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Biomedical subjects

K J Tracey

Publications and source records attributed to K J Tracey.

At least 19 recordsLinked to original sources
PubMed1992

Macrophage inflammatory protein 1 modulates macrophage function.

Macrophage inflammatory protein 1 (MIP 1), initially purified from the conditioned medium of endotoxin-stimulated macrophages, is a low m.w. heparin-binding protein doublet comprising two peptides, MIP 1 alpha and MIP 1 beta. Although native doublet MIP 1 has previously been shown to exert pyrogenic, mitogenic, and proinflammatory effects on other cell types, its actions on its cell of origin, the macrophage, have not been well catalogued. Our study reports several aspects of macrophage function that are modulated by MIP 1. MIP 1 was not directly cytotoxic for WEHI tumor cells, but MIP 1-treated macrophage exhibited enhanced antibody-independent macrophage cytotoxicity for tumor targets. MIP 1 treatment stimulated proliferation of mature tissue macrophages, and this effect was enhanced upon costimulations with either CSF-1 or granulocyte-macrophage-CSF. Thioglycollate-elicited peritoneal exudate macrophages incubated with native doublet MIP 1-secreted bioactive TNF and IL-6, as well as immunoreactive IL-1 alpha, and these effects were enhanced significantly when the cells were costimulated with IFN-gamma. Purified preparations of the recombinantly derived MIP 1 alpha peptide alone stimulated the secretion of TNF, IL-1 alpha, and IL-6 by peritoneal macrophages, but MIP 1 beta did not. In fact, as little as eightfold excess MIP 1 beta blocked TNF-induction by MIP 1 alpha to a significant degree. By contrast to these apparent "macrophage activating" properties of MIP 1, the cytokine failed to trigger the macrophage oxidative burst, or to up-regulate the expression of Ia on the macrophage surface. Taken together, these data reveal that MIP 1 peptides act as autocrine modulators of their cells of origin, and raise the possibility that MIP 1 peptides may play a role in modulating macrophage responses to inflammatory stimuli in vivo.

Animals↗
PubMed1992

Tumor necrosis factor and regulation of metabolism in infection: role of systemic versus tissue levels.

Tumor necrosis factor (TNF), a pleiotropic cytokine, is produced by macrophages and other cells in a variety of infectious and noninfectious diseases. Ultimately, the net biological effects of TNF may be either beneficial or injurious to the host. For instance, during overwhelming bacterial infection, the acute overproduction of TNF causes septic shock syndrome characterized by hypotension, organ failure, and death. Antibodies against TNF prevent and reverse these sequelae in animal models of septic shock, and their use in humans is currently under investigation in clinical trials. In another instance, TNF has been implicated as an injurious mediator in the state of malnutrition that complicates the course of chronic infection and cancer. Termed cachexia, this chronic syndrome inevitably causes the afflicted host to succumb from weight loss, anorexia, and catabolism of protein and lipid. Experimental studies of animals exposed to TNF for protracted periods indicate that this cytokine is capable of causing cachexia, and the biochemical basis for these catabolic changes has been identified. More recent data indicate that the detrimental metabolic effects of TNF are not dependent upon its circulating levels in the bloodstream, but rather are dependent upon its actions locally in vital organs (e.g., brain). Thus, the metabolic basis for cachexia in infection may be largely dependent upon the amount of cytokine produced in metabolically important tissues. As a result, circulating TNF levels in cachectic patients may not accurately reflect the metabolic state of the host, and do not correlate to weight loss.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Tumor necrosis factor in metabolism of disease: hormonal actions versus local tissue effects.

Tumor necrosis factor is a cytokine that participates in the mediation of numerous diseases associated with inflammation, cachexia, shock, and tissue injury. Early studies of the biology of TNF delineated its hormonal actions as well as its systemic toxicity. More recent investigations have drawn attention to its paracrine actions that predominate when it is produced locally in the brain or vital organs. For instance, when compartmentalized production of TNF occurs in the central nervous system it directly mediates fever, anorexia, and altered whole-body metabolism. Since these changes are mediated within the neural network they occur independently of simultaneously sampled serum TNF levels. These paracrine actions of TNF have implications for diseases associated with production of TNF in tissues (e.g. HIV cerebritis, multiple sclerosis, cerebral malaria and cancer), because they may differ markedly from the hormone like-actions associated with systemic release. Since TNF may be beneficial in some diseases yet injurious in others, both the hormonal and paracrine actions must be precisely defined in order to formulate novel treatment strategies based on either enhancing its useful effects, or suppressing toxicity.

Animals↗
PubMed1991

Long-term inhibition of tumor growth by tumor necrosis factor in the absence of cachexia or T-cell immunity.

The relationship between detrimental (cachectic) and beneficial (antitumor) effects of tumor necrosis factor (TNF) was studied in mice bearing murine tumors transfected to secrete human TNF. In vitro, the TNF-producing transfectants were resistant to the secreted TNF and grew at rates similar to those of untransfected cells or transfected cells that did not secrete TNF. However, tumors formed by the TNF-secreting cells in vivo remained much smaller than the nonsecreting (transfected and untransfected) tumors. This inhibition of tumor growth required only relatively low serum levels of TNF, persisted for many weeks, and was independent of T cells since it occurred in nude mice. Growth of the TNF-secreting tumors increased dramatically after treatment with anti-human TNF antibody, indicating that extracellular TNF secreted by the tumor cells was necessary for the tumor inhibition. Severe weight loss characteristic of cachexia only occurred in animals with very high serum TNF levels (250 pg/ml) and could be prevented or reversed by anti-TNF antibody treatment. These data are consistent with the existence of a therapeutic window in which persistent exposure to human TNF can lead to prolonged inhibition of tumor growth in the absence of T-cell immunity or severe weight loss and without development of resistant tumor variants.

Animals↗
PubMed1991

Advanced glycosylation products quench nitric oxide and mediate defective endothelium-dependent vasodilatation in experimental diabetes.

Nitric oxide (an endothelium-derived relaxing factor) induces smooth muscle relaxation and is an important mediator in the regulation of vascular tone. Advanced glycosylation end products, the glucose-derived moieties that form nonenzymatically and accumulate on long-lived tissue proteins, have been implicated in many of the complications of diabetes and normal aging. We demonstrate that advanced glycosylation products quench nitric oxide activity in vitro and in vivo. Acceleration of the advanced glycosylation process in vivo results in a time-dependent impairment in endothelium-dependent relaxation. Inhibition of advanced glycosylation with aminoguanidine prevents nitric oxide quenching, and ameliorates the vasodilatory impairment. These results implicate advanced glycosylation products as important modulators of nitric oxide activity and endothelium-dependent relaxation.

Animals↗
PubMed1991

Tumor necrosis factor (cachectin) in the biology of septic shock syndrome.

The high mortality of septic shock syndrome has prompted extensive investigation into its pathogenesis. Tumor necrosis factor (TNF), a cytokine that is often over-produced during Gram-negative or Gram-positive infection, occupies a critical role in triggering this catastrophic illness. The net effects of TNF are dependent upon its concentration in certain vital tissues, and may be dissociated from the presence of the invading pathogens. Agents that inhibit TNF have been developed; these protect against shock and tissue injury and are currently being investigated in clinical trials of septic shock syndrome.

Animals↗
PubMed1990

Cytokine production in a model of wound healing: the appearance of MIP-1, MIP-2, cachectin/TNF and IL-1.

Macrophages are essential for normal wound repair and many of their effects on healing wounds are likely to be mediated by the secretion of cytokines. This study examines the appearance of messenger RNA (mRNA) for cachectin/tumor necrosis factor (TNF), IL 1, and macrophage inflammatory proteins 1 and 2 (MIP-1 and MIP-2), as well as the mature peptides, in a model of wound healing using wound chambers. RNA for all four cytokines can be detected in wound inflammatory cells by polymerase chain reaction amplification throughout the first 7 days. Cachectin/TNF and IL 1 protein levels peaked on the first day after wound chamber implantation, and MIP-1 and MIP-2 were detected only on day 3. The data suggest that these cytokines participate in the early inflammatory response to wounding.

Animals↗
PubMed1990

Metabolic responses to cachectin/TNF. A brief review.

Cachectin/tumor necrosis factor (TNF-alpha) is a macrophage-secreted cytokine initially found to be a lipoprotein lipase-suppressing serum factor in cachectic, parasite-infected animals. Cloning of the cDNA encoding the gene for cachectin enabled biosynthesis of recombinant human cachectin and proof that the protein is identical to TNF-alpha. Numerous biological activities have subsequently been attributed to this pluripotent cytokine. In addition to suppressing LPL, cachectin/TNF mediates decreased lipogenic enzyme synthesis in adipocytes, causing a state of "cellular cachexia" in vitro. Similarly, catabolic cellular energy responses are induced by cachectin/TNF in cultured skeletal muscle cells which exhibit accelerated glycogenolysis, enhanced lactate production, and increased expression of hexose transporters. Persistent cachectin/TNF production occurs in chronic infection and malignancy, and chronic exposure induces a cachexia syndrome characterized by anorexia, weight loss, and anemia. Acute systemic appearance of cachectin/TNF is capable of inducing a state of lethal shock, disseminated hemorrhagic necrosis, catabolic hormone release, and multiple organ injury. Inhibiting the toxic effects of cachectin/TNF with monoclonal anti-cachectin antibodies during overwhelming Gram-negative bacteremia confers protection against septic shock. In these studies, the unprotected controls succumbed within hours, but baboons immunized against cachectin/TNF did not develop the characteristic increases of IL-1, IL-6, or catabolic stress hormones and did not die, suggesting that cachectin/TNF is a pivotal, proximal factor in the humoral cascade mediating septic shock syndrome. Recent evidence indicates that when produced in lesser quantities, cachectin/TNF may participate in the degradative and reparative mechanisms of physiological tissue remodelling and homeostasis. Future studies of the immunological and metabolic effects of cachectin/TNF should lead to a better understanding of the pathogenesis of infection and inflammation.

Animals↗
PubMed1990

Metabolic effects of cachectin/tumor necrosis factor are modified by site of production. Cachectin/tumor necrosis factor-secreting tumor in skeletal muscle induces chronic cachexia, while implantation in brain induces predominantly acute anorexia.

We have developed a murine model of wasting by injecting intracerebrally cells which continuously secrete h-cachectin/TNF (CHO-TNF) to: (a) determine the effects of cachectin/TNF produced continuously in the central nervous system (CNS), and (b) compare the metabolic effects of cachectin/TNF-secreting tumor in the brain to the cachexia caused by CHO-TNF tumor in peripheral tissue (IM). Intracerebral CHO-TNF tumors produced increased serum h-cachectin/TNF levels with lethal hypophagia and weight loss (mean survival time of 11 d); these changes were not observed in association with nonsecretory control brain tumors. The metabolic consequences of intracerebral cachectin/TNF production were indistinguishable from acute, lethal starvation: whole-body lipid content was decreased significantly but protein was conserved. Although intramuscular cachectin/TNF-secreting tumors caused similar increases of serum h-cachectin/TNF levels, profound anorexia did not develop; wasting developed after a longer period of tumor burden (50 d) with classical signs of cachexia (i.e., anemia and depletion of both protein and lipid). These studies provide a reproducible animal model of site-specific cytokine production and suggest that, regardless of serum levels, cachectin/TNF produced locally in brain influences both the rate of development of wasting and its net metabolic effects.

Animals↗
PubMed1990

Influence of enterectomy on peripheral tissue glutamine efflux in critically ill patients.

Glutamine and alanine are dominant nitrogen carriers from skeletal muscle stores to splanchnic organs. In addition, these amino acids may also serve as a primary energy source for the gastrointestinal tract during injury. To investigate these contributions, we studied extremity amino acid efflux during hypocaloric dextrose feedings and during total parenteral nutrition in a population of normal volunteers (NL VOL) (n = 9), a group of patients with sepsis who had undergone laparotomy without bowel resection and were in the intensive care unit (ICU) (n = 7), and patients with sepsis after laparotomy (PT) (n = 2) who had recently undergone greater than 80% bowel resection. Circulating alanine and glutamine levels were significantly lower in the patients compared with NL VOL under both feeding conditions. The peripheral output of alanine was higher in the ICU group than in the NL VOL during hypocaloric feedings. Glutamine efflux, however, was independent of either the counterregulatory hormone or substrate background. By contrast, enterectomy was associated with a marked decrease of extremity glutamine efflux compared with NL VOL or the ICU patients who did not undergo enterectomy (-62 +/- 9 nmol/min/dl tissue in the PT vs -265 +/- 32 nmol/min/dl tissue in the NL VOL and -311 +/- 58 nmol/min/dl tissue in the ICU group) during the dextrose feedings; this difference persisted during subsequent total parenteral nutrition (+12 +/- 13 nmol/min/dl tissue in PT vs -178 +/- 56 nmol/min/dl tissue in the NL VOL and -287 +/- 81 nmol/min/dl tissue in the ICU group). These data suggest that distinct mechanisms regulate peripheral alanine and glutamine balance and that the gastrointestinal tract provides a feedback signal to peripheral tissues to maintain glutamine mobilization under both nonstressed and stressed conditions.

Adult↗
PubMed1990

Serum cachectin/tumor necrosis factor in critically ill patients with burns correlates with infection and mortality.

Serum cachectin/tumor necrosis factor (TNF), a cytokine implicated in the pathogenesis of septic shock, may appear in the circulation during serious infection, but the frequency of detection of elevated serum levels during protracted critical burn injury is unknown. Serial serum samples taken from 43 critically ill patients with burns with and without sepsis were analyzed for TNF using an enzyme-linked immunosorbent assay (ELISA). TNF was detectable (greater than 34 picograms per milliliter) at one or more time points in 69 per cent of the patients with sepsis versus 33 per cent of those without sepsis, in 71 per cent of the patients who died versus only 31 per cent of the survivors and in only one healthy normal control patient (n = 21). The frequency of the appearance of TNF correlated with both infection and mortality rate. Moreover, all three patients with TNF levels greater than 540 picograms per milliliter died. Neither the size of the burn nor injury from inhalation correlated with detection of TNF. A subset of 16 patients was studied longitudinally from admission until resolution of injury and these data demonstrate that TNF appears transiently and repetitively in the circulation of patients during infection and protracted critical burn injury. Also, serum cortisol levels were significantly higher during sepsis and death in the absence of serum TNF, compared with sepsis and death with detectable cachectin, suggesting that cortisol may interact with the production or detection of this cytokine during ongoing infection and lethal injury. In this study, we have demonstrated that serum TNF is detectable with greater frequency and in higher concentration in patients with sepsis and in those who ultimately succumb to the burn injury, that serum TNF appears transiently and repetitively in the circulation during injury and that higher serum cortisol levels are correlated with the absence of serum TNF during sepsis and lethal injury.

Burns↗
PubMed1989

Antibodies to cachectin/tumor necrosis factor reduce interleukin 1 beta and interleukin 6 appearance during lethal bacteremia.

Cytokines secreted in response to invading micro-organisms are important mediators of detrimental hemodynamic and metabolic changes in the host. To test whether cachectin/TNF plays a role in triggering release of other cytokines in the setting of infection, anesthetized baboons were passively immunized against systemic cachectin/TNF before infusion of a LD100 dose of live Escherichia coli. Bacteremia led to significant increases in circulating levels of cachectin/TNF, IL-1 beta, and IL-6. Although bacterial endotoxin/lipopolysaccharide is a potent stimulus for the synthesis and release of IL-1 and IL-6 in vitro, specific neutralization of cachectin/TNF in vivo with mAb pretreatment significantly attenuated both the IL-1 beta and the IL-6 responses despite fulminant overwhelming bacteremia. These data suggest that cachectin/TNF is essential for the initiation or amplification of IL-1 and IL-6 release during lethal gram-negative septic shock syndrome.

Animals↗
PubMed1989

Cachectin/tumor necrosis factor and other cytokines in infectious disease.

The studies reviewed here represent but a fraction of those published in the field last year, but they serve to illustrate two important points: (1) the cytokine network possesses enormous diversity of biological function, and (2) it is redundant, such that overlapping and synergistic effects are observed between many different cytokines. The impact of this system on the host is pervasive and readily amplifiable, and integrates the diverse responses to infectious disease which may be either beneficial, protecting against infection, or deleterious, causing tissue injury and death. The example of cachectin/TNF illustrates this type of scenario: during local infection or inflammation, low levels of cachectin/TNF act to enhance immune responsiveness, stimulate blood-vessel growth, increase energy mobilization, induce the release of other cytokines, and promote wound-healing; when overwhelming infection occurs, as in septicemia, large quantities of cachectin/TNF reach the circulation and cause shock, MSOF, and death; if a persisting infection develops and cachectin/TNF is chronically secreted, it mediates a state of cachexia which may be fatal. Future studies will undoubtedly advance our understanding of these effects, and that of the other cytokines. The development of novel therapies for inflammation, septic shock, and cachexia may be based on such advances.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Exercise-mediated peripheral tissue and whole-body amino acid metabolism during intravenous feeding in normal man.

1. The effect of a daily submaximal exercise regimen on whole-body and peripheral tissue amino acid metabolism during weight-stable intravenous feeding (IVF) was evaluated in 11 normal volunteers. Five of the subjects performed 1 h of daily bicycle exercise at 75 W during IVF, while the remaining six subjects received IVF without daily exercise. Body nitrogen balance, leg and forearm plasma amino acid flux and whole-body kinetics were measured before and on day 10 of IVF using a [1-13C]leucine and [15N]glycine tracer. 2. At the end of the IVF period, exercised subjects demonstrated leg uptake of total amino acids (237 +/- 103 nmol min-1 100 ml-1 of tissue, mean +/- SEM) which was significantly (P less than 0.05) different than in non-exercised subjects (-1101 +/- 253 nmol min-1 100 ml-1 of tissue). 3. In the non-exercised forearm, a significant (P less than 0.05) decrease in total amino acid flux was observed in exercised subjects (-162 +/- 88 nmol min-1 100 ml-1 of tissue) compared with non-exercised subjects (-460 +/- 105 nmol min-1 100 ml-1 of tissue) on day 10 of IVF. 4. Efflux of 3-methylhistidine significantly (P less than 0.05) decreased from the leg in those subjects who performed daily exercise (-0.29 +/- 0.12 nmol min-1 100 ml-1 of tissue) compared with those subjects receiving IVF without daily exercise (-1.46 +/- 0.35 nmol min-1 100 ml-1 of tissue).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗