Infusion Of TNF-alpha Research Articles

Tumor necrosis factor's effects on lung mechanics, gas exchange, and airway reactivity in sheep

The macrophage- and monocyte-produced cytokine tumor necrosis factor alpha (TNF alpha) has been proposed as a major mediator of endotoxin-induced injury. To determine if TNF alpha could reproduce the effects of endotoxin on the lung, we intravenously administered 10 micrograms/kg of human recombinant TNF alpha into five chronically instrumented unanesthetized sheep on two occasions to characterize the TNF alpha response and its reproducibility. We assessed changes in lung mechanics, pulmonary and systemic hemodynamics, gas exchange, and the number and type of peripheral blood leukocytes. We also determined airway reactivity by use of aerosolized histamine before and after TNF alpha infusion. Pulmonary arterial pressure (Ppa) peaked within 30 min of initiating the TNF alpha infusion [47.7 +/- 2.2 vs. 15.9 +/- 0.4 (SE) cmH2O at base line] and then returned toward base line over 4 h. There was a brief decline in left atrial pressure after TNF alpha. Pulmonary hypertension was accompanied by leukopenia, neutropenia, and increases in the alveolar-arterial O2 difference (AaDO2). Dynamic lung compliance (Cdyn) declined after TNF alpha, reaching a nadir within 15 min of the initiation of the TNF alpha infusion [0.045 +/- 0.007 vs. 0.093 +/- 0.007 (+/- SE) l/cmH2O at base line]. Resistance to airflow across the lung (RL) increased from 1.2 +/- 0.2 cmH2O.l-1.s at base line, peaking at 5.4 +/- 1.3 cmH2O.l-1.s 30 min after the start of the TNF alpha infusion. Alterations in Cdyn and RL persisted for 4 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Tumor Necrosis Factor-Induced Neonatal Pulmonary Hypertension: Effects of Dazmegrel Pretreatment

The endogenously produced cytokine, tumor necrosis factor-alpha (TNF-alpha), has been shown in adult animal models to be associated with many of the pathophysiologic effects of sepsis, including systemic hypotension and hemorrhagic necrosis. TNF-alpha can induce the release of various vasoactive arachidonic acid metabolites, suggesting that TNF-alpha may act either directly or via intermediary substances in producing its effects. The pathophysiologic role of TNF-alpha in neonatal sepsis, especially its potential effect on pulmonary vascular tone, is presently unknown. To assess the role of TNF-alpha in neonatal sepsis, 19 piglets (19 +/- 5 d old) were anesthetized, intubated, paralyzed, mechanically ventilated, and catheterized to assess pulmonary and systemic vascular hemodynamics and pulmonary gas exchange. The multiple inert gas elimination technique was used to assess ventilation perfusion matching. A 30-min infusion of human recombinant TNF-alpha (250 micrograms/kg total dose) was administered to animals pretreated with either 10 mg/kg dazmegrel, a thromboxane synthase inhibitor (n = 9) or placebo (n = 10). TNF-alpha alone induced a prompt and sustained rise in pulmonary arterial pressure and pulmonary vascular resistance that continued at least for 2 h after onset of the infusion. In contrast, the animals pretreated with dazmegrel demonstrated no rise in pulmonary vascular resistance until 2 h after the onset of the infusion. Neither group of animals demonstrated a significant decline in arterial PO2 or evidence from inert gas analysis of VA/Q mismatching or increase in intrapulmonary shunt.(ABSTRACT TRUNCATED AT 250 WORDS)

Tumor Necrosis Factor and Hypermetabolism

Letters and Corrections1 May 1990Tumor Necrosis Factor and HypermetabolismTimothy B. Seaton, MD, Nancy Coombe, Abraham Mittelman, MDTimothy B. Seaton, MDSearch for more papers by this author, Nancy CoombeSearch for more papers by this author, Abraham Mittelman, MDSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-112-9-715_2 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptTo the Editor: The role of tumor necrosis factor (cachectin) in the pathogenesis of cachexia from cancer and other chronic diseases remains to be fully explored. Tumor necrosis factor (TNF) inhibits lipoprotein lipase in vitro and causes depletion of fat stores and muscle wasting in animal models (1). We suggest that TNF may also be responsible for alterations in resting metabolic rate.We measured the resting metabolic rate and respiratory quotient in the fasting state by indirect calorimetry in two patients receiving a 24-hour infusion of human recombinant TNF-alpha (200 µg/m2body surface area daily) as part of a phase...

Metabolic effects of tumour necrosis factor alpha in NMRI mice

Following a single injection of 7.5 x 10(7) U kg-1 of human recombinant tumour necrosis factor-alpha (TNF-alpha) to female NMRI mice, marked hypoglycaemia was observed within a 2 h period, accompanied by a severe depletion of liver glycogen and a drop in rectal body temperature when compared with pair-fed controls. There was no alteration in plasma alanine, lactate or pyruvate values, but an elevation of acetoacetate and 3-hydroxybutyrate when compared with pair-fed controls. Production of 14CO2 from U-14C-glucose was reduced in TNF-alpha treated animals, while production of 14CO2 from U-14C-palmitate was not significantly different from controls, suggesting that the glucose was not being used to provide an increased metabolic rate. Glucose utilisation by different tissues was investigated by the 2-deoxyglucose tracer method. This showed that 2 h following TNF-alpha infusion glucose utilisation was increased in colon, liver, kidney and spleen by 500, 350, 36 and 25% respectively. However, when calculated on a whole-animal basis the major contributor to the increased glucose consumption was the liver. Plasma levels of both FFA and triglycerides were also elevated in TNF-alpha treated animals, suggesting that increased consumption of glucose by the liver may be utilised for lipogenesis. The rate of conversion of glucose into lipids in the liver was more than doubled 2 h after TNF-alpha administration with a concomitant rise in plasma and adipose tissue. These results suggest that administration of TNF-alpha produces a severe hypoglycaemia in order to serve an increased lipogenesis in liver and adipose tissue, which appears to be independent of the anorectic effect.

Human recombinant tumor necrosis factor alpha infusion mimics endotoxemia in awake sheep.

The macrophage-derived cytokine tumor necrosis factor alpha (TNF alpha) has been proposed as the major mediator of endotoxin-induced injury. To examine whether a single infusion of human recombinant TNF alpha (rTNF alpha) reproduces the pulmonary effects of endotoxemia, we infused rTNF alpha (0.01 mg/kg) over 30 min into six chronically instrumented awake sheep and assessed the ensuing changes in hemodynamics, lung lymph flow and protein concentration, and number of peripheral blood and lung lymph leukocytes. In addition, levels of thromboxane B2, 6-ketoprostaglandin F1 alpha, prostaglandin E2, and leukotriene B4 were measured in lung lymph. Pulmonary arterial pressure (Ppa) peaked within 15 min of the start of rTNF alpha infusion [base-line Ppa = 22.0 +/- 1.5 (SE) cmH2O; after 15 min of rTNF alpha infusion, Ppa = 54.2 +/- 5.4] and then fell toward base line. The pulmonary hypertension was accompanied by hypoxemia and peripheral blood and lung lymph leukopenia, both of which persisted throughout the 4 h of study. These changes were followed by an increase in protein-rich lung lymph flow (base-line lymph protein clearance = 1.8 +/- 0.4 cmH2O; 3 h after rTNF alpha infusion, clearance = 5.6 +/- 1.2), consistent with an increase in pulmonary microvascular permeability. Cardiac output and left atrial pressure did not change significantly throughout the experiment. Light-microscopic examination of lung tissue at autopsy revealed congestion, neutrophil sequestration, and patchy interstitial edema. We conclude that rTNF alpha induces a response in awake sheep remarkable similar to that of endotoxemia. Because endotoxin is a known stimulant of TNF alpha production, TNF alpha may mediate endotoxin-induced lung injury.