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• W2023117694 abstract "Endotoxemia is associated with rapid and marked declines in serum levels of LDL and HDL by unknown mechanisms. Six normal volunteers received a single, small intravenous (iv) dose of endotoxin (Escherichia coli 0113, 2 ng/kg) or saline in a random order, cross-over design. After endotoxin treatment, volunteers had mild, transient flu-like symptoms and markedly increased serum levels of tumor necrosis factor and its soluble receptors, interleukin-6, cortisol, serum amyloid A, and C-reactive protein. Triglyceride (TG), VLDL-TG, and nonesterified fatty acid increased (peak at 3–4 h), then TG declined (nadir at 9 h), and then cholesterol, LDL cholesterol, apolipoprotein B (apoB), and phospholipid declined (nadirs at 12–24 h). HDL cholesterol and apoA-I levels were not affected, but half of the decrease in phospholipid was HDL phospholipid. Lipopolysaccharide binding protein (LBP) rose 3-fold (peak at 12 h), with smaller and later decreases in the activities of phospholipid transfer protein and cholesteryl ester transfer protein.In conclusion, a decline in LDL was rapidly induced in normal volunteers with a single iv dose of endotoxin. The selective loss of phospholipid from HDL may have been mediated by LBP and, after more intense or prolonged inflammation, could result in increased HDL clearance and reduced HDL levels. Endotoxemia is associated with rapid and marked declines in serum levels of LDL and HDL by unknown mechanisms. Six normal volunteers received a single, small intravenous (iv) dose of endotoxin (Escherichia coli 0113, 2 ng/kg) or saline in a random order, cross-over design. After endotoxin treatment, volunteers had mild, transient flu-like symptoms and markedly increased serum levels of tumor necrosis factor and its soluble receptors, interleukin-6, cortisol, serum amyloid A, and C-reactive protein. Triglyceride (TG), VLDL-TG, and nonesterified fatty acid increased (peak at 3–4 h), then TG declined (nadir at 9 h), and then cholesterol, LDL cholesterol, apolipoprotein B (apoB), and phospholipid declined (nadirs at 12–24 h). HDL cholesterol and apoA-I levels were not affected, but half of the decrease in phospholipid was HDL phospholipid. Lipopolysaccharide binding protein (LBP) rose 3-fold (peak at 12 h), with smaller and later decreases in the activities of phospholipid transfer protein and cholesteryl ester transfer protein. In conclusion, a decline in LDL was rapidly induced in normal volunteers with a single iv dose of endotoxin. The selective loss of phospholipid from HDL may have been mediated by LBP and, after more intense or prolonged inflammation, could result in increased HDL clearance and reduced HDL levels. The release of endotoxin or lipopolysaccharide (LPS) from the cell walls of gram-negative bacteria into the circulation precipitates an acute inflammatory response that often leads to shock and death (1Parrillo J.E. Pathogenetic mechanisms of septic shock.N. Engl. J. Med. 1993; 328: 1471-1477Crossref PubMed Scopus (1503) Google Scholar, 2Gabay C. Kushner I. Acute-phase proteins and other systemic responses to inflammation.N. Engl. J. Med. 1999; 340: 448-454Crossref PubMed Scopus (5109) Google Scholar). A less-recognized component of the acute-phase response to endotoxemia and a variety of inflammatory states in humans is a rapid and marked decline in serum levels of cholesterol, phospholipid, apolipoprotein B (apoB), and apoA-I carried in LDL and HDL (3Gordon B.R. Parker T.S. Levine D.M. Saal S.D. Wang J.C.L. Sloan B. Barie P.S. Rubin A.L. Relationship of hyperlipidemia to cytokine concentrations and outcomes in critically ill surgical patients.Crit. Care Med. 2001; 29: 1563-1568Crossref PubMed Scopus (150) Google Scholar, 4Barlage S. Frohlich D. Bottcher A. Jauhiainen M. Muller H.P. Noetzel F. Rothe G. Schutt C. Linke R.P. Lackner K.L. Ehnholm C. Schmitz G. ApoE-containing high density lipoproteins and phospholipid transfer protein activity increase in patients with a systemic inflammatory response.J. Lipid Res. 2001; 42: 281-290Abstract Full Text Full Text PDF PubMed Google Scholar, 5Sammalkorpi K. Valtonen V. Kerttula Y. Nikkila E. Taskinen M. Changes in serum lipoprotein pattern induced by acute infections.Metabolism. 1988; 37: 859-865Abstract Full Text PDF PubMed Scopus (238) Google Scholar). Low levels of cholesterol, in turn, predict a poor prognosis in hospitalized (3Gordon B.R. Parker T.S. Levine D.M. Saal S.D. Wang J.C.L. Sloan B. Barie P.S. Rubin A.L. Relationship of hyperlipidemia to cytokine concentrations and outcomes in critically ill surgical patients.Crit. Care Med. 2001; 29: 1563-1568Crossref PubMed Scopus (150) Google Scholar) and chronically ill patients (6Jacobs D. Blackburn H. Higgins M. Reed D. Iso H. McMillan G. Neaton J. Nelson J. Potter J. Rifkind B. Rossouw J. Shekelle R. Yusuf S. Report of the conference on low blood cholesterol: mortality associations.Circulation. 1992; 86: 1046-1060Crossref PubMed Scopus (623) Google Scholar, 7Bologa R.M. Levine D.M. Parker T.S. Cheigh J.S. Serur D. Stenzel K.H. Rubin A.L. Interleukin-6 predicts hypoalbuminemia, hypocholesterolemia, and mortality in hemodialysis patients.Am. J. Kidney Dis. 1998; 32: 107-114Abstract Full Text Full Text PDF PubMed Scopus (520) Google Scholar). It has been proposed that the lipoproteins protect against the lethal effects of endotoxin by binding it and reducing the secretion of proinflammatory cytokines by monocytes and macrophages (8Ulevitch R.J. Johnston A.R. Weinstein D.B. New function for high density lipoproteins. Isolation and characterization of a bacterial lipopolysaccharide-high density lipoprotein complex formed in rabbit plasma.J. Clin. Invest. 1981; 67: 827-837Crossref PubMed Scopus (165) Google Scholar, 9Levine D.L. Parker T.S. Donnelly T.M. Walsh A. Rubin A.L. In vivo protection against endotoxin by plasma high density lipoprotein.Proc. Natl. Acad. Sci. USA. 1993; 90: 12040-12044Crossref PubMed Scopus (428) Google Scholar, 10Rauchhaus M. Coats A.J.S. Anker S.D. The endotoxin-lipid hypothesis.Lancet. 2000; 356: 930-933Abstract Full Text Full Text PDF PubMed Scopus (459) Google Scholar, 11Khovidhunkit W. Memon R.A. Feingold K.R. Grunfeld C. Infection and inflammation-induced protatherogenic changes of lipoproteins.J. Infect. Dis. 2000; 181: S462-S472Crossref PubMed Scopus (330) Google Scholar). Thus, a better understanding of the mechanism(s) of the decrease in plasma lipoproteins by circulating endotoxin may result in new therapeutic approaches to increase lipoproteins in patients who have, or are at high risk for, endotoxemia and inflammation. This may include treatment of low HDL levels that may result from and contribute to the inflammation of atherosclerotic cardiovascular disease (12Ross R. Atherosclerosis—an inflammatory disease.N. Engl. J. Med. 1999; 340: 115-126Crossref PubMed Scopus (19278) Google Scholar). The injection of a single dose of endotoxin into experimental animals or humans has been used for decades as a model to study the interrelationships between infection and the host response (13Martich G.D. Boujoukos A.J. Suffredini A.F. Response of man to endotoxin.Immunobiology. 1993; 187: 403-416Crossref PubMed Scopus (237) Google Scholar, 14Suffredini A.F. Hochstein H.D. McMahon F.G. Dose-related inflammatory effects of intravenous endotoxin in humans: evaluation of a new clinical lot of Escherichia coli O113 endotoxin.J. Infect. Dis. 1999; 179: 1278-1282Crossref PubMed Scopus (130) Google Scholar, 15Hardardottir I. Grunfeld C. Feingold K.R. Effects of endotoxin and cytokines on lipid metabolism.Curr. Opin. Lipidol. 1994; 5: 207-215Crossref PubMed Scopus (268) Google Scholar). In humans, there is a well-characterized dose-related response to intravenous (iv) endotoxin consisting of mild fever, flu-like symptoms, marked increases in tumor necrosis factor α (TNFα), interleukin-6 (IL-6), cortisol, epinephrine, serum amyloid A (SAA), and C-reactive protein (CRP), and changes in other cytokines, hormones, and inflammatory markers. However, there are no detailed studies in humans of the response of plasma lipoproteins to iv endotoxin. In animals, the time course and nature of the lipoprotein response has varied depending on the host species, the source and dose of endotoxin, and the preceding diet. In rodents, rabbits, and hamsters with lipoprotein profiles and metabolism distinctly different from those of humans, endotoxin raised cholesterol and LDL cholesterol (15Hardardottir I. Grunfeld C. Feingold K.R. Effects of endotoxin and cytokines on lipid metabolism.Curr. Opin. Lipidol. 1994; 5: 207-215Crossref PubMed Scopus (268) Google Scholar). In contrast, a single dose of endotoxin given to nonhuman primates with lipoprotein levels and metabolism more similar to those of humans rapidly decreased LDL and HDL cholesterol ester, apoA-I, and HDL particle size by 24 h (16Auerbach B.J. Parks J.S. Lipoprotein abnormalities associated with lipopolysaccharide-induced lecithin:cholesterol acyltransferase and lipase deficiency.J. Biol. Chem. 1989; 264: 10264-10270Abstract Full Text PDF PubMed Google Scholar, 17Ettinger W.H. Miller L.D. Albers J.J. Smith T.K. Parks J.S. Lipopolysaccharide and tumor necrosis factor cause a fall in plasma concentration of lecithin:cholesterol acyltransferase in cynomolgus monkeys.J. Lipid Res. 1990; 31: 1099-1107Abstract Full Text PDF PubMed Google Scholar). In addition, endotoxin increased triglyceride (TG) and VLDL, which has consistently occurred in other animal models due to increased fatty acid synthesis, increased VLDL production, and/or decreased clearance (15Hardardottir I. Grunfeld C. Feingold K.R. Effects of endotoxin and cytokines on lipid metabolism.Curr. Opin. Lipidol. 1994; 5: 207-215Crossref PubMed Scopus (268) Google Scholar). However, in humans, TG levels are variably affected by infection (3Gordon B.R. Parker T.S. Levine D.M. Saal S.D. Wang J.C.L. Sloan B. Barie P.S. Rubin A.L. Relationship of hyperlipidemia to cytokine concentrations and outcomes in critically ill surgical patients.Crit. Care Med. 2001; 29: 1563-1568Crossref PubMed Scopus (150) Google Scholar). In an uncontrolled study of normal volunteers, TG (and cholesterol) levels did not change from baseline at 2 h, 6 h, or 24 h after a single iv dose of endotoxin (18Van der Poll T. Braxton C.C. Coyle S.M. Boermeester M.A. Wang J.C.L. Jansen P.M. Montegut W.J. Calvano S.E. Hack C.E. Lowry S.F. Effect of hypertriglyceridemia on endotoxin responsiveness in humans.Infect. Immun. 1995; 63: 3396-3400Crossref PubMed Google Scholar). Using this established model of endotoxemia in normal volunteers after a controlled diet, we compared the effects of a single iv dose of endotoxin to saline on serum lipids, lipoproteins, and lipid transfer proteins. By matching the fatty acid composition of the diet to each subject's adipose tissue and comparing it to the composition of VLDL-TG, we also determined whether endotoxin increased fatty acid synthesis and newly formed palmitate in VLDL (19Hudgins L.C. Hellerstein M.K. Seidman C.E. Neese R.A. Tremaroli J.D. Hirsch J. Relationship between carbohydrate-induced hypertriglyceridemia and fatty acid synthesis in lean and obese subjects.J. Lipid Res. 2000; 41: 595-604Abstract Full Text Full Text PDF PubMed Google Scholar). Six normal volunteers (three males, three females, ages 23–35) were admitted to The Rockefeller University Clinical Research Center in a random-order cross-over design twice for 8 days with a 6 week washout period between admissions. After a diet stabilization period, they received either a single iv dose of endotoxin or saline. Healthy volunteers, aged 21 to 45, who did not smoke or take prescription medications were eligible for the study. Body weight was at least 110 pounds, within 10% of current weight for at least 6 months, and within 80–120% desirable body weight by the 1959 Metropolitan Life Insurance Table. The fasting lipid profiles of participants met the following criteria: LDL cholesterol < 160 mg/dl, TG < 200 mg/dl, and HDL cholesterol between 35 and 70 mg/dl. A physical exam and screening tests performed within 2 months of admission, including a complete blood count, biochemical screen, HIV, hepatitis B and C, thyroid stimulating hormone, pregnancy test, urinalysis, chest X-ray, and EKG, were all normal. Aspirin, nonsteroidal anti-inflammatory drugs, or vitamins were discontinued at least 1 week prior to admission. Patients with histories of alcohol or substance abuse, psychiatric disease, asthma, severe allergic reactions, or a febrile illness within the month prior to admission were excluded. All participating subjects gave informed written consent, and the study was approved by The Rockefeller University Institutional Review Board. During both admissions, each subject received identical single-menu solid food diets as three meals/day with 35% of calories as fat, 50% as carbohydrate, and a starch/sugar ratio of 70:30. The distribution of calories was achieved with food items used in previous studies that tested the effects of dietary carbohydrates on fatty acid synthesis and was chosen to ensure that fatty acid synthesis was not stimulated in the basal state (19Hudgins L.C. Hellerstein M.K. Seidman C.E. Neese R.A. Tremaroli J.D. Hirsch J. Relationship between carbohydrate-induced hypertriglyceridemia and fatty acid synthesis in lean and obese subjects.J. Lipid Res. 2000; 41: 595-604Abstract Full Text Full Text PDF PubMed Google Scholar). As required by the linoleate dilution method to measure fatty acid synthesis, a mixture of corn oil, olive oil, and lard was added to a 2% fat solid food diet. The fatty acid composition of each diet was matched to the composition of each subject's adipose tissue and compared with the composition of VLDL-TG (19Hudgins L.C. Hellerstein M.K. Seidman C.E. Neese R.A. Tremaroli J.D. Hirsch J. Relationship between carbohydrate-induced hypertriglyceridemia and fatty acid synthesis in lean and obese subjects.J. Lipid Res. 2000; 41: 595-604Abstract Full Text Full Text PDF PubMed Google Scholar, 20Hudgins L.C. Hellerstein M. Seidman C. Neese R. Diakun J. Hirsch J. Human fatty acid synthesis is stimulated by a eucaloric low fat, high carbohydrate diet.J. Clin. Invest. 1996; 97: 2081-2091Crossref PubMed Scopus (289) Google Scholar). By chance, the volunteers had similar percentages of fatty acids in adipose tissue (range for linoleate, 17–20%; palmitate, 18–20%; and oleate, 40–43%). Cholesterol was added to total 200 mg/day in all diets. The total calories to maintain constant weight were estimated from the surface area as 1,360 kcal/meter2. On Day 5, after the endotoxin or saline bolus (see below), the diet (except water) was withheld for 24 h and then given again for the next 2 days until discharge on Day 8. On Day 5 at 9 AM after a 12 h overnight fast, either endotoxin (US Standard Reference Endotoxin from Escherichia coli 0113, 2 ng/kg, 200 ng/ml sterile water) or saline in a plastic syringe was slowly administered intravenously over 1 min, close to the 18 gauge catheter insertion site in the antecubital fossa. This was followed by a slow flush of 10 ml sterile saline and then a saline infusion at 20 ml/h. The endotoxin was stored as a lyophilized powder in single-use vials provided by the Pharmacy Department of The National Institutes of Health, Bethesda, MD. For hydration, additional saline was infused at 100 ml/h through an 18 gauge catheter in the other arm to total 120 ml/h for 24 h. Water by mouth was also encouraged. Baseline vital signs were obtained twice, 5 min before the injection and then approximately every 15 min for the first 3 h, every 1/2 h for the next 3 h, and then every 3 h for the remainder of the 24 h period. Blood pressure, pulse, respirations, EKG, and O2 saturation were monitored using a Datascope (first two subjects) or Hewlett Packard Veridia. Symptoms of headache, chills, muscle aches, backache, nausea, and vomiting were recorded by the nurse as: absent, 0; mild, 1; moderate, 2; or severe, 3. The principal investigator and two nurses were continuously present for the first 4 h after each endotoxin infusion. For the fasting specimens on Days 1, 4–8, and, on Day 5, at 1.5 h, 3 h, and then every 3 h until the following morning, 7 ml of blood was drawn in EDTA on ice. The plasma was separated by low-speed centrifugation at 4°C for 20 min, and VLDL was isolated by density-gradient ultracentrifugation. The fatty acid composition of VLDL-TG was analyzed by capillary gas chromatography after chloroform-methanol extraction of lipids; separation of TG by thin-layer chromatography (TLC) with silica gel G and a solvent system of hexane, diethyl ether, and glacial acetic acid, 60:40:1; and transmethylation with 5% methanolic HCL to form fatty acid methyl esters (20Hudgins L.C. Hellerstein M. Seidman C. Neese R. Diakun J. Hirsch J. Human fatty acid synthesis is stimulated by a eucaloric low fat, high carbohydrate diet.J. Clin. Invest. 1996; 97: 2081-2091Crossref PubMed Scopus (289) Google Scholar). The fatty acid compositions of the total lipid extracts from the diets and subcutaneous adipose tissue sampled from the gluteal site prior to admission were similarly analyzed by gas chromatography. The phospholipid subclasses phosphatidyl choline (PC), lysophosphatidyl choline (LPC), sphingomyelin (SM), phosphatidyl ethanolamine (PE), phosphatidyl inositol (PI), and phosphatidyl serine (PS), in total lipid extracts from serum obtained at the time of maximum difference in serum total phospholipid 12–24 h after iv endotoxin or saline, were separated by TLC using silica gel H and a solvent system of chloroform, methanol, acetic acid, and H20 (25:15:4:2) (21Christie W.W. Gas Chromatography and Lipids. The Oily Press, Alloway, United Kingdom1989: 40Google Scholar). The minor amounts of PI and PS migrated as a single band and are presented as a single value. The fatty acid compositions of each phospholipid class were determined as above after methylation with 5% methanolic HCL. C17:0 PC and LPC were added as internal recovery standards at the start of lipid extraction to quantitate the total amount of each respective lipid; C 17:0 PC was added at the TLC step to quantitate PE and PS-PI. Due to lower recovery and the lack of an internal recovery marker, SM was measured in triplicate using an enzymatic kit with bacterial sphingomyelinase (Cardiovascular Target, Inc., New York) and an interassay coefficient of variation of 3%. At the above time points, and, on Day 5, at 1 h, 2 h, and 4.5 h, other lipid assays were performed. Total serum cholesterol and TG were measured using enzymatic methods on a COBAS Integra (Roche Diagnostic Systems, Indianapolis, IN). The concentration of HDL cholesterol was measured after precipitation of β-lipoproteins with dextran sulfate and magnesium chloride (22Warnick G. Benderson J. Albers J. Dextran sulfate-Mg2+ precipitation procedure for quantitation of high-density-lipoprotein cholesterol.Clin. Chem. 1982; 28: 1379-1388Crossref PubMed Scopus (1812) Google Scholar). LDL cholesterol was calculated using the Friedewald equation. Immunoturbidimetric methods were used to measure apoA-I and apoB (Roche Diagnostic Systems). SAA was measured by a double antibody sandwich ELISA method (BioSource International, Camarillo, CA). Serum phospholipid and nonesterified fatty acids (NEFAs) were measured by enzymatic methods (Wako Chemical USA, Inc., Richmond, VA) in blood samples placed immediately on ice and spun in a refrigerated centrifuge to prevent ex vivo hydrolysis. The phospholipid assay measured the amount of choline-containing phospholipids (PC, LPC, and SM). Fast protein liquid chromatography (FPLC) was used to measure the amounts of cholesterol, TG phospholipid, apoA-I, apoB, and SAA in VLDL, LDL, and HDL at the time of maximum difference in the concentration of phospholipid (12–24 h after endotoxin injection). Serum samples of 200 μl were chromatographed in phosphate-buffered saline (0.5 ml/min) from two Superose 6 columns (Pharmacia/LKB) connected in series. Fractions (650 μl) were collected and analyzed by methods described above after slight modification (23Li J. Fang B. Eisensmith R.C. Li X.H.C. Nasonkin I. Lin-Lee Y-C. Mims M.P. Hughs A. Montgomery C. Roberts J. Parker T.S. Levine D.M. Woo S.L.C. In vivo therapy for hyperlipidemia: phenotypic correction in Watanabe rabbits by hepatic delivery of the rabbit LDL receptor gene.J. Clin. Invest. 1995; 95: 768-773Crossref PubMed Google Scholar). For all assays, the mean recoveries were greater than 85%. To measure HDL size, serum lipoproteins were separated by flotation from 1.24 g/ml NaBr in a Beckman TL 100 rotor at 100,000 RPM for 3 h at 20°C. Native gradient gel electrophoresis was done on 4–20% Tris-Glycine polyacrylamide gel gradient gels from Invitrogen (Grand Island, NY) stained with Coomassie blue (Bio Rad G250), as described by Nichols (24Nichols A.V. Krauss R.M. Musliner T.A. Nondenaturing polyacrylamide gradient gel electrophoresis.Methods Enzymol. 1986; 128: 417-431Crossref PubMed Scopus (448) Google Scholar) and scanned by laser densitometry. Serum obtained at 0 h, 12 h, 24 h, 48 h, and 72 h after endotoxin or saline was assayed for the activities of phospholipid transfer protein (PLTP) and cholesteryl ester transfer protein (CETP) in triplicate using assay kits (Cardiovascular Target, Inc., and Roar Biomedical, Inc., New York). Incubation of donor and acceptor particles with 3 μl of human plasma results in the PLTP- or CETP-mediated transfer of fluorescent phospholipid or neutral lipid, which is quenched when associated with the donor. The transfer is determined by the increase in fluorescence intensity as the fluorescent lipid is removed from the donor and transferred to the acceptor. The interassay coefficient of variation for both assays was 3%. The serum concentration of LPS binding protein (LBP) was measured by an enzyme-amplified chemiluminescent method on an Immulite Analyzer (Diagnostic Products Corp., Los Angeles, CA). Blood samples were obtained at the above time points and placed immediately on ice, and the serum was separated in a refrigerated centrifuge. TNFα was measured by ELISA (RPN 2148 and 2755, Amersham Life Science, Little Chalfont, Buckinghamshire, England). IL-6 and the soluble receptors for TNFα (p55, p75) were measured by enzyme immunoassay (BioSource International) on the Roche COBAS Core II (Roche Diagnostics Systems, Basel, Switzerland). At 0 and 5 min from the start of the injection of endotoxin or saline, 4 ml blood was drawn into endotoxin-free tubes with heparin, spun within 1/2 h at 2,500 rpm, 4°C, for 5 min, and the platelet-rich plasma was stored at −80°C until assayed. Concentrations of endotoxin were measured in triplicate by a kinetic limulus amebocyte lysate method (Coamatic Endotoxin, Associates of Cape Cod, Falmouth, MA). A Molecular Devices Thermomax Microplate Reader and SoftMax Pro software were used to collect kinetic data for 20 min. High sensitivity CRP was measured by a latex-enhanced immunoturbidimetric method on the Roche COBAS Integra. White blood cells were measured on a Bayer Advia 120 (Bayer Diagnostics, Tarrytown, NY). Cortisol was measured by enzyme-amplified chemiluminescence on an Immulite Analyzer by Diagnostic Products Corp. Catecholamines (epinephrine, norepinephrine, and dopamine) were measured by HPLC in acidified urine collected from 6 AM–6 PM and 6 PM–6 AM on the day of the endotoxin or saline injection. Means and SD or SE (figures) were calculated for six subjects at each time point. Two-tailed paired Student's t-tests were performed to compare values after endotoxin or saline. Simple linear regression was used to assess the relationships among the lipids, lipid transfer proteins, and inflammatory markers. Statistical significance was defined as P < 0.05. Excel and SigmaStat statistical softwares were used. The incidence of clinical effects and average clinical scores after iv endotoxin are shown in Table 1. All six volunteers manifested typical flu-like symptoms: headache, chills, muscle ache, backache, and/or nausea. These symptoms peaked at 1–2 h and were resolved 6–9 h after the injection. One subject vomited and had a vasovagal reaction with a brief drop in blood pressure and pulse. Another subject received supplemental O2 by nasal canula for peripheral cyanosis. The mean maximum oral temperature ± SD was 38.2 ± 0.4°C (range, 37.8–38.7°C) and peaked 3–4 h after endotoxin. The mean pulse increased from baseline (64 ± 12 vs. 92 ± 18), but there was no significant change in systolic or diastolic blood pressure. There were no complaints or significant changes in vital signs from subjects after the saline injection. Baseline levels of endotoxin were low, but were 10-fold higher 5 min after injection of endotoxin compared with saline (7.7 ± 11.3 vs. 0.7 ± 0.5 U/ml).TABLE 1Clinical response to iv endotoxinScoreIncidenceMeanRangeHeadache61.21–2Chills61.71–3Myalgia41.00–2Backache40.80–2Nausea20.70–3iv, intravenous. Symptoms in six volunteers were rated as: 0, absent; 1, mild; 2, moderate; 3, severe. Open table in a new tab iv, intravenous. Symptoms in six volunteers were rated as: 0, absent; 1, mild; 2, moderate; 3, severe. For all measurements, baseline values were not significantly different before endotoxin and saline injections. The top three panels of Fig. 1show that, as expected after iv endotoxin, serum TNFα, IL-6, and cortisol rapidly and markedly increased (14Suffredini A.F. Hochstein H.D. McMahon F.G. Dose-related inflammatory effects of intravenous endotoxin in humans: evaluation of a new clinical lot of Escherichia coli O113 endotoxin.J. Infect. Dis. 1999; 179: 1278-1282Crossref PubMed Scopus (130) Google Scholar) and then returned to control levels by 9 h. TNFα first peaked at 1.5 h (381 ± 343 vs. 2.3 ± 3.2 pg/ml, P = 0.02), then IL-6 at 2 h (3,395 ± 2,542 vs. 4.7 ± 6.4 pg/ml, P = 0.02), and then cortisol at 3 h (36 ± 4.3 vs. 7 ± 3.5 μg/dl, P < 0.001). The peak levels of TNFα and IL-6 were positively correlated with each other (P = 0.02). During the saline infusion, IL-6, but not TNFα or cortisol, slightly increased above baseline (peak at 12 h of 19.2 ± 25 pg/ml). The next two panels in Fig. 1 show that the soluble receptors of TNFα, p55, and p75 also sharply increased after endotoxin and peaked at 2–3 h, but slowly declined to baseline levels over the next 48–72 h (peak p55-3.1 ± 1.1 vs. 0.8 ± 0.2 ng/ml; p75-10.1 ± 1.6 vs. 2.3 ± 0.6 ng/ml, P < 0.01). The bottom two panels show that, compared with the cytokines, cortisol, and cytokine receptors, SAA and CRP more sluggishly increased after endotoxin, peaking at 24 h and then slowly declining (peak SAA 510 ± 259 vs. 6 ± 5 mg/l; CRP 30.8 ± 13.8 vs. 0.6 ± 1.1 mg/l, P < 0.01). Both were still elevated compared with the saline period at discharge 72 h later (SAA 137 ± 166 vs. 7 ± 5 mg/l; CRP 6.2 ± 3.1 vs. 0.5 ± 0.8 mg/l). Despite their parallel time course, SAA and CRP were not significantly correlated with one another or with the cytokines. These concentrations of the cytokines and acute-phase proteins after endotoxin were within the ranges reported in acute inflammatory disease (3Gordon B.R. Parker T.S. Levine D.M. Saal S.D. Wang J.C.L. Sloan B. Barie P.S. Rubin A.L. Relationship of hyperlipidemia to cytokine concentrations and outcomes in critically ill surgical patients.Crit. Care Med. 2001; 29: 1563-1568Crossref PubMed Scopus (150) Google Scholar, 4Barlage S. Frohlich D. Bottcher A. Jauhiainen M. Muller H.P. Noetzel F. Rothe G. Schutt C. Linke R.P. Lackner K.L. Ehnholm C. Schmitz G. ApoE-containing high density lipoproteins and phospholipid transfer protein activity increase in patients with a systemic inflammatory response.J. Lipid Res. 2001; 42: 281-290Abstract Full Text Full Text PDF PubMed Google Scholar, 25Buttenschoen K. Buttenschoen D.C. Berger D. Vasilescu C. Schafheutle S. Goeltenboth B. Seidelmann M. Beger H.G. Endotoxemia and acute-phase proteins in major abdominal surgery.Am. J. Surgery. 2001; 181: 36-43Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar). The expected changes in white blood cells occurred after endotoxin: an initial, sharp decrease at 1 h (3.0 ± 0.6 vs. 5.6 ± 1.8 thousand cells/μl, P = 0.02), then a marked increase between 6 and 9 h (14.9 ± 4.4 vs. 6.0 ± 2.0, P = 0.03), 90% as neutrophils, then a slow return to baseline by 48 h (data not shown). Two hours after endotoxin, the platelet count transiently decreased 17% from baseline values. In four subjects with complete urine collections, total urinary epinephrine in the first 12 h after endotoxin was twice that after saline (10 ± 5 vs. 5 ± 4 μg, P = 0.05). The mean values for norepinephrine and dopamine in the first 12 h urine collection were also higher after endotoxin than after saline, but the differences did not reach statistical significance. Figure 2shows the sequential changes in serum lipids and lipoproteins following iv endotoxin and saline. After saline injection, all lipid and lipoprotein levels except NEFAs slightly declined from baseline levels, as would be expected after a 36 h fast and dilution from iv fluids, and returned to baseline by 48–72 h. NEFA levels plateaued above baseline levels at 9–15 h of fasting and were back to baseline at 48 h. After endotoxin at 3–4.5 h, shortly after the sharp peaks in TNFα, IL-6 and cortisol, NEFA, and TG peaked 106% and 26% above control values. The percent increase in NEFA and TG were inversely correlated with each other (r = −0.85, P = 0.03), and positively correlated with maximum IL-6 and CRP (P = 0.03 for both). NEFA and TG then abruptly declined so that at 9 h, NEFA was at control values but TG was 24% below control levels, returning to control values by 18 h. VLDL-TG changed in parallel with the total TG (data not shown). Following the decline in TG were small (11–20%) but s" @default.
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• W2023117694 title "A single intravenous dose of endotoxin rapidly alters serum lipoproteins and lipid transfer proteins in normal volunteers" @default.
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