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Biomedical subjects

S F Lowry

Publications and source records attributed to S F Lowry.

At least 73 records · Page 4Linked to original sources
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

The metabolic effects of platelet-activating factor antagonism in endotoxemic man.

OBJECTIVE: To determine if the inflammatory phospholipid platelet-activating factor (PAF) participated in the symptomatologic, metabolic, and counterregulatory hormonal responses of human endotoxemia. DESIGN: In a double-blind, placebo-controlled study, five subjects received 10 mg of the PAF antagonist Ro 24-4736 orally, while five control subjects received a placebo. Eighteen hours later, all subjects were administered 4 ng/kg of endotoxin (lipopolysaccharide) intravenously. SETTING: The Clinical Research Center of The New York Hospital-Cornell Medical Center. PARTICIPANTS: Healthy male volunteers. MAIN OUTCOME MEASURES: Repeated measurements of vital signs, symptoms, cytokine and hormone levels, resting energy expenditure, platelet aggregation, and bleeding times were performed during a 24-hour period. RESULTS: Subjects who were pretreated with the PAF antagonist experienced fewer symptoms, including rigors at 1 hour (P < .05) and myalgias at 1 through 4 hours (P < .05) after administration of lipopolysaccharide. This was in concert with a diminished peak cortisol level (668 +/- 107 vs 959 +/- 159 nmol/L in controls; P < .05), epinephrine secretion (1057 +/- 165 vs 2029 +/- 431 nmol/L in controls; P < .05), and almost complete inhibition of PAF-induced platelet aggregation ex vivo. CONCLUSIONS: These findings in the face of unaltered circulating cytokines tumor necrosis factor alpha, interleukin 1 beta, and interleukin 6, as well as the tumor necrosis factor receptor-I s, suggest that PAF may influence some endotoxin-induced, counterregulatory hormonal responses and symptoms through cytokine-independent mechanisms. This study further supports the role of PAF antagonists as an adjunct to cytokine blockade in the treatment of gram-negative sepsis.

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

Anti-endotoxin therapy in primate bacteremia with HA-1A and BPI.

OBJECTIVE: The in vivo neutralizing activities of an anti-lipopolysaccharide (LPS) antibody HA-1A (Centoxin [Centocor, Malvern, PA]), a human immunoglobulin M monoclonal antibody, and of bactericidal/permeability-increasing protein (BPI), an endogenously produced human LPS-neutralizing protein, were studied in a primate model of lethal Escherichia coli bacteremia. SUMMARY BACKGROUND DATA: HA-1A has been used with variable success against LPS activity in some animal models and in a recently reported clinical trial. However, no data assessing the efficacy of this agent in subhuman primates is available. Bactericidal/permeability-increasing protein is a product of polymorphomononuclear cells (PMNs) that is stored in azurophilic granules and exhibits LPS-neutralizing activity in vitro and in some in vivo models. METHODS: Immediately after E. coli infusion and in a blinded fashion, three baboons were treated with BPI (5 mg/kg bolus infusion and 95 micrograms/kg/min infusion over 4 hr). Three animals received 3 mg/kg BW of HA-1A, whereas another three baboons received a placebo treatment. RESULTS: The BPI-treated animals demonstrated significantly (p < 0.03) lower circulating LPS-limulus amoebocyte lysate (LAL) activity compared with the control animals, but this reduction in LPS-LAL activity was not associated with improved survival. HA-1A treatment did not reduce LPS-LAL activity. However, both BPI and HA-1A treatment did attenuate the pro-inflammatory cytokine response. CONCLUSION: The current data suggests that incomplete neutralization of endotoxin activity does not alter mortality from severe bacteremia. Given the diversity of mediator production under such circumstances, a strategy of combination therapy in the form of anti-lipopolysaccharide and anticytokine treatment may be necessary to achieve optimal survival.

Amino Acid Sequence↗
PubMed1994

Whole body and splanchnic leucine, phenylalanine, and glucose kinetics during endotoxemia in humans.

To examine the whole body and splanchnic tissue substrate handling during endotoxemia, an intravenous bolus of endotoxin was given to six healthy volunteers during primed, continuous infusions of [1-13C]leucine, [ring-2H5]phenylalanine, and [6,6-2H2]glucose. Whole body protein breakdown, based on whole body Leu and Phe appearance rates (Ra), increased in response to endotoxin given at time 0 (RaLeu 77 +/- 2 mol.kg-1 x h-1, t = 0 h; 88 +/- 6, t = 4 h; P < 0.05) (RaPhe 39 +/- 2 mol.kg-1 x h-1, t = 0; 46 +/- 3, t = 4 h; P < 0.05). Splanchnic amino acid balance (Bal) increased (BalLeu 7 +/- 4 mol.kg-1 x h-1, t = 0; 21 +/- 5, t = 2 h; P < 0.05) (BalPhe 3 +/- 2 mol.kg-1 x h-1, t = 0; 16 +/- 4, t = 2 h; P < 0.05) and can be accounted for by increased splanchnic uptake (Rd) of Phe and Leu (RdLeu 21 +/- 3 mol.kg-1 x h -1, t = 0; 37 +/- 7, t = 120 min; P < 0.05) (RdPhe 10 +/- 3 mol.kg-1 x h-1, t = 0; 24 +/- 5, t = 120 min; P < 0.05). Splanchnic conversion of Leu to ketoisocaproate increased with endotoxin administration (0.7 +/- 0.6 mol.kg-1 x h-1, t = 0; 8 +/- 3, t = 360 min; P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Acute-Phase Proteins↗
PubMed1994

Role of interleukin-1 and the therapeutic potential of interleukin-1 receptor antagonist in sepsis.

Clinical trials of anticytokines in sepsis have not been as straightforward as had been anticipated from results in animal models of sepsis and the role of cytokines in sepsis is now in question. Retrospective analysis of the results of a phase III trial of interleukin-1 (IL-1) receptor antagonist suggests that sepsis-induced adult respiratory distress syndrome (ARDS), disseminated intravascular coagulation (DIC), renal dysfunction, and shock are valuable markers of patients in whom IL-1 is a pathogenic mediator and in whom IL-1ra can reduce mortality. A re-examination of the effects of IL-1ra in animal models of sepsis supports the validity of this analysis. A new phase III clinical trial will confirm or disprove the hypothesis that IL-1 is a mediator of pathology, and IL-1ra is a valuable therapy for sepsis complicated by ARDS, DIC, renal dysfunction, or shock.

Disseminated Intravascular Coagulation↗
PubMed1994

Nutrient modification of inflammatory mediator production.

Recent evidence suggests that dietary manipulations may influence the production of endogenous inflammatory mediators. Hence, nutritional modulation during critical illness may affect survival through mechanisms far more complex than the maintenance of mere caloric and nitrogen balance. Provision of nutrients through parenteral routes to normal volunteers promotes an exaggerated cytokine response after an endotoxin challenge. Similarly, alterations in the specific protein, lipid, and micronutrient intake in septic animal models can dramatically influence the elaboration of inflammatory mediators generated by septic stimuli. However, unlike clinical work examining the differential outcome of parenterally and enterally fed patients, the theoretical advantages of specific amino acid or lipid modulation await confirmation by controlled human investigation and clinical trials.

Bacteremia↗
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↗
PubMed1993

Cytokine mediators of immunity and inflammation.

The remarkable advances in molecular and cell biology occurring over the past four decades have served the cause of surgical science well. Our understanding of basic disease mechanisms and insights into potential new therapeutic strategies have occurred at a staggering pace. Perhaps nowhere in surgical biology are these mechanistic insights and therapeutic prospects more evident than in research defining the cytokine mediators of inflammation, injury, and repair. These proteins are secreted to some degree by virtually all immune cell types as well as by a diverse array of other nucleated cells, and their functions encompass a regulatory role on and among many components of the immune system. Such intense interest is well deserved because abnormalities or dysregulation of tissue and wound repair as well as of natural (innate) or specific (acquired) immune function underlie much of the morbidity and mortality associated with surgical practice. Indeed, it is evident that the insights gained from the study of such inflammatory mediators cross virtually every specialty of surgery, from the acute sequelae of severe injury and invasive infection to the chronic manifestations of benign and malignant processes.

Cytokines↗
PubMed1993

Cachexia and the acute-phase protein response in inflammation are regulated by interleukin-6.

Cachexia and the acute-phase response are common manifestations of inflammation and are presumed to be the product of increased synthesis and release of cytokines, including tumor necrosis factor (TNF), interleukin-1 (IL-1) and interleukin-6 (IL-6). IL-1 receptor blockade has been previously shown to attenuate the weight loss, anorexia and acute-phase protein responses associated with a turpentine abscess. However, IL-1 receptor blockade was also associated with a reduced plasma IL-6 response, suggesting that the benefit achieved by IL-1 receptor blockade may be mediated by reduced systemic IL-6 production. To gain a better understanding of the role of IL-6 in this model of inflammation, C57BL/6 mice were passively immunized with either a monoclonal anti-IL-6 antibody (20F3), an anti-IL-1 type I receptor monoclonal antibody (35F5), a non-immune rat IgG, or a combined therapy of 35F5 and 20F3, before receiving a sterile turpentine abscess. IL-6 or IL-1 receptor blockade equally spared body weight and food intake. Compared to IL-1 receptor blockade, passive immunization against IL-6 further reduced the hepatic acute-phase protein response, as represented by serum amyloid P and complement 3. Combined blockade of IL-6 and IL-1 receptor did not result in a further sparing of body weights or improvement of food intake. These results confirm that IL-1 contributes to host cachexia and the acute-phase response following a turpentine abscess, but also show that these actions are dependent upon an IL-6 response. We conclude that the influence of IL-1 on cachexia and the acute-phase response is mediated, at least in part, through IL-6 and, thus, IL-6 may play a pivotal role in the cachexia and acute-phase response to inflammation.

Acute-Phase Reaction↗
PubMed1993

Comparison of peripheral blood leukocyte kinetics after live Escherichia coli, endotoxin, or interleukin-1 alpha administration. Studies using a novel interleukin-1 receptor antagonist.

OBJECTIVE: This study was undertaken to evaluate whether hematologic and immunologic effects observed after bacteremia and endotoxemia in the host could be replicated by administration of recombinant human interleukin-1 alpha (IL-1 alpha) in a primate model. Furthermore, to determine whether endogenously produced interleukin-1 (IL-1) contributes to the changes observed during endotoxemia or gram-negative septic shock, a specific IL-1 receptor antagonist (IL-1 ra) was administered. SUMMARY BACKGROUND DATA: The lipopolysaccharide (LPS) component of the outer membrane of gram-negative bacteria initiates a constellation of metabolic and immunologic host responses. IL-1, a macrophage-derived cytokine, acts as a key mediator in the host response to infection and inflammation. METHODS: Baboons were randomly assigned to receive either recombinant human IL-1 alpha, LPS, or live Escherichia coli both with or without concomitant administration of IL-1ra. Blood was collected hourly and analyzed using flow cytometric techniques. RESULTS: Both endotoxemia and live E. coli bacteremia induced an acute granulocytopenia; however, the granulocytopenia gradually resolved in the endotoxemic group, but was sustained in the bacteremic group. An early lymphopenia and monocytopenia was elicited by LPS or E. coli and persisted throughout the experiment. Recombinant human IL-1 alpha induced the following: (1) an early, transient decline in granulocytes followed by a sustained granulocytosis; (2) a lymphopenia; and (3) a transient monocytopenia followed by a gradual return to baseline. Although IL-1ra had no effect on leukocyte kinetics with either live E. coli or LPS, the IL-1ra significantly abrogated the monocytopenia seen with recombinant human IL-1 alpha administration alone. CONCLUSIONS: These results suggest that administration of recombinant human IL-1 alpha can replicate some of the characteristic patterns of hematologic change associated with bacteremia and endotoxemia. However, an endogenous IL-1 response is not required for these changes to occur. Rather, the data suggest that other inflammatory mediators induced by endotoxemia or gram-negative bacteremia, such as tumor necrosis factor-alpha (TNF alpha), may be involved.

Animals↗
PubMed1993

Anticytokine therapies in sepsis.

The pro-inflammatory cytokines, tumor necrosis factor (TNF) and interleukin-1 (IL-1), are widely assumed to participate in the initial systemic manifestations of sepsis. While the toxicities of excessive cytokine activity have been well described in animal models, clinical evaluations often fail to detect circulating forms of these mediators in critically ill patients. It is now evident that a diverse array of host mechanisms serve to attenuate or block excessive cytokine influences. This homeostatic response includes the generation of natural antagonists, such as soluble receptors of TNF and an antagonist of IL-1 that prevents binding of the cytokine to its receptor. Recombinantly derived forms of these natural cytokine antagonists have proven effective in preventing many of the adverse consequences of sepsis. Prospective clinical trials of these agents are currently underway. While results of such trials are not fully available at present, it is likely that one or more therapies directed against TNF and IL-1 may prove effective in the management of septic shock.

Animals↗
PubMed1993

Insulin-like growth factor-1 activity is inhibited by interleukin-1 alpha, tumor necrosis factor-alpha, and interleukin-6.

With evidence that several proteins inhibit insulin-like growth factor (IGF) activity, we evaluated whether cytokines, which are elevated in many catabolic states, also affect IGF-1-mediated proteoglycan synthesis. Cartilage from hypophysectomized rats was exposed to the cytokines interleukin-1 alpha (IL-1 alpha), tumor necrosis factor-alpha (TNF-alpha) or interleukin-6 (IL-6) in the presence or absence of IGF-1. IL-1 alpha inhibited IGF-1-stimulated proteoglycan (PG) synthesis > 95% at 20 ng/ml (p < 0.01). TNF-alpha and IL-6 caused a maximum inhibition of 56 and 54%, respectively, both at 200 ng/ml. Only in the absence of IGF-1 did IL-1 alpha inhibit PG synthesis below unstimulated levels, suggesting that although IL-1 alpha can directly inhibit PG synthesis, IL-1 alpha, TNF-alpha, TNF-alpha, and IL-6 each promotes cartilage loss also by inhibiting IGF-1-mediated anabolism.

Animals↗