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Biomedical subjects

S E Calvano

Publications and source records attributed to S E Calvano.

At least 19 recordsLinked to original sources
PubMed2007

Nicotine exposure alters in vivo human responses to endotoxin.

The alpha 7 nicotinic receptor is reportedly a key element in the cholinergic anti-inflammatory pathway. Because a prototypical ligand for this receptor is nicotine, we studied the in vivo human response to bacterial endotoxin or lipopolysaccharide (LPS) in the context of nicotine or placebo pretreatment. Twelve adult male normal subjects were studied prospectively. Six received overnight transcutaneous nicotine administration by application of a standard patch (7 mg). Six hours later, all subjects were given an intravenous dose of endotoxin (2 ng/kg) and were evaluated for an additional 24 h for circulating levels of inflammatory biomarkers, vital signs and symptoms. The nicotine subjects had elevated blood levels of the nicotine metabolite, continine, prior to and throughout the 24-h post-endotoxin exposure phase. Subjects receiving nicotine exhibited a significantly lower temperature response as well as attenuated cardiovascular responses for 2.5-6 h after LPS exposure. In addition, increased circulating interkeukin (IL)-10 and cortisol levels were also noted in nicotine subjects. These data indicate an alteration in LPS-induced systemic inflammatory responses in normal subjects exposed to transcutaneous nicotine. In this model of abbreviated inflammation, nicotine exposure attenuates the febrile response to LPS and promotes a more prominent anti-inflammatory phenotype.

Administration, Cutaneous↗
PubMed2005

Expression of tumour necrosis factor receptor and Toll-like receptor 2 and 4 on peripheral blood leucocytes of human volunteers after endotoxin challenge: a comparison of flow cytometric light scatter and immunofluorescence gating.

Toll-like receptors (TLRs) are involved in the recognition of bacterial products and thus participate in the induction of the inflammatory cascade. However, much less is known about the evolution of leucocyte TLR expression during human inflammatory stress. We hypothesized that a decrease in leucocyte TLRs could account for the so-called tolerance or hyporesponsiveness state to subsequent stimulation with bacteria-derived products. Because of the profound monocytopenia that ensues after in vivo lipopolysaccharide (LPS) challenge, we also compared monocyte TLR expression using two different techniques of flow cytometric gating. In a first set of experiments, 17 healthy volunteers underwent LPS challenge. Blood was drawn at different time-points and analysed by flow cytometry using light scatter gating and one-colour analysis to assess the expression of the tumour necrosis factor receptor (TNFR) and TLR2 and TLR4 on both monocytes and granulocytes. In a second set of experiments, the assessment of those receptors was made using a more specific gating method that utilized light scatter and CD14 immunofluorescence in a two-colour analysis. This was performed using whole blood drawn from five healthy volunteers and incubated ex vivo for different time periods with or without LPS and in 12 volunteers who underwent LPS challenge in vivo. The pattern of expression for monocyte TNFR was similar for both types of gating. Using only the light scatter gating, an initial drop of TLR 2 and 4 was observed on monocytes. By contrast, when using light scatter x immunofluorescence gating, an up-regulation of these two receptors following both in vivo and in vitro LPS exposure was observed. LPS up-regulates the expression of TLRs on monocytes and granulocytes. Depending upon the methodology utilized, contrasting results were obtained with respect to TLR2 and TLR4 expression. The flow cytometric gating technique used is of importance in determining cellular TLR2 and TLR4 expression, especially in blood samples exhibiting significant monocytopenia.

Adolescent↗
PubMed2001

The effects of glucocorticoid therapy on inflammatory responses to coronary artery bypass graft surgery.

HYPOTHESIS: Delayed or reduced polymorphonuclear leukocyte (PMN) apoptosis may contribute to prolongation of systemic inflammation after cardiopulmonary bypass. BACKGROUND/OBJECTIVE: Preoperative administration of glucocorticoids has been used ostensibly to attenuate the systemic inflammation associated with cardiopulmonary bypass. Therefore, this study evaluated, in patients undergoing cardiopulmonary bypass, the efficacy of glucocorticoids in restoring peripheral blood PMN apoptosis and modulating PMN surface receptors (CD95, tumor necrosis factor receptor [TNFR]) known to be involved in proapoptotic or antiapoptotic signal transduction. DESIGN: Randomized control study. SETTING: Medical school and affiliated tertiary care hospital. PATIENTS: Thirteen patients undergoing coronary artery bypass grafting. INTERVENTION: Patients were randomly assigned to the control group (n = 7) or to receive 1 g of methylprednisolone sodium succinate on anesthetic induction (n = 6). MAIN OUTCOME MEASURES: Blood samples were drawn before induction, 20 minutes after sternotomy and bypass, immediately postoperatively, and on postoperative day 1. Isolated PMNs were incubated for 6 hours with or without the CD95 agonist CH 11. Polymorphonuclear leukocyte apoptosis was measured using propidium iodide-RNAase staining and flow cytometry. Levels of PMN cell-associated receptors (TNFR and CD95), cytokines (TNF-alpha, interleukin 6 [IL-6], IL-8, and IL-10), and soluble receptors (sTNFR1 and sTNFR2) were measured. RESULTS: In all 13 patients, spontaneous and Fas-mediated PMN apoptosis decreased more than 80% from baseline (P<.001) by postoperative day 1. Polymorphonuclear leukocyte CD95 increased (P<.003) by postoperative day 1 compared with baseline, whereas PMN TNFR was unchanged. Methylprednisolone administration did not modulate PMN apoptosis or immunocyte receptor expression; however, such treatment did decrease postoperative IL-6 secretion (P<.001) and increase postoperative IL-10 secretion (P<.001). CONCLUSIONS: The complications of major surgery include persistent inflammation, which can lead to multisystem organ failure. Polymorphonuclear leukocyte resistance to apoptosis may contribute to this process. A single preoperative dose of glucocorticoids did not effect PMN apoptosis or receptor phenotype.

Anti-Inflammatory Agents↗
PubMed2000

Inflammatory cytokines and cell response in surgery.

The systemic inflammatory response as mediated by the cytokine network is undoubtedly complex. While inflammatory cytokines are indispensable in wound healing and the restoration of homeostasis, it is often the excessive activity of either proinflammatory or anti-inflammatory cytokines that causes injury to the host or renders the host immunocompromised, respectively. Central to the functional biology of cytokines in surgical injury and infections are the responses of immune cells to such insults. It is clear that immunocytes are the source of cytokine production, and these products possess important autocrine, as well as systemic activities. The ability to alter immunocyte function through extracellular hormonal influences or by manipulating intracellular signaling mechanisms are potential strategies for regulating the inflammatory cytokine response during injury.

Animals↗
PubMed1999

Preproenkephalin mRNA and enkephalin levels in the adult Syrian hamster: the influence from glucocorticoids.

Proenkephalin (Penk) gene structure in hamsters and humans are similar but they differ from rats. In this study hamster Penk gene expression was examined after hypophysectomy+/-glucocorticoid receptor blockade with RU 486 (mifepristone). In contrast to rats, basal Penk gene expression in hamster adrenals did not change after treatments that reduced both the influence from glucocorticoids and phenylethanolamine-N-methyltransferase mRNA levels. Meanwhile, striatal preproenkephalin mRNA levels increased under these conditions.

Adrenal Glands↗
PubMed1998

Altered macrophage intracellular signaling induced by protein-calorie malnutrition.

Protein-calorie malnutrition (PCM) contributes to increased morbidity and mortality through impairment of host defense mechanisms and reduced macrophage function. The present study examined alterations in macrophage intracellular signaling associated with the impairment in host defense capabilities. Mice were randomized to either control (regular diet) or protein-free diets (PCM) and pair-fed for 1 week. Following endotoxin stimulation, peritoneal macrophages from PCM mice produce significantly less TNF-alpha and IL-6 product and had significantly less cell-associated IL-6 when compared to macrophages from control mice. Similarly, macrophages from PCM mice had a significant reduction in mRNA levels for both TNF-alpha and IL-6. Other macrophage intracellular signaling mechanisms, such as calcium flux and tyrosine kinase phosphorylation were also altered by PCM. The etiology of PCM-induced defects in macrophage function and intracellular signaling remain unknown but may be related to the neuroendocrine response to PCM.

Animals↗
PubMed1998

The influence of human endotoxemia on CD95-induced apoptosis.

BACKGROUND: The responses of monocyte and neutrophil tumor necrosis factor receptor type 1 (TNFR-1) and TNFR-2 during systemic inflammation have been described previously. Several other members of the TNFR superfamily also appear to have regulatory roles in immunocyte function, including apoptosis. However, the response of these other receptor members, such as CD95, to systemic inflammation is unclear. OBJECTIVES: To compare the response of CD95 with that of TNFR during systemic inflammation and to assess the influence of the inflammatory milieu on CD95 function. SETTING: Adult clinical research center of a university hospital. SUBJECTS AND METHODS: Five healthy male subjects were administered intravenous endotoxin (2 ng/kg), and systemic response was measured by cytokine analysis and receptor expression assays during a 48-hour period. CD95 function during systemic inflammation was assessed using a Jurkat cell bioassay for degree of apoptosis. RESULTS: Monocyte and neutrophil CD95 expression exhibited changes parallel to that of TNFR following endotoxin injection. In contrast to soluble TNFR, which was transiently elevated during endotoxemia, soluble CD95 levels remained unchanged from baseline. Jurkat cells incubated in normal and post-endotoxin serum samples equally exhibited less than 10% spontaneous apoptosis. No soluble CD95 ligand was detectable in experimental human endotoxemia. CONCLUSIONS: Cell-associated CD95 exhibited changes parallel to its receptor family member TNFR following endotoxin administration. Soluble CD95 is present in human serum samples, but the levels remained unchanged following endotoxin administration. No soluble CD95 ligand activity was detectable by enzyme-linked immunosorbent assay or by functional assay. The potential protective role of soluble CD95 in human serum samples against CD95 ligand-induced apoptosis remains to be defined.

Adult↗
PubMed1998

Multivariate analysis of 9 disease-associated variables for outcome prediction in patients with sepsis.

OBJECTIVE: To assess the ability of 9 clinical or biological variables to predict outcome (survival or nonsurvival) using multiple regression and classification analyses. DESIGN: Prospective, descriptive cohort study with no interventions. SETTING: Surgical intensive care unit of a tertiary care hospital and a medical school research laboratory. PATIENTS: Eighteen patients with a documented source of infection who met currently accepted criteria for sepsis syndrome or septic shock. MAIN OUTCOME MEASURES: Prediction of survival or nonsurvival based on analysis of clinical (Multiple Organ Dysfunction score, Acute Physiology and Chronic Health Evaluation III scores) and biological (plasma levels of cortisol, interleukin 6, interleukin 10, phospholipase A2, soluble tumor necrosis factor receptor p75, and monocyte membrane tumor necrosis factor receptor levels) variables, with comparison of predicted and actual outcomes. RESULTS: Plasma interleukin 6, interleukin 10, and phospholipase A2 concentrations were not significantly (P>.05) different between survivors and nonsurvivors. By standard, forward stepwise, and backward stepwise multiple regression analyses, only monocyte membrane tumor necrosis factor receptor levels measured at the onset of sepsis significantly predicted outcome in all 3 analyses. However, by both standard and backward stepwise analyses, Multiple Organ Dysfunction scores based on evaluation at the onset of sepsis and 24 hours later were also significant predictors of outcome. Classification analysis showed that assignment to outcome group was statistically significant when based on monocyte membrane tumor necrosis factor receptor levels determined at the onset of sepsis or on Multiple Organ Dysfunction scores assessed 24 hours after sepsis was diagnosed. CONCLUSION: Although these findings were based on a relatively small cohort, both multiple regression and classification analyses indicated that only monocyte membrane tumor necrosis factor receptor levels are able to discriminate survivors from nonsurvivors at the onset of sepsis.

Biomarkers↗
PubMed1998

Trauma-induced alterations in macrophage function.

BACKGROUND: The juxtaposition of immune suppression and a hyperactive inflammatory response after injury represents a paradox in immune function. The aim of this study was to evaluate the delayed macrophage hypersecretion of inflammatory mediators in relation to functional macrophage defects. METHODS: BALB/c mice were randomized to control or trauma (femur fracture plus 40% blood volume hemorrhage) groups. One and 7 days after injury, splenic macrophages were isolated and assayed for antigen presentation and the production of inflammatory mediators tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, prostaglandin E2, H2O2, and nitric oxide. RESULTS: One day after injury, there were significantly diminished macrophage antigen presentation and decreased mean production of TNF-alpha, IL-6, and H2O2. In contrast, 7 days after injury, splenic macrophages produced significantly increased mean amounts of TNF-alpha, IL-6, prostaglandin E2, H2O2, and nitric oxide, with a persistent functional defect in antigen presentation. CONCLUSIONS: This phasic response to trauma suggests a persistent state of macrophage dysregulation that may help explain the paradox of immune suppression, manifested by functional defects predisposing patients to increased infections, in the setting of inflammatory mediator hypersecretion, predisposing patients to the systemic inflammatory response syndrome/multiple organ dysfunction syndrome.

Animals↗
PubMed1997

Effects of IL-10 on systemic inflammatory responses during sublethal primate endotoxemia.

IL-10 protects mice from LPS-induced lethality. To determine the effects of IL-10 on LPS-induced inflammatory responses, six Papio anubis baboons were i.v. injected with a sublethal dose of LPS (Salmonella typhimurium; 500 microg/kg) directly preceded by either human rIL-10 (n = 3, 500 microg/kg) or diluent (n = 3). IL-10 strongly inhibited LPS-induced release of TNF, IL-6, IL-8, and IL-12 (all p < 0.05). By contrast, IL-10 did neither influence the activation of the coagulation system (plasma levels of thrombin/antithrombin III complexes), nor the activation of the fibrinolytic system (plasma levels of tissue-type plasminogen activator, plasminogen activator inhibitor type I, and plasmin/alpha 2-antiplasmin complexes). IL-10 modestly attenuated neutrophilic leukocytosis and neutrophil degranulation (plasma concentrations of elastase/alpha1-antitrypsin complexes) (both p < 0.05). Changes in surface TNF receptor expression on circulating granulocytes were not affected by IL-10. These results suggest that during sublethal endotoxemia the predominant anti-inflammatory effect of IL-10 treatment is inhibition of proinflammatory cytokine release.

Animals↗
PubMed1997

Epinephrine attenuates down-regulation of monocyte tumor necrosis factor receptors during human endotoxemia.

Epinephrine inhibits lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF) production by increasing intracellular cAMP concentrations. Because agents that increase cAMP levels can enhance TNF receptor expression in vitro, granulocyte and monocyte TNF receptors were determined by FACS-analysis in 7 normal humans who were receiving a constant 24-h infusion of epinephrine (30 ng/kg/min), and in 15 normal subjects after intravenous injection of LPS (2 ng/kg), while they were receiving a continuous infusion of epinephrine started either 3 h (EPI-3) or 24 h (EPI-24) before LPS injection or an infusion of normal saline (LPS; n = 5 per group). Infusion of epinephrine per se did not influence TNF receptor expression. LPS induced a transient decrease in monocyte TNF receptors and a more sustained decrease in granulocyte TNF receptors (both P < 0.05). EPI-3 partly prevented LPS-induced down-modulation of monocyte TNF receptors (P < 0.05 vs. LPS only), but did not affect LPS-induced down-modulation of granulocyte TNF receptors. EPI-24 had no effect on TNF receptor expression. These data suggest that epinephrine not only influences the bioavailability of TNF by an effect on the production of this proinflammatory cytokine, but also by modulating the expression of its receptors.

Adult↗
PubMed1997

Candida infection following severe trauma exacerbates Th2 cytokines and increases mortality.

Following trauma, there is an increase of Th2 cytokines (IL-4, IL-6, and IL-10) and a decrease in Th1 cytokines (IFN-gamma and IL-2) that may account for impaired cellular immunity. However, the functional significance of a dominant Th2 pattern to the host remains unclear. The aim of this study was to evaluate whether Candida albicans (CA) sepsis in the setting of a Th2 response to trauma leads to increased mortality and to examine the mediators involved. Female BALB/c mice were randomized (12 per group) to receive no injury (C); trauma, consisting of a combined femur fracture and 40% total blood loss (T); no injury plus CA infection (C+CA); and CA infection 1 week following trauma (T+CA). Survival was then followed for 3 weeks. In a separate study, mice were treated as above (5 per group) and sacrificed. Harvested splenocytes were evaluated for concanavalin A-stimulated cytokine production and liver and kidney homogenates were plated to evaluate CA growth per organ and examined histologically. Candida infection at 1 week following trauma resulted in significantly increased mortality compared to infected controls. Furthermore, the Th2 dominant cytokine pattern was significantly augmented in the presence of CA infection in both C+CA and T+CA groups. Additional analysis showed significant growth of CA in liver and kidney homogenates from T+CA compared to C+CA mice. These results suggest that injured and infected mice demonstrate augmentation of Th2 dominant responses above that of injury or infection alone, as well as a decreased ability to clear Candida which may partially explain the increase in mortality observed. Therapies designed to neutralize Th2 cytokines or augment Th1 cytokines may prove beneficial in the setting of sepsis following trauma.

Acute Disease↗
PubMed1997

Catecholamines increase monocyte TNF receptors and inhibit TNF through beta 2-adrenoreceptor activation.

Postinjury deficits in monocyte tumor necrosis factor receptors (moTNFR) activity may alter beneficial functions during an inflammatory response. Several counter-regulatory hormones elicited during inflammation may modulate tumor necrosis factor (TNF) activity, but little is known about their influence on moTNFR. Also, catecholamines inhibit TNF production, but the adrenoreceptor mechanism of this effect has not been fully clarified. To determine the effect of catecholamines and corticosteroids on moTNFR, whole blood was coincubated for up to 8 (moTNFR) or 24 h (cytokines) in the presence of lipopolysaccharide (100 ng/ml) and 1) epinephrine (Epi, 10(-6) M), dexamethasone (Dex, 10(-6) M) or both (EpiDex, 10(-6) M) to assess the expression of total moTNFR, moTNFR-I, and moTNFR-II. 2) Epi and norepinephrine (EpiNE, 10(-6) M) and the alpha 1 + 2-, beta 1 + 2-, beta 1-, or beta 2-adrenergic antagonists were used to assess the role of such adrenoreceptors on total moTNFR and TNF production, and N6,2'-O-dibutyryl adenosine 3',5'-cyclic monophosphate (DBcAMP) alone or in combination with the phosphodiesterase inhibitor Ro-20-1724/000, to study the cAMP-dependent pathway on total moTNFR. We found that Epi upregulated total moTNFR and moTNFR-II. Dex did not significantly influence total moTNFR or moTNFR-II. Also, EpiNE increased total moTNFR and inhibited TNF by a beta 2-dependent mechanism. DBcAMP (10(-5) M) modestly enhanced total moTNFR. This suggests a common mechanism for acutely enhancing moTNFR and attenuation of soluble TNF appearance during conditions of severe stress.

4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone↗
PubMed1996

Protection against lethal Escherichia coli bacteremia in baboons (Papio anubis) by pretreatment with a 55-kDa TNF receptor (CD120a)-Ig fusion protein, Ro 45-2081.

Fusion proteins of the human 55-kDa TNF receptor extracellular domain with hinge and C2/C3 constant domains of human IgG1 or IgG3 heavy chains were tested in a primate sepsis model. Twenty-four baboons received 4.6, or 0.2 mg/kg of TNFR5-G1,3, or placebo, before the administration of a lethal dose of live Escherichia coli. Treatment with TNFR5-G1,3 decreased 5-day mortality from 88% in the placebo group to 12% in the TNFR5-G1,3-treated animals (p < 0.01 by Fisher's exact test). Treatments with TNR5-G1 and TNFR5-G3 in doses from 0.2 to 4.6 mg/kg were efficacious. Free plasma TNF was neutralized by all treatments, but inactive TNF/TNFR5-G1,3 complexes remained in circulation for prolonged periods. TNFR5-1,3 treatments attenuated the hemodynamic disturbances, reduced fluid requirements, and decreased the systemic IL-1 beta, IL-6, and IL-8 responses. In addition, TNFR5-G1,3 treatment shortened the granulocytopenia and reduced the loss of cellular TNF receptors from granulocytes. The decrease in fibrinogen concentrations and increase in prothrombin and partial thromboplastin times were significantly attenuated by TNFR5-G1,3 treatment. TNFR5-G1,3 treatment markedly attenuated the rise in plasma lactate concentration. Histologic studies of TNFR5-G1,3 revealed dose-dependent protection against tissue injury by Escherichia coli administration.

Animals↗
PubMed1996

Monocyte tumor necrosis factor receptor levels as a predictor of risk in human sepsis.

OBJECTIVE: To assess peripheral blood monocyte tumor necrosis factor receptor (TNFR) levels and plasma soluble tumor necrosis factor receptor (sTNFR) concentrations in critically ill patients with sepsis syndrome. DESIGN: Prospective, descriptive cohort study with no interventions. SETTING: Surgical intensive care unit of a tertiary-care hospital associated with a university medical school. PATIENTS: Twenty-one patients with a documented source of infection who met currently accepted criteria for sepsis syndrome/septic shock. MAIN OUTCOME MEASURES: Plasma sTNFR p55 and p75 values were quantified by enzyme-linked immunosorbent assay, and monocyte TNFR levels were assessed by fluorescence flow cytometry after the monocytes were stained with biotinylated human recombinant TNF-alpha and streptavidin-phycoerythrin. RESULTS: Compared with healthy controls, plasma sTNFR p55 and p75 values were significantly higher (P <.01) in both surviving and nonsurviving patients with sepsis; in nonsurviving patients with sepsis, however, only sTNFR p55 values were significantly (P < .05) higher than in surviving patients with sepsis. By contrast, monocytes from the nonsurviving patients with sepsis manifested a significant (P < .01) and sustained (up to 4 days) decrease in cell surface TNFR values compared with either the normal controls or the surviving patients with sepsis. CONCLUSIONS: Assessment of monocyte surface TNFR values may provide a rapid prognostic indicator for patients with sepsis who are at increased risk of death.

Analysis of Variance↗
PubMed1996

Dominance of T-helper 2-type cytokines after severe injury.

OBJECTIVE: To determine whether severe injury leads to a dominance of splenocyte-produced T-helper (Th) 2-type cytokines, partly explaining the observed defects in cellular immune responses in the posttraumatic state. DESIGN: Female BALB/c mice (n = 6 per group) were randomized to receive anesthesia alone (control) or a combined femur fracture and a hemorrhage of 40% of total blood volume (trauma). On days 1 and 7 after injury, mice were killed and spleens were harvested. Splenocytes were stimulated in vitro with 2.5 micrograms of concanavalin A per milliliter. After 72 hours of incubation, splenocyte proliferation was determined by means of tritiated thymidine uptake. Production of interferon-gamma and interleukins (IL) -2, -4, -5, -6, and -10 from supernatants harvested after 24 or 72 hours of incubation was quantified by enzyme-linked immunosorbent assay. SETTING: Surgical immunology research laboratory of a medical college. MAIN OUTCOME MEASURES: Mouse spleen weight, splenocyte number, and proliferation in addition to cytokine production (interferon-gamma, IL-2, IL-4, IL-5, IL-6, and IL-10). RESULTS: Splenocyte proliferative capacity was unaffected at day 1 after injury but was significantly suppressed (P < .05) by day 7 after injury. Similarly, there were no changes in splenocyte cytokine production in a comparison of control and injured mice at day 1. At day 7, however, there was nearly a 90% decrease in the Th1-type cytokines (interferon-gamma and IL-2; P < or = .002) and at least a 30% increase in the Th2-type cytokines IL-4, IL-5, IL-6, and IL-10 (P = .06 for IL-6 and P < or = .03 for IL-4, IL-5, and IL-10). CONCLUSIONS: These data indicate that a shift to a Th2-type splenocyte cytokine response occurs late, at 7 days after injury. Modulation of Th cell cytokine responses may partially explain defects observed in cellular immune responses in postinjury states. Therapies that augment Th1-type cytokine production and/or neutralize Th2-type cytokines may prove beneficial.

Animals↗
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↗