Infusion Of Tumor Necrosis Factor-alpha Research Articles

Pathophysiology of Hypertension During Preeclampsia: Role of Inflammatory Cytokines

Preeclampsia is defined as new onset hypertension with proteinuria during pregnancy. The initiating event in preeclampsia is postulated to be reduced uteroplacental perfusion which leads to widespread dysfunction of the maternal vascular endothelium. Inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF alpha) are thought to be important links between placental ischemia and cardiovascular and renal dysfunction. Supporting a potential role of cytokines in preeclampsia are findings that plasma levels of TNF and IL-6 are elevated in women with preeclampsia. Important blood pressure regulatory systems such as the renin-angiotensin system, sympathetic nervous system, and endothelial factors interact with pro-inflammatory cytokines such as IL-6 and TNF. Pro-inflammatory cytokines also affect vascular function and endothelium-derived factors involved in blood pressure regulation. Thus, endothelial dysfunction associated with preeclampsia may be mediated by cytokines. Recent studies have indicated that chronic reductions in placental perfusion in pregnant animals are associated with enhanced production of inflammatory cytokines, such as TNF alpha and IL-6. In addition, chronic infusion of either TNF alpha or IL-6 into normal pregnant rats results in significant increases in arterial pressure and a decrease in renal hemodynamics. TNF alpha activates the endothelin system in placenta, renal and vascular tissues whereas IL-6 stimulates the renin-angiotensin system. Collectively, these findings suggest that inflammatory cytokines play a role in causing hypertension in response to chronic reductions in uterine perfusion during pregnancy by activating multiple neurohumoral and endothelial factors. Keywords: endothelin (ET-1), IL-6, tumor necrosis factor (TNF) alpha, rennin-angiotensin system (RAS), angiotensin II

Low-dose prostacyclin has potent capillary permeability-reducing effect in cat skeletal muscle in vivo.

The dose-response effects of intravenous infusion of prostacyclin on capillary permeability (the capillary filtration coefficient technique), hydrostatic capillary pressure, transcapillary filtration, and vascular tone were analyzed in vivo on cat skeletal muscle from a normal and an increased permeability level. Increased permeability was accomplished by intra-arterial infusion of tumor necrosis factor-alpha or histamine. Permeability effects of bradykinin were also analyzed. Prostacyclin decreased capillary permeability by 8% at a dose of 0.1 ng.kg-1.min-1 and at most by 30% below control attained at 2 ng.kg-1.min-1, also with no effect on vascular tone and hydrostatic capillary pressure. The permeability increase by tumor necrosis factor-alpha and histamine (by 54 and 73%) was more than counteracted by the simultaneous infusion of prostacyclin at 2 ng.kg-1.min-1. The vasodilator effect of tumor necrosis factor-alpha was also restituted. Indomethacin (prostacyclin inhibitor)-induced increase in capillary permeability (25%) was more than restituted by prostacyclin at 2 ng.kg-1.min-1. Surprisingly, bradykinin decreased capillary permeability. We conclude that endogenous prostacyclin may be a physiological regulator of capillary permeability and that low-dose prostacyclin infusion may have clinical relevance in states of increased permeability.

Experimental liver cancer: Improved response after hepatic artery ligation and infusion of tumor necrosis factor-alpha and interferon-gamma

The aim of this study is to investigate whether regional infusion of tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) could improve the therapeutic results of hepatic artery ligation (HAL) on liver cancer in a rat model. Morris hepatoma 3924A was implanted intrahepatically in 50 ACI rats. Two weeks after tumor implantation, 40 rats underwent hepatic artery cannulation and ligation. The cannula was connected to an infusion port implanted subcutaneously. Animals were then divided into four groups of 10 each to receive seven daily intraarterial injections of IFN-gamma 100,000 IU/rat/day (HAL + IFN group), TNF-alpha 30 micrograms/rat/day (HAL + TNF group), IFN + TFN (HAL + IFN + TNF group), or normal saline solution (HAL group). The remaining 10 rats received a laparotomy only and served as untreated controls. Tumor volume, viable tumor area, and histopathology were assessed after 3 weeks. The tumor growth was significantly retarded in the HAL group compared with the controls (tumor volume 683 +/- 245 mm3 vs 2424 +/- 596 mm3, p < 0.05 ANOVA). HAL + TNF (221 +/- 93 mm3) and HAL + IFN + TNF groups (74 +/- 31 mm3), but not the HAL + IFN group (493 +/- 164 mm3), were much more effective than the HAL group in controlling tumor growth (p < 0.05). HAL + IFN + TNF achieved the best tumor control resulting in a 60% tumor-free rate (p < 0.05 vs all other groups). These data suggest that HAL combined with regional infusion of TNF-alpha and IFN-gamma significantly reduces tumor growth in a rat liver model. This attractive concept of combined modality therapy may have utility in the clinical setting in instances of unresectable liver cancer.

Effect of tumor necrosis factor-alpha on triglyceride and phospholipid content and fatty acid composition of liver and carcass in rats.

We have previously shown that a continuous infusion of tumor necrosis factor-alpha (TNF-alpha) in rats results in an increase in plasma triglyceride (TG), liver protein and DNA, and at the same time a reduction in muscle protein. However, there is no information on the associated effects of TNF-alpha on liver and muscle lipids. The present study, therefore, determined the effect of TNF-alpha on the TG and phospholipid (PL) content and their fatty acid composition, in the liver and carcass of rats and correlated with the plasma levels of insulin, corticosterone, and catecholamines. Total parenteral nutrition that met the daily nutrient requirements was continuously infused for 10 d through a central vein catheter in two groups of rats, one receiving infused TNF-alpha (100 micrograms/kg/d) and a control group. Hepatic TG and PL, expressed either as mg/g dry weight or total organ content, were significantly increased in the TNF-alpha-infused group compared with controls. Livers of TNF-alpha infused rats contained significantly less saturated and monounsaturated fatty acids and significantly more polyunsaturated fatty acids (PUFA) of the omega 3 and omega 6 series than controls. The carcass, on the other hand, contained significantly more monounsaturated and significantly less polyunsaturated fatty acids of the omega 6 series than controls. There were no changes in corticosterone level. Although plasma glucose levels were comparable between control and TNF-alpha infused rats, the latter had a marked increase in insulin levels, demonstrating insulin resistance. In addition TNF-alpha infused rats had raised norepinephrine levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Synergism between IL-1 beta and TNF-alpha on the activity of the pituitary-adrenal axis and on food intake of rats.

We investigated the effects of separate and combined intraperitoneal administration for 3 days of recombinant human interleukin-1 beta (IL-1) and recombinant human tumor necrosis factor-alpha (TNF) on plasma adrenocorticotropic hormone (ACTH) and corticosterone (B) levels, adrenal weight, food intake, and rectal temperature. Rats were equipped with a jugular cannula for daily blood sampling and with an intraperitoneally implanted Alzet osmotic minipump loaded with either saline, IL-1 (2.0 micrograms/day), TNF (0.2, 2.0, or 10.0 micrograms/day), or IL-1 in combination with TNF. Plasma ACTH and B levels and adrenal weight were significantly increased, in a dose-dependent way, by simultaneous infusion of IL-1 and TNF but not by administration of either cytokine alone. Chronic administration of IL-1 alone induced a significant decrease in food intake and a significant elevation of rectal temperature, whereas infusion of only the highest dose of TNF significantly elevated rectal temperature. Coinfusion of IL-1 and TNF induced both effects in a dose-dependent and synergistic way. Our data show that simultaneous infusion of IL-1 and TNF in rats has a synergistic effect on the activity of the pituitary-adrenal axis as well as on food intake and rectal temperature. The existence of two pathways, which act synergistically, may increase the sensitivity of the host to respond to subtle inflammatory stimuli.

Cardiopulmonary effects of tumor necrosis factor-alpha in the piglet: influence of cyclooxygenase inhibition.

Tumor necrosis factor-alpha (TNF) is believed to play an important role in mediating many of the pathophysiologic changes accompanying bacterial sepsis. In order to characterize the cardiopulmonary responses to TNF in a young animal model and to determine to what extent these changes were secondary to cyclooxygenase byproducts, three groups of mechanically ventilated piglets received an infusion of either TNF, indomethacin followed by TNF (Indo+TNF) or neither (control). Compared to controls at 120 min, TNF resulted in the following changes beginning 30-60 min after the infusion began: mean pulmonary artery pressure (Ppa) increased from 1.7 +/- 0.3 to 4.4 +/- 0.7 kPa (13 +/- 2 to 33 +/- 5 mm Hg) (p < 0.001); cardiac output (CO) fell from 0.28 +/- 0.05 to 0.20 +/- 0.07 liters/kg/min (p < 0.01); mean arterial blood pressure (Psa) decreased from 9.5 +/- 1.2 to 7.9 +/- 1.9 kPa (71 +/- 9 to 59 +/- 14 mm Hg) as did pH from 7.49 +/- 0.04 to 7.13 +/- 0.17 (p < 0.001). Dynamic lung compliance (Cdyn) also decreased; however, pulmonary resistance (RI) remained unchanged. Thromboxane B2 (TxB2) rose in all animals at 60 min coincident with Psa elevation and was significantly blocked by Indo (p < 0.03). In the Indo+TNF group the early TNF-induced rise in Psa was blunted compared to the TNF group [2.9 +/- 1.2 vs. 3.6 +/- 0.8 kPa (22 +/- 3 vs. 27 +/- 6 mm Hg; p < 0.04)] as were the late decreases in pH and Psa (p < 0.04). There were no significant changes in Cdyn secondary to Indo. Although delayed, the hemodynamic changes observed with TNF infusion are similar to those reported for piglets receiving group B streptococci; however, in contrast to the latter the early changes secondary to TNF are only mildly effected by indomethacin. The significant improvement in the late occurring hypotension and acidosis suggests that TNF may act in part via the cyclooxygenase pathway as a mediator of the late hypotension associated with sepsis.

Decrease in left ventricular contractility after tumor necrosis factor-alpha infusion in dogs

Whether systolic contractility or diastolic compliance changes soon after tumor necrosis factor-alpha (TNF-alpha) exposure is not known. Accordingly, we measured hemodynamics, left ventricular contractility using the slope of the end-systolic pressure-volume relationship, and diastolic pressure-volume relationships in six control dogs and in six dogs receiving 60 micrograms.kg-1.h-1 i.v. of TNF-alpha. Mean aortic pressure decreased by 22% 1 h after TNF-alpha infusion and remained decreased (P < 0.05). Cardiac output increased by 19% 1 h after TNF-alpha infusion and remained significantly greater than control values (P < 0.05). Left ventricular contractility decreased by 23% (P < 0.05) 1 h after TNF-alpha infusion and decreased by 52% (P < 0.01) 5 h after TNF-alpha infusion. The diastolic pressure-volume relationship did not change in the TNF-alpha group or the control group. Ejection fraction did not change after TNF-alpha infusion despite the decrease in contractility because afterload decreased. We conclude that TNF-alpha is important in causing the hypotensive, hyperdynamic circulation of sepsis. The new finding that left ventricular contractility is decreased shortly after TNF-alpha infusion suggests that TNF-alpha, or another mediator released very soon after TNF-alpha, is an important myocardial depressant factor.

Left ventricular systolic and diastolic dysfunction after infusion of tumor necrosis factor-alpha in conscious dogs.

We used a load-insensitive index of systolic left ventricular (LV) function and an analysis of diastolic pressure-dimension relationships to test the hypothesis that recombinant human (rh) tumor necrosis factor-alpha (TNF alpha) impairs LV function in dogs. Animals were studied 7-10 d after aseptic implantation of instrumentation to monitor cardiac output, external anterior-posterior LV diameter, and LV and pleural pressures. Data were analyzed from seven dogs that received active rhTNF alpha (100 micrograms/kg over 60 min) and from five dogs that received heat-inactivated rhTNF alpha. At 24 h after infusion of active rhTNF alpha, the slope of the LV end-diastolic dimension-stroke work relationship decreased significantly, indicating a decrement in LV systolic contractility. Simultaneously, LV unstressed dimension increased significantly, suggesting diastolic myocardial creep. The end-diastolic relationship between LV transmural pressure and normalized LV dimension (strain) was markedly displaced to the left, suggesting increased diastolic elastic stiffness. Despite these changes in LV performance, cardiac index was maintained by tachycardia. The abnormalities in LV function were resolved by 72 h. We conclude that rhTNF alpha reversibly impairs LV systolic and diastolic function in unanesthetized dogs. Because dysfunction occurs greater than 6 h after the infusion of rhTNF alpha and persists for 24-48 h, the mechanism underlying this phenomenon may involve secondary mediators or a change in myocardial gene expression.