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Biomedical subjects

S F Lowry

Publications and source records attributed to S F Lowry.

At least 127 records · Page 7Linked to original sources
PubMed1989

Anticachectin/tumor necrosis factor-alpha antibodies attenuate development of cachexia in tumor models.

C57BL/6 mice bearing either a transplantable methylcholanthrene-induced sarcoma or Lewis lung adenocarcinoma were passively immunized every other day with a rabbit immunoglobulin fraction raised against murine cachectin/tumor necrosis factor-alpha. Mice bearing methylcholanthrene-induced sarcoma developed tumor-associated hypophagia that was attenuated by anticachectin immunoglobulin treatment. In the same tumor-bearing animals, anticachectin treatment also significantly reduced the extent of carcass protein and fat loss, and reduced tumor weight. Mice bearing Lewis lung adenocarcinoma did not develop significant anorexia or carcass lean tissue depletion as tumor growth progressed, but they lost carcass lipid. Treatment of Lewis lung adenocarcinoma bearing mice with anticachectin antibodies diminished the degree of carcass lipid depletion and prevented plasma hypertriglyceridemia. However, in both tumor models, anticachectin treatment did not affect either the development of anemia, hypoalbuminemia or the increase in serum amyloid P concentrations seen with increasing tumor burden. We conclude that an endogenous cachectin response, inhibitable by exogenously administered antibody, contributes to anorexia and to changes in body fat and protein metabolism in these tumor-bearing animals. Neutralizing endogenous cachectin production with antibodies offers the potential to reduce tissue wasting that is frequently associated with neoplastic disease, but it does not appear to affect all of the hematologic and acute phase responses in these murine tumor models.

Adenocarcinoma↗
PubMed1989

Peripheral blood leukocyte kinetics following in vivo lipopolysaccharide (LPS) administration to normal human subjects. Influence of elicited hormones and cytokines.

Lipopolysaccharide (LPS, endotoxin) administration to human subjects elicits significant elevations in plasma cachectin/TNF, epinephrine, and cortisol. This study examined the temporal relationship between changes in blood leukocyte subsets and plasma mediators following endotoxin administration to normal human subjects. A five-minute intravenous infusion of purified LPS (20 units/kg Escherichia coli) was administered to 12 healthy volunteers. Blood samples were obtained at varying intervals after infusion and analyzed for differential cell counts and lymphocyte subsets (CD2, CD3, CD4, CD8, CD20, and HLA-DR) by flow microfluorimetry, and also assayed for plasma cachectin/TNF, epinephrine, and cortisol. Plasma cachectin/TNF was significantly elevated at 75 and 90 minutes after infusion with a peak concentration of 261 +/- 115 pg/ml noted 75 minutes after infusion. A significant plasma epinephrine elevation of 181 +/- 75 pg/ml was demonstrated one hour after infusion, while significant elevations in plasma cortisol were noted from one to five hours after infusion with a peak level of 34 +/- 3 micrograms/dl three hours after infusion. A profound monocytopenia (p less than 0.01) was noted one hour after infusion. Temporally associated with the rise in plasma cortisol was a reversal of the early granulocytopenia to a significant granulocytosis (p less than 0.01 versus preinfusion mean), whereas a marked lymphocytopenia (p less than 0.01) was observed from one to six hours after infusion. During the period of hypercortisolemia, CD2, CD3, and CD4 lymphocyte percentages were decreased (p less than 0.01) while CD20 and HLA-DR lymphocyte percentages were increased (p less than 0.01). There was a small percentage decrease in CD8 lymphocytes from one to 24 hours after infusion (p less than 0.01), although relative to the one-hour nadir, there was a significant rise in the percentage during the time of elevated plasma cortisol concentrations. A six-hour infusion of epinephrine (30 ng/kg/min) administered to six healthy volunteers resulted in a monocytosis (p less than 0.05) and granulocytosis (p less than 0.01) without a change in lymphocyte number or lymphocyte subset percentage. Previous reports have shown that in vivo corticosteroid infusion causes a prominent granulocytosis, monocytopenia, and lymphocytopenia with a decrease in the percentages of CD3 and CD4 lymphocytes. The peripheral blood leukocyte dynamics documented in the current study are similar to patterns observed following in vivo corticosteroid administration. This study suggests that the acute adrenocortical response to endotoxemia primarily mediates the subsequent changes in leukocyte subsets.

Adult↗
PubMed1989

Total parenteral nutrition and bowel rest modify the metabolic response to endotoxin in humans.

Intestinal mucosal atrophy, as induced by total parenteral nutrition (TPN) and/or prolonged bowel rest, is hypothesized to enhance bowel endotoxin (LPS) translocation and may alter host responses to infection. To examine the effect of TPN-induced bowel atrophy on the response to LPS, 12 healthy volunteers were randomized to receive either enteral feedings (ENT, n = 6) or seven days of TPN without oral intake (TPN, n = 6). Enteral or TPN feedings were terminated 12 hours before the study period when a constant dextrose infusion (50 mg/kg/hour) was initiated and continued throughout the subsequent study period. After placement of arterial, hepatic vein, and femoral vein catheters, metabolic parameters were determined before and for six hours after an intravenous E. coli LPS challenge (20 U/kg). Subsequent peak levels of arterial glucagon (ENT, 189 +/- 39 pg/mL; TPN, 428 +/- 48; p less than 0.01), arterial epinephrine (ENT, 236 +/- 52 pg/mL; TPN, 379 +/- 49; p less than 0.05) and hepatic venous cachectin/tumor necrosis factor (cachectin/TNF) (ENT, 250 +/- 56 pg/mL; TPN, 479 +/- 136; p less than 0.05) were significantly higher in the TPN group than in the ENT group. The extremity efflux of lactate (ENT, -16 +/- 4 micrograms/min-100cc tissue; TPN, -52 +/- 13; t = 2 hours; p less than 0.05) and of amino acids (ENT, -334 +/- 77 nmol/min-100cc tissue; TPN, -884 +/- 58; t = 4 hours; p less than 0.05) were higher in the TPN subjects after the endotoxin challenge. Circulating C-reactive Protein (CRP) levels measured 24 hours postendotoxin were also significantly higher in the TPN subjects (ENT, 1.7 +/- 0.2 mg/dL; TPN, 3.2 +/- 0.3; p less than 0.01). Hence the counter-regulatory hormone and splanchnic cytokine responses to LPS were enhanced after TPN and bowel rest. This is associated with a magnified acute-phase response, peripheral amino acid mobilization, and peripheral lactate production. Thus antecedent TPN may influence the metabolic alterations seen in infection and sepsis via both an exaggerated counter-regulatory hormone response as well as an enhanced systemic and splanchnic production of cytokines.

Adult↗
PubMed1989

Intravenous refeeding blocks growth hormone (GH)-provoked rises in serum free fatty acids and blunting of somatotroph response to GH-releasing hormone in normal men.

We measured the serum GH responses to GHRH (1 micrograms/kg) in six normal men who had been rendered hyperinsulinemic and hypolipidemic by 10 days of total parenteral nutrition (TPN subjects) with a 25% dextrose-amino acid solution. The men underwent GHRH testing after 3 h of infusion of NaCl or Met-human (h) GH (2 micrograms/kg.h). The results of these tests were compared with those of five men tested in the post-absorptive state (PA subjects). The serum GH response to GHRH during NaCl infusion was significantly lower in the TPN subjects than in the PA subjects. During the Met-hGH infusion, the serum GH response to GHRH in the PA subjects was significantly lower than that after the NaCl infusion, whereas in the TPN subjects the response was similar to that during the NaCl infusion. The mean integrated areas under the GH response-time curve after GHRH treatment were 3963 +/- 2086 min/micrograms.L following NaCl infusion and 413 +/- 64 min/micrograms.L following Met-hGH infusion in PA subjects; they were 1127 +/- 500 min/micrograms.L following NaCl infusion and 1456 +/- 682 min/micrograms.L during Met-hGH infusion in the TPN subjects. The Met-hGH infusions resulted in a significant increase in serum FFA concentrations in the PA, but not the TPN, subjects. These results suggest that hyperalimentation induces a metabolic background which inhibits GH secretion, as manifested by a diminished serum GH response to GHRH administered after NaCl infusion. The absent FFA response to Met-hGH infusion in the TPN subjects may explain why the Met-hGH infusion in them did not result in a reduced serum GH response to GHRH as occurred in the PA subjects. Hence, FFA may play an important role in the effects of short term Met-hGH infusion on GH secretion.

Adult↗
PubMed1989

Interleukin-1 alpha and tumor necrosis factor alpha cause placental injury in the rat.

Bacterial endotoxins (LPS) causes placental injury and fetal demise in pregnant animals. Because several biological effects of LPS are mediated by interleukin-1 (IL-1) and tumor necrosis factor (TNF), the hypothesis that these cytokines could cause placental injury similar to that seen in LPS-treated pregnant rats was tested. On day 12 of gestation, rats were injected intraperitoneally with saline, LPS, native or heat-inactivated (HI) rHIL 1 alpha, or rH-TNF alpha. Seven days later, grossly abnormal implantation sites and fetal demise were observed in rats injected with rHIL-1, rHTNF, or LPS but not in those injected with saline or HI-cytokines. Necrosis of placental, decidual, and fetal tissues was observed in cytokine-treated animals. The necrosis was more severe in LPS-treated rats, in which no fetal remains were identifiable. These data suggest that IL-1 and TNF may play a role in the fetoplacental injury observed in LPS-treated pregnant rats.

Animals↗
PubMed1989

Endogenous cachectin/tumour necrosis factor-alpha production contributes to experimental cancer-associated cachexia.

Several lines of investigation suggest that the endogenous synthesis of cachectin contributes to the host changes that occur in cancer. Although serum appearance of cachectin in tumour-bearing animals and patients with cancer cannot be measured with current techniques, there is accumulating evidence to suggest that tissue macrophage production of cachectin is accelerated in organisms with tumours. Production of cachectin, coupled with the simultaneous synthesis of other cytokines that act synergistically with cachectin may explain many of the host changes in the absence of detectable circulating levels.

Cachexia↗
PubMed1988

Appearance of hybridoma growth factor/interleukin-6 in the serum of mice bearing a methylcholanthrene-induced sarcoma.

Serum concentrations of hybridoma growth factor/interleukin-6 progressively increased in mice bearing a transplantable methylcholanthrene-induced sarcoma with tumor growth. Elevated HGF/interleukin-6 concentrations were also positively correlated with increased serum concentrations of the hepatic acute phase reactant protein, amyloid P. Daily Indomethacin treatment of sarcoma-bearing mice prolonged survival and reduced the magnitude of the serum amyloid P response, but failed to attenuate either tumor growth or serum HGF/interleukin-6 responses. Since previous studies have demonstrated that neither interleukin-1 nor tumor necrosis factor-alpha can be detected in the serum of these sarcoma-bearing mice, and that HGF/interleukin-6 is a principal mediator of the hepatic acute phase response, we conclude that circulating HGF/interleukin-6 may contribute significantly to the host responses which accompany experimentally-introduced cancer. Furthermore, prostanoid inhibition does not appear to regulate the synthesis and release of HGF/interleukin-6 during tumor growth.

Animals↗
PubMed1988

Macrophages secrete a novel heparin-binding protein with inflammatory and neutrophil chemokinetic properties.

We report the identification and purification of a new inflammatory monokine synthesized by the macrophage tumor cell line RAW 264.7 in response to endotoxin. This monokine, which we term "macrophage inflammatory protein" (MIP), is a doublet with an apparent molecular mass of approximately 8,000 daltons on SDS-PAGE but forms aggregates of greater than 2 x 10(6) daltons as assessed by gel filtration. Partial NH2-terminal amino acid sequence data reveal no significant homology with any previously described protein. Although the monokine is anionic under physiological conditions, it is one of two major macrophage-secreted proteins that bind to heparin at high salt concentrations. At 100 ng/ml or greater, MIP is chemokinetic for human polymorphonuclear cells and triggers hydrogen peroxide production. Subcutaneous injection of 10 ng or greater of MIP into footpads of C3H/HeJ mice elicits an inflammatory response, characterized by neutrophil infiltration. These findings suggest that MIP is an endogenous mediator that may play a role in the host responses that occur during endotoxemia and other inflammatory events.

Amino Acid Sequence↗
PubMed1988

Cachectin/TNF production in experimental burns and Pseudomonas infection.

Burn injury and infection result in significant losses of lean tissue. The cytokine cachectin/tumor necrosis factor has been implicated in this process but is not uniformly detected during infection. We sought to determine the relationship between body composition changes and in vivo hepatic levels of pretranslational message for cachectin (messenger RNA) in a burn and infection rodent model. Adult Wistar rats were grouped as follows: (1) freely fed, (2) 30% burn, (3) 30% burn with Pseudomonas aeruginosa infection, (4) pair fed, and (5) 30% burn and infection with recombinant cachectin. Compared with controls or animals only burned, burned and infected rats had a 100% increase in hepatic cachectin messenger RNA content, lost carcass protein, and exhibited muscle loss with sparing of liver mass. Tissue production of cachectin as well as other cytokines may be sufficient to mediate several body composition changes observed in response to injury and infection.

Animals↗
PubMed1988

Tumor necrosis factor-enhanced leukotriene B4 generation and chemotaxis in human neutrophils.

In an in vivo study of five normal volunteers infused with endotoxin (20 U/kg of US reference endotoxin lot EC-5), increased neutrophil (PMN) generation of leukotriene B4 and chemotaxis to leukotriene B4 were found concomitantly with elevated plasma tumor necrosis factor (TNF) levels. To clarify the role of TNF in PMN activation, neutrophil responsiveness after in vitro treatment with TNF was examined. Neutrophils from seven normal subjects were incubated with TNF for 30 minutes and tested for chemotaxis to leukotriene B4, formyl-methionyl-leucyl-phenylalanine and zymosan-activated serum, or the calcium ionophore A23187 to assess leukotriene B4 generation. A range of 10(-13) to 10(-9) mol/L of TNF was used for these assays. When 10(-9) mol/L of TNF was used, the amount of leukotriene B4 that was produced was significantly greater than in control cells. The effect of TNF on PMN chemotaxis was uniformly inhibitory for the three stimuli at 10(-10) mol/L compared with untreated cells. At a picomolar range, PMN migration to leukotriene B4, but not to zymosan-activated serum or formyl-methionyl-leucyl-phenylalanine, was significantly increased over that of PMNs not exposed to TNF. This suggests that TNF has a specific facilitatory effect on PMN responsiveness for both leukotriene B4 production and chemotaxis to leukotriene B4 and may be the same signal for this phenomenon in endotoxemic patients.

Calcimycin↗
PubMed1988

Influence of substrate background on peripheral tissue responses to growth hormone.

To evaluate the effects of substrate and hormonal background on the peripheral response to methionyl human growth hormone (met-hGH), metabolic measurements were performed in 10 normal subjects before and at the end of a 6-hr infusion of met-hGH. Five subjects were studied in the postabsorptive state and five were studied on the 10th day of intravenous repletion. Measurements of hormonal levels, serum amino acid levels, and free fatty acid levels, as well as extremity amino acid and free fatty acid fluxes, were performed. Met-hGH in the postabsorptive setting had no effect on extremity amino acid flux but significantly increased extremity free fatty acid efflux. In contrast, met-hGH in the background of intravenous feeding produced a significant extremity uptake of total amino acids but had no effect on free fatty acid flux. These data suggest a relationship between the substrate background and the actions of met-hGH on both peripheral protein and lipid metabolism. Therefore, the adequacy and composition of the feeding regimen may be important when considering growth hormone as an adjunct to nutritional therapy.

Adult↗
PubMed1988

Protein and substrate metabolism during starvation and parenteral refeeding.

1. Healthy male volunteers underwent 10 days of hospitalized protein-calorie starvation and a subsequent 10 day repletion phase with complete intravenous nutritional support (IVF). Non-protein calories were provided as either all D-glucose or as 50% D-glucose/50% lipid. 2. In comparison with starvation, whole-body protein breakdown, as assessed by [15N]glycine, [13C]leucine and urinary excretion of 3-methylhistidine (3-MH), was diminished during IVF. The administration of parenteral nutrition did not specifically suppress peripheral tissue protein breakdown, as measured by extremity 3-MH efflux. 3. Despite the differential insulin response to D-glucose/amino acid (50 +/- 6 m-units/ml) as compared with the D-glucose/lipid/amino acid regimen (25 +/- 4 m-units/ml), there was no difference in nitrogen retention between the regimens. Indirect calorimetric determinations revealed that oxidation of substrate during IVF was related to the proportion of D-glucose and lipid infusion.

Adult↗
PubMed1988

Cachectin: a hormone that triggers acute shock and chronic cachexia.

Septic shock and invasive infection are diseases caused by humoral mediators of both exogenous and endogenous origin. The search for and identification of these factors has led to the discovery and molecular cloning of cachectin. This pyrogenic cytokine is identical to tumor necrosis factor (TNF) and, when released into the circulation, causes profound shock and multiple organ injury. Cachectin antibodies protect against the lethal effects of mice given endotoxin and baboons given E. coli, a result suggesting that this mediator is both necessary and sufficient to provoke septic shock. Cachectin is produced in humans after endotoxin infusion; the infusion of small doses of TNF is associated with fever, rigors, headache, and hypotension. Septicemic patients also produce cachectin, and during meningococcal infection, patients with the highest serum levels of cachectin die. Chronic cachectin production causes a potentially lethal syndrome of cachexia, anemia, and protein and lipid wasting. Future investigation is being directed toward the development of cachectin antibodies for use in treating the humorally mediated systemic complications of infectious disease.

Animals↗
PubMed1988

Submaximal exercise during intravenous hyperalimentation of depleted subjects.

The peripheral nitrogen wasting and loss of functional capacity caused by the malnutrition of disease and the immobilization of hospitalization may not be readily reversed by refeeding alone. In order to examine submaximal exercise as an adjunctive anabolic stimulus to intravenous refeeding (IVF) in depleted subjects, 14 volunteers were studied in the postabsorptive (PA) state, after 10 days of total starvation, and again after 10 days of nutritional repletion with I.V. feedings. The subjects were randomized to one group that received IVF alone and one group that performed 1 hour of submaximal (51% of VO2max) stationary bicycle exercise daily during IVF. The exercised group was not significantly different from the nonexercised group in urinary nitrogen balance, resting energy expenditure, extremity amino acid flux, or maximal oxygen consumption. Acute exercise did not induce significant derangements in electrolytes or counter-regulatory hormone concentrations. Ten days of submaximal exercise does not appear to be detrimental in this population recovering from moderate hospitalized malnutrition, but additional anabolic stimulae may be needed for improvements in protein accrual or functional capacity.

Adult↗