripheral blood leukocyte counts and phenotype in normal humans.

We studied the role of lipopolysaccharide and the associated hypercortisolemic response as mediators of leukocyte changes associated with endotoxemia. Normal human subjects were given continuous, 12-hour, intravenous infusions of cortisol. After 6 hours of cortisol infusion, lipopolysaccharide (20 U/kg) was administered in an intravenous bolus. Plasma cortisol and blood leukocyte counts and lymphocyte subset proportions were evaluated every hour throughout the 12-hour study period. After 6 hours of cortisol infusion, lymphocyte counts and proportions of CD4+ helper/inducer T cells had declined significantly. The fact that these cells did not decline further in response to lipopolysaccharide and continued cortisol infusion suggests that lipopolysaccharide-induced lymphocyte changes are cortisol dependent. In contrast, the granulocytosis normally observed after lipopolysaccharide administration was unaffected by cortisol infusion. Finally, the monocyte counts and proportions of B cells (HLA-DR+ or CD20+ cells) responded to cortisol infusion and LPS in a pattern distinct from that of lipopolysaccharide alone. These results indicate that lipopolysaccharide-induced hypercortisolemia plays a role in immune modulation during endotoxemia.

Adult↗
PubMed1992

Influence of hypercortisolemia on the acute-phase protein response to endotoxin in humans.

BACKGROUND: The response to systemic infection includes the coordinated appearance of hepatic acute-phase proteins, the production of which may be influenced by a counterregulatory hormonal background. This study sought to assess the potential for hypercortisolemic conditions to influence fibrinogen kinetics and other acute-phase protein responses in humans with endotoxemia. METHODS: Eleven hospitalized healthy male volunteers underwent two separate determinations of fibrinogen kinetics, one baseline and one after administration of endotoxin (2 ng/kg intravenously; lot EC-5). Seven volunteers were studied without hormonal manipulation and four in the presence of a hypercortisolemic background (hydrocortisone infusion, 3 micrograms/kg/min). Fibrinogen fractional synthetic rates were estimated from the incorporation of orally administered 15N-glycine, and fibrinogen, C-reactive protein, cortisol, tumor necrosis factor-alpha, and interleukin-6 levels were also determined. RESULTS: The presence of an antecedent hypercortisolemic background resulted in an attenuated interleukin-6 response, as well as decreased fibrinogen synthesis and C-reactive protein appearance. CONCLUSIONS: The current data suggest that glucocorticoid hormonal influences are of importance in the regulation of endotoxin-induced cytokine and acute-phase protein responses.

Acute-Phase Proteins↗
PubMed1989

Total parenteral nutrition and bowel rest modify the metabolic response to endotoxin in humans.

Intestinal mucosal atrophy, as induced by total parenteral nutrition (TPN) and/or prolonged bowel rest, is hypothesized to enhance bowel endotoxin (LPS) translocation and may alter host responses to infection. To examine the effect of TPN-induced bowel atrophy on the response to LPS, 12 healthy volunteers were randomized to receive either enteral feedings (ENT, n = 6) or seven days of TPN without oral intake (TPN, n = 6). Enteral or TPN feedings were terminated 12 hours before the study period when a constant dextrose infusion (50 mg/kg/hour) was initiated and continued throughout the subsequent study period. After placement of arterial, hepatic vein, and femoral vein catheters, metabolic parameters were determined before and for six hours after an intravenous E. coli LPS challenge (20 U/kg). Subsequent peak levels of arterial glucagon (ENT, 189 +/- 39 pg/mL; TPN, 428 +/- 48; p less than 0.01), arterial epinephrine (ENT, 236 +/- 52 pg/mL; TPN, 379 +/- 49; p less than 0.05) and hepatic venous cachectin/tumor necrosis factor (cachectin/TNF) (ENT, 250 +/- 56 pg/mL; TPN, 479 +/- 136; p less than 0.05) were significantly higher in the TPN group than in the ENT group. The extremity efflux of lactate (ENT, -16 +/- 4 micrograms/min-100cc tissue; TPN, -52 +/- 13; t = 2 hours; p less than 0.05) and of amino acids (ENT, -334 +/- 77 nmol/min-100cc tissue; TPN, -884 +/- 58; t = 4 hours; p less than 0.05) were higher in the TPN subjects after the endotoxin challenge. Circulating C-reactive Protein (CRP) levels measured 24 hours postendotoxin were also significantly higher in the TPN subjects (ENT, 1.7 +/- 0.2 mg/dL; TPN, 3.2 +/- 0.3; p less than 0.01). Hence the counter-regulatory hormone and splanchnic cytokine responses to LPS were enhanced after TPN and bowel rest. This is associated with a magnified acute-phase response, peripheral amino acid mobilization, and peripheral lactate production. Thus antecedent TPN may influence the metabolic alterations seen in infection and sepsis via both an exaggerated counter-regulatory hormone response as well as an enhanced systemic and splanchnic production of cytokines.

Adult↗