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Original Article |

Attenuation of the Acute-Phase Response in Thermally Injured Rats by Cholesterol-Containing Cationic Liposomes Used as a Delivery System for Gene Therapy FREE

Marc G. Jeschke, MD; Robert E. Barrow, PhD; J. Regino Perez-Polo, PhD; David N. Herndon, MD
[+] Author Affiliations

From the Departments of Surgery (Drs Jeschke, Barrow, and Herndon) and Human Biological Chemistry and Genetics (Dr Perez-Polo), Shriners Burns Hospital, Galveston, Tex.


Arch Surg. 1999;134(10):1098-1102. doi:10.1001/archsurg.134.10.1098.
Text Size: A A A
Published online

Hypothesis  Cholesterol-containing cationic liposomes alone modulate the acute-phase response and cytokine expression in thermally injured rats and are an effective delivery system for gene therapy in trauma.

Setting  Laboratory.

Intervention  Fifty-six adult male Sprague-Dawley rats with a full-thickness scald burn covering 60% of total body surface area were randomly divided into 2 groups to receive either intravenous injections of cholesterol-containing cationic liposomes or saline (control).

Main Outcome Measures  Body weights, muscle and liver dry-wet weights, serum levels of constitutive hepatic proteins, acute-phase protein levels, and cytokine levels were determined at 1, 2, 5, and 7 days after thermal injury.

Results  Rats receiving cholesterol-containing cationic liposomes had less body weight loss, increased serum transferrin levels, and decreased serum α1-acid glycoprotein levels when compared with controls (P<.05). Serum interleukin 1β and tumor necrosis factor α levels were decreased in rats receiving liposomes at 1 and 2 days after burn compared with controls (P<.05).

Conclusions  These results suggest that cholesterol-containing cationic liposomes alone may have a beneficial effect in modulating the hypermetabolic response after burn injury by decreasing type 1 acute-phase proteins and the expression of the proinflammatory cytokines interleukin 1β and tumor necrosis factor α. Therefore, cholesterol-containing cationic liposomes appear to be suitable as a delivery system for gene therapy in trauma.

Figures in this Article

GENE THERAPY is a promising approach for the treatment of various clinical disorders. The success of this approach depends on the selection of appropriate vectors for gene delivery.1,2 Viruses have been used as delivery vectors because of their specificity and tissue penetration via consecutive cell transfection.1,2 The disadvantages of viral vectors, such as viral infection–associated toxic effects, immunological compromise, and mutagenic or carcinogenic effects, restrict its potential use in humans.1 Recent modifications to incorporate cholesterol into cationic liposomes have increased their efficiency of transfection to levels previously achieved only with adenoviral constructs.35 Thus, liposomes have now become an efficient delivery system for gene therapy in the fields of oncology, neurology, and cardiology.16 The use of liposomal gene complexes in trauma is a new approach to improve clinical outcome and mortality. The suitability of liposomes as a delivery system for gene therapy in trauma has not been defined. We attempted to determine the suitability of liposomes as a delivery system for gene therapy by measuring the effects of liposomes on the hepatic acute-phase response and cytokine concentrations.

The hepatic acute-phase response represents a cascade of events characterized by the up-regulation of types 1 and 2 acute-phase proteins, mediated by proinflammatory cytokines, and the down-regulation of constitutive hepatic proteins.79 These events are initiated to restore homeostasis after trauma.9 In clinical studies, however, it has been shown that a sustained or increased acute-phase response may contribute to multiple-organ failure, hypermetabolism, morbidity, and mortality.1012 Thus, the uncontrolled and prolonged action of proinflammatory cytokines and acute-phase proteins is potentially dangerous.1012 An attenuation of the overexpression of proinflammatory and acute-phase proteins thus may be beneficial, whereas an increase may be detrimental.1012

There is evidence that cholesterol-containing cationic liposomes, a delivery system for gene therapy, can exert a beneficial effect during the hypermetabolic response by increasing body weight and muscle protein concentration.11 We therefore propose that cholesterol-containing cationic liposomes modulate constitutive hepatic proteins, acute-phase proteins, proinflammatory cytokines (interleukin [IL] 1β, IL-6, and tumor necrosis factor [TNF] α), and losses in body weight during the hypermetabolic response and are therefore an effective delivery system for gene therapy in trauma. To test this hypothesis, we measured the effect of cholesterol-containing cationic liposomes on the hepatic acute-phase response in thermally injured rats.

Fifty-six adult male Sprague-Dawley rats (weight, 350-375 g) were studied according to a blinded protocol. Rats were housed in wire-bottom cages and kept in a temperature-controlled room with a 12-hour light-dark cycle. All animals were acclimatized to their environment for 7 days before the start of the study. All received the same amount of a liquid diet (Sustacal; Mead Johnson Nutritionals, Evansville, Ind) and water ad libitum throughout the study.

Rats received full-thickness scald burns covering 60% of their total body surface area as previously described13 and were randomly divided into 2 groups to receive injections of (1) cholesterol-containing cationic liposomes (20 µL of liposomes in 180 µL of isotonic sodium chloride solution intravenously; n=28) or (2) isotonic sodium chloride solution (control, 200 µL intravenously; n=28).

To determine the time course of liposomal effects, liposomes were injected intravenously into the tail vein 0.5 hour after the thermal injury and changes were examined during a 7-day period. The content of the injected solution was unknown to the investigators. The liposomes were a cholesterol-containing cationic type, 1,2-dimyristyloxypropyl-3-dimethyl-hydroxyl ethyl ammonium bromide (DMRIE-C Reagent; Life Technologies, Rockville, Md), prepared with cholesterol membrane-filtered water. The doses used were 10% liposomes; this is the highest concentration used in DNA transfer experiments that does not have deleterious consequences on DNA solubility and is compatible with gene transfer paradigms. The volume of 200 µL is an amount that can be administered into the tail vein of a rat without causing deleterious side effects, such as cardiac arrest.

Body weights were measured at the same time each day. Rats were killed by decapitation 1, 2, 5, or 7 days after burn. Blood was collected into serum and plasma separators, spun at 1000g for 15 minutes, decanted, and frozen at −73°C. Liver and gastrocnemius muscle tissues were harvested, weighed, and sectioned and samples of each were dried at 60°C to a constant weight. The dry-wet weight ratios were used to estimate protein content.

Serum cholesterol and free fatty acids were measured on a nephelometer (Nephelometer 100; Behringwerke AG, Marburg, Germany).

Serum acute-phase proteins (haptoglobin and α2-macroglobulin), constitutive hepatic proteins (total protein, transferrin, and albumin), and glucose were measured on a nephelometer (Behringwerke AG). Serum α1-acid glycoprotein level was determined by enzyme-linked immunosorbent assay (Wako Chemicals Inc, Richmond, Va). The standard curve for rat α1-acid glycoprotein concentrations was linear from 0 to 1500 pg/mL on a logarithmic scale.

Plasma TNF-α levels were determined by enzyme-linked immunosorbent assay (Endogen, Woburn, Mass). The standard curve used for the quantification of rat TNF-α was linear from 0 to 833 pg/mL on a logarithmic scale. Serum IL-1β levels were determined by enzyme-linked immunosorbent assay (Biosource Int, Camarillo, Calif); its standard curve used for the quantification of rat IL-1β was linear from 0 to 1500 pg/mL on a logarithmic scale. Serum IL-6 level was determined by bioassay by means of B9 cells (mouse hybridoma line) in log phase of growth treated with increasing serum concentrations. Cell proliferation in response to additional serum was measured spectrophotometrically by the attenuated mitochondrial metabolism of tetrazolium salt.

The study was reviewed and approved for humane animal treatment by the Animal Care and Use Committee of the University of Texas Medical Branch, Galveston, assuring that all animals received humane care according to the criteria outlined in the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health, Bethesda, Md. Statistical comparisons were made by analysis of variance and t test with Bonferroni correction. Data are expressed as mean±SEM. Significance was acceptance at P<.05.

All rats survived the 60% total body surface area scald burn and experimental drugs with no evidence of deleterious side effects. The percentage change in total body weight increased in both groups during the first 2 days, followed by a decrease in body weight 2 days after burn. Rats receiving liposomes maintained their body weight better than the saline-treated controls (significant on days 3 and 4 at P=.01 and on day 5 at P=.02) (Figure 1). There were no differences in dry-wet ratios between liposome-treated and control animals for gastrocnemius muscle and liver.

Place holder to copy figure label and caption
Figure 1.

Percentage change in body weights during the 7-day study. Asterisk indicates significant difference between groups at 3, 4, and 5 days after burn (P=.05, P=.02, and P=.06, respectively). Data are presented as mean±SEM.

Graphic Jump Location

Serum total protein concentration decreased in both groups after burn injury. Rats receiving liposomes showed an increase in serum total protein level 5 days after burn (liposomes, 56±1 g/L, vs controls, 52±1 g/L) (P=.03). Serum transferrin level decreased after burn injury to below normal in both groups. Those treated with liposomes showed a significant increase in serum transferrin level at 2 and 5 days after burn compared with controls (P=.004 and P=.02, respectively) (Figure 2). There were no significant differences in serum albumin level between groups. No significant difference in serum cholesterol, free fatty acid, and glucose levels could be demonstrated throughout the study period.

Place holder to copy figure label and caption
Figure 2.

Serum transferrin concentrations during the 7-day study period, showing a decrease after burn injury. Liposomes attenuated the drop at 2 and 5 days after burn. Asterisk indicates significant difference between groups (P<.05). Data are presented as mean±SEM (reference serum transferrin level, >0.72 g/L).

Graphic Jump Location

Type 1 acute-phase proteins, serum haptoglobin, and α1-acid glycoprotein levels increased after thermal injury. Liposomes decreased serum α1-acid glycoprotein levels 1 and 5 days after burn (P=.002 and P<.001, respectively) (Figure 3). There were no significant differences in serum haptoglobin levels between rats receiving liposomes and controls. Type 2 acute-phase protein increased in both groups after burn by nearly 50%. There were no differences in serum α2-macroglobulin levels between liposome-treated animals and control animals.

Place holder to copy figure label and caption
Figure 3.

Serum α1-acid glycoprotein levels 1 to 7 days after thermal injury. Asterisk indicates significant difference between saline and liposomes (P<.05). Data are presented as mean±SEM (serum α1-acid glycoprotein level reference range, 55-70 pg/mL).

Graphic Jump Location

Levels of all measured cytokines increased after the thermal injury. Serum IL-1β level decreased during the first day after burn (P=.002) (Figure 4) and serum TNF-α level at 1 and 2 days after burn in rats receiving liposomes compared with controls (P=.01) (Figure 5). No change in serum IL-6 level was observed in liposome-treated rats compared with controls.

Place holder to copy figure label and caption
Figure 4.

Serum interleukin 1β (IL-1β) levels 1 to 7 days after thermal injury. Asterisk indicates significant difference between saline and liposome administration (P<.05). Data are presented as mean±SEM (serum IL-1β level reference range, 4-20 pg/mL).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 5.

Serum tumor necrosis factor α (TNF-α) levels 1 to 7 days after thermal injury. Asterisk indicates significant difference between saline and liposomes (P<.05). Data are presented as mean±SEM (serum TNF-α level reference range, 1-10 pg/mL).

Graphic Jump Location

One major contributor to the hypermetabolism associated with a thermal injury is the increase in acute-phase proteins and cytokines.911 In this in vivo study, we showed that administration of cholesterol-containing cationic liposomes improved body weight and the expression of the constitutive hepatic proteins transferrin and total protein after burn compared with saline. We further showed that liposomes decrease serum levels of type 1 acute-phase proteins and the proinflammatory cytokines responsive to type 1 acute-phase proteins, serum TNF-α and IL-1β. It is likely that the decrease in IL-1β and TNF-α levels subsequently leads to a decrease in levels of these acute-phase proteins. No effect of liposomes on type 2 acute-phase proteins and the proinflammatory cytokine IL-6 could be shown, indicating a partial effect of liposomes on the hepatic acute-phase response.

Although the reasons for the beneficial effects associated with liposomes are not fully understood, they may result from the direct effect of the liposomal lipid moieties on damaged cell membranes or from an enhancement of the uptake of extracellular nutrients and the in situ encapsulation and protection of the endogenous growth factors and cytokines elaborated locally as part of the hypermetabolic response that is triggered by acute-phase proteins and cytokines.14 Proinflammatory cytokines, in particular TNF-α, inhibit protein synthesis and induce weight loss.1517 After a thermal injury, as well as in sepsis, TNF-α serum levels increase along with sepsis-induced muscle proteolysis.1820 Decreased serum TNF-α levels are associated with an improvement in net protein balance and a reduction in body weight loss in thermally injured pediatric patients.21,22 Thus, as shown in this study, a decrease in serum TNF-α level may preserve body weight and increase serum transferrin levels. Several studies have attempted to determine the mechanisms by which cationic liposomes exert an inhibitory effect on cytokine expression in vitro23; however, the exact mechanisms are currently not defined.2429 It seems likely that nuclear factor κB (NF-κB) plays an important role.26 The NF-κB is a transcription signal and is crucial in the development of the cellular immune and inflammatory response.26 Because of electrostatic interactions between cells and cationic liposomes, the liposomes bind to the receptor for oxidized low-density lipoproteins.27,28 Sambrano and Steinberg have shown that this competitive binding and subsequent activation of the oxidized low-density lipoprotein receptor indirectly suppress activation and/or binding of NF-κB to its cognate DNA site.27 Furthermore, it has been shown that cationic liposomes inhibit tyrosine phosphorylation of p41, a protein of the mitogen-activated protein kinase transcription factor family, which consecutively leads to a down-regulation of NF-κB.24,25 The inhibition of p41 and NF-κB inhibits the induction of inducible nitric oxide synthetase, which subsequently decreases nitric oxide expression.2426,29 These changes in the signal pathway have been hypothesized to be responsible for the selective inhibition of TNF-α expression at the posttranscriptional level.24,25,30 Given that nitric oxide and inducible nitric oxide synthetase stimulate IL-1β expression, it seems likely that the inhibition of nitric oxide or inducible nitric oxide synthetase activity through cationic liposomes leads to decreased IL-1β expression.31,32

The administration of cholesterol-containing cationic liposomes modulates the hypermetabolic response by affecting cytokine expression, although the effects of the injection are not likely to persist beyond 5 days. There were no differences in serum cytokine and protein level 7 days after burn between liposome-treated and control animals. Furthermore, serum transferrin decreased from day 5 to day 7 after burn in rats receiving liposomes, whereas control-treated animals showed an increase in serum transferrin levels from day 5 to day 7 after burn. In addition, serum haptoglobin level increased from day 5 to day 7 in the liposome-treated group, while serum haptoglobin level decreased during the same period in control animals.

In summary, cholesterol-cationic liposomes increased levels of constitutive hepatic proteins and decreased levels of type 1 acute-phase proteins, with associated decreases in IL-1β and TNF-α levels. Thus, cholesterol-cationic liposomes appear to be suitable as a delivery system for gene therapy in trauma, because liposomes favorably modulate the trauma-induced hypermetabolic response and do not display the cytotoxic effects typically associated with the use of other cationic liposomes in vivo.4,7 We therefore suggest that cholesterol-cationic liposomes should be used as a vector-delivery system for gene therapy in the trauma-induced hypermetabolic response.

This study was supported by grants from the Shriners Hospitals for Children, Galveston, Tex, and the Clayton Foundation for Research, Houston, Tex.

Corresponding author: Robert E. Barrow, PhD, Shriners Hospital for Children, 815 Market St, Galveston, TX 77550 (e-mail: RBarrow@sbi.utmb.edu).

Friedmann  T Overcoming the obstacles to gene therapy. Sci Am. 1997;696- 101
Felgner  PL Nonviral strategies for gene therapy. Sci Am. 1997;6102- 106
Link to Article
Felgner  PLTsai  YLSukhu  L Improved cationic lipid formulations for in vivo gene therapy. Ann N Y Acad Sci. 1995;772126- 139
Link to Article
Felgner  PL Improvements in cationic liposomes for in vivo gene transfer. Hum Gene Ther. 1996;71791- 1793
Link to Article
Wheeler  CJFelgner  PLTsai  YT A novel cationic lipid greatly enhances plasmid DNA delivery and expression in mouse lung. Proc Natl Acad Sci U S A. 1996;9311454- 11459
Link to Article
Sharata  HHKatz  KH Liposomes. Int J Dermatol. 1996;35761- 769
Link to Article
Fey  GGauldie  J The acute phase response of the liver in inflammation. Popper  HSchaffner  Feds.Progress in Liver Disease Philadelphia, Pa WB Saunders Co1990;89- 116
Rothschild  MAOratz  MSchreiber  SS Serum albumin. Hepatology. 1988;8385- 401
Link to Article
Moshage  H Cytokines and the hepatic acute phase response. J Pathol. 1997;181257- 266
Link to Article
Selzman  CHShames  BDHarken  A  et al.  Therapeutic implications of interleukin-10 in surgical disease. Shock. 1998;10309- 318
Link to Article
Gilpin  DAHsieh  CCKunninger  DTHerndon  DNPapaconstantinou  J Regulation of the acute phase response genes alpha1-acid glycoprotein and alpha1-antitrypsin correlates with sensitivity to thermal injury. Surgery. 1996;119664- 673
Link to Article
Jarrar  DWolf  SEJeschke  MG  et al.  Growth hormone attenuates the acute phase response to thermal injury. Arch Surg. 1997;1321171- 1176
Link to Article
Herndon  DNWilmore  DWMason  AD  JrPruitt  BA  Jr Development and analysis of a small animal model simulating the human postburn hypermetabolic response. J Surg Res. 1978;25394- 403
Link to Article
Jeschke  MGBarrow  REHawkins  HK  et al.  IGF-I gene transfer in thermally injured rats. Gene Ther. In press
Beutler  BCerami  A The common mediator of shock, cachexia and tumor necrosis. Adv Immunol. 1988;42213- 231
Moldawer  LLLowry  SFCerami  A Cachectin: its impact on metabolism and nutritional status. Annu Rev Nutr. 1988;8585- 609
Link to Article
Frost  RALang  CHGelato  MC Transient exposure of human myoblasts to tumor necrosis factor-α inhibits serum and insulin-like growth factor-I stimulated protein synthesis. Endocrinology. 1997;1384153- 4159
Marano  MFong  YMoldawer  LL  et al.  Cachectin/TNF in the serum of ICU and burn patients [abstract].  Proceedings of the 29th Annual Meeting of the American Burn Association March 23-35, 1998 Seattle, WashVol 20 Chicago, Ill American Burn Association1988;Abstract 18
Yamada  YEndo  SInada  K Plasma cytokine levels in patients with severe burn injury: with reference to the relationship between infection and prognosis. Burns. 1996;22587- 593
Link to Article
Balteskard  LUnneberg  KHalvorsen  D  et al.  The influence of growth hormone on tumour necrosis factor and neutrophil leukocyte function in sepsis. Scand J Infect Dis. 1997;29393- 399
Link to Article
Gore  DCHoneycutt  DJahoor  FWolfe  RRHerndon  DN Effect of exogenous growth hormone on whole-body and isolated-limb protein kinetics in burned patients. Arch Surg. 1991;12638- 43
Link to Article
Chrysopoulo  MTJeschke  MGRamirez  RJBarrow  REHerndon  DN Growth hormone attenuates tumor necrosis factor α in burned children. Arch Surg. 1999;134283- 286
Link to Article
Pennanen  NLapinjoki  SUrtti  AMoenkoennen  J Effect of liposomal and free biphosphanates on the IL-1β, IL-6 and TNF-α secretion from RAW 264 cells in vitro. Pharmacol Res. 1995;12916- 922
Link to Article
Aramaki  YNitta  FMatsuno  RMorimura  YTsuciya  S Inhibitory effects of negatively charged liposomes on nitric oxide production from macrophages stimulated by LPS. Biochem Biophys Res Commun. 1996;2201- 6
Link to Article
Aramaki  YMatsuno  RNitta  FTsuciya  S Negatively charged liposomes inhibit tyrosine phosphorylation of 41-kDa protein in murine macrophages stimulated with LPS. Biochem Biophys Res Commun. 1997;231827- 830
Link to Article
Sherman  MPAeberhard  EEWong  VZGriscavage  JMIgnarro  LJ Pyrrolidine dithiocarbamate inhibits induction of nitric oxide synthase activity in rat alveolar macrophages. Biochem Biophys Res Commun. 1993;1911301- 1308
Link to Article
Sambrano  GRSteinberg  D Recognition of oxidatively damaged and apoptotic cells by an oxidized low density lipoprotein receptor on mouse peritoneal macrophages: role of membrane phosphatidylserine. Proc Natl Acad Sci U S A. 1995;921396- 1400
Link to Article
Shackelford  REMisra  UKFlorine-Casteel  KTai  SFPizzo  SAdams  DO Oxidized low density lipoprotein suppresses activation of NFκB in macrophages via a pertussis toxin-sensitive signaling mechanism. J Biol Chem. 1995;2703475- 3478
Link to Article
Mulsch  ASchray-Utz  BMordvintcev  PIHauschildt  SBusse  R Diethyldithiocarbamate inhibits induction of macrophage NO synthase. FEBS Lett. 1993;321215- 218
Link to Article
Brisseau  GFKresta  ASchouten  D  et al.  Unilamellar liposomes modulate secretion of tumor necrosis factor by lipopolysaccharide-stimulated macrophages. Antimicrob Agents Chemother. 1994;382671- 2675
Link to Article
Xiao  BGBail  XFZhang  GXHedlund  GLink  H Linomide-mediated protection of oligodendrocytes is associated with inhibition of nitric oxide production and IL-1β expression in Lewis rat glial cells. Neurosci Lett. 1998;24917- 20
Link to Article
Arnush  MHeitmeier  MRScarim  ALMarino  MHManning  PTCorbett  JA IL-1 produced and released endogenously within human islets inhibits beta cell function. J Clin Invest. 1998;102516- 526
Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Percentage change in body weights during the 7-day study. Asterisk indicates significant difference between groups at 3, 4, and 5 days after burn (P=.05, P=.02, and P=.06, respectively). Data are presented as mean±SEM.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Serum transferrin concentrations during the 7-day study period, showing a decrease after burn injury. Liposomes attenuated the drop at 2 and 5 days after burn. Asterisk indicates significant difference between groups (P<.05). Data are presented as mean±SEM (reference serum transferrin level, >0.72 g/L).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Serum α1-acid glycoprotein levels 1 to 7 days after thermal injury. Asterisk indicates significant difference between saline and liposomes (P<.05). Data are presented as mean±SEM (serum α1-acid glycoprotein level reference range, 55-70 pg/mL).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.

Serum interleukin 1β (IL-1β) levels 1 to 7 days after thermal injury. Asterisk indicates significant difference between saline and liposome administration (P<.05). Data are presented as mean±SEM (serum IL-1β level reference range, 4-20 pg/mL).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 5.

Serum tumor necrosis factor α (TNF-α) levels 1 to 7 days after thermal injury. Asterisk indicates significant difference between saline and liposomes (P<.05). Data are presented as mean±SEM (serum TNF-α level reference range, 1-10 pg/mL).

Graphic Jump Location

Tables

References

Friedmann  T Overcoming the obstacles to gene therapy. Sci Am. 1997;696- 101
Felgner  PL Nonviral strategies for gene therapy. Sci Am. 1997;6102- 106
Link to Article
Felgner  PLTsai  YLSukhu  L Improved cationic lipid formulations for in vivo gene therapy. Ann N Y Acad Sci. 1995;772126- 139
Link to Article
Felgner  PL Improvements in cationic liposomes for in vivo gene transfer. Hum Gene Ther. 1996;71791- 1793
Link to Article
Wheeler  CJFelgner  PLTsai  YT A novel cationic lipid greatly enhances plasmid DNA delivery and expression in mouse lung. Proc Natl Acad Sci U S A. 1996;9311454- 11459
Link to Article
Sharata  HHKatz  KH Liposomes. Int J Dermatol. 1996;35761- 769
Link to Article
Fey  GGauldie  J The acute phase response of the liver in inflammation. Popper  HSchaffner  Feds.Progress in Liver Disease Philadelphia, Pa WB Saunders Co1990;89- 116
Rothschild  MAOratz  MSchreiber  SS Serum albumin. Hepatology. 1988;8385- 401
Link to Article
Moshage  H Cytokines and the hepatic acute phase response. J Pathol. 1997;181257- 266
Link to Article
Selzman  CHShames  BDHarken  A  et al.  Therapeutic implications of interleukin-10 in surgical disease. Shock. 1998;10309- 318
Link to Article
Gilpin  DAHsieh  CCKunninger  DTHerndon  DNPapaconstantinou  J Regulation of the acute phase response genes alpha1-acid glycoprotein and alpha1-antitrypsin correlates with sensitivity to thermal injury. Surgery. 1996;119664- 673
Link to Article
Jarrar  DWolf  SEJeschke  MG  et al.  Growth hormone attenuates the acute phase response to thermal injury. Arch Surg. 1997;1321171- 1176
Link to Article
Herndon  DNWilmore  DWMason  AD  JrPruitt  BA  Jr Development and analysis of a small animal model simulating the human postburn hypermetabolic response. J Surg Res. 1978;25394- 403
Link to Article
Jeschke  MGBarrow  REHawkins  HK  et al.  IGF-I gene transfer in thermally injured rats. Gene Ther. In press
Beutler  BCerami  A The common mediator of shock, cachexia and tumor necrosis. Adv Immunol. 1988;42213- 231
Moldawer  LLLowry  SFCerami  A Cachectin: its impact on metabolism and nutritional status. Annu Rev Nutr. 1988;8585- 609
Link to Article
Frost  RALang  CHGelato  MC Transient exposure of human myoblasts to tumor necrosis factor-α inhibits serum and insulin-like growth factor-I stimulated protein synthesis. Endocrinology. 1997;1384153- 4159
Marano  MFong  YMoldawer  LL  et al.  Cachectin/TNF in the serum of ICU and burn patients [abstract].  Proceedings of the 29th Annual Meeting of the American Burn Association March 23-35, 1998 Seattle, WashVol 20 Chicago, Ill American Burn Association1988;Abstract 18
Yamada  YEndo  SInada  K Plasma cytokine levels in patients with severe burn injury: with reference to the relationship between infection and prognosis. Burns. 1996;22587- 593
Link to Article
Balteskard  LUnneberg  KHalvorsen  D  et al.  The influence of growth hormone on tumour necrosis factor and neutrophil leukocyte function in sepsis. Scand J Infect Dis. 1997;29393- 399
Link to Article
Gore  DCHoneycutt  DJahoor  FWolfe  RRHerndon  DN Effect of exogenous growth hormone on whole-body and isolated-limb protein kinetics in burned patients. Arch Surg. 1991;12638- 43
Link to Article
Chrysopoulo  MTJeschke  MGRamirez  RJBarrow  REHerndon  DN Growth hormone attenuates tumor necrosis factor α in burned children. Arch Surg. 1999;134283- 286
Link to Article
Pennanen  NLapinjoki  SUrtti  AMoenkoennen  J Effect of liposomal and free biphosphanates on the IL-1β, IL-6 and TNF-α secretion from RAW 264 cells in vitro. Pharmacol Res. 1995;12916- 922
Link to Article
Aramaki  YNitta  FMatsuno  RMorimura  YTsuciya  S Inhibitory effects of negatively charged liposomes on nitric oxide production from macrophages stimulated by LPS. Biochem Biophys Res Commun. 1996;2201- 6
Link to Article
Aramaki  YMatsuno  RNitta  FTsuciya  S Negatively charged liposomes inhibit tyrosine phosphorylation of 41-kDa protein in murine macrophages stimulated with LPS. Biochem Biophys Res Commun. 1997;231827- 830
Link to Article
Sherman  MPAeberhard  EEWong  VZGriscavage  JMIgnarro  LJ Pyrrolidine dithiocarbamate inhibits induction of nitric oxide synthase activity in rat alveolar macrophages. Biochem Biophys Res Commun. 1993;1911301- 1308
Link to Article
Sambrano  GRSteinberg  D Recognition of oxidatively damaged and apoptotic cells by an oxidized low density lipoprotein receptor on mouse peritoneal macrophages: role of membrane phosphatidylserine. Proc Natl Acad Sci U S A. 1995;921396- 1400
Link to Article
Shackelford  REMisra  UKFlorine-Casteel  KTai  SFPizzo  SAdams  DO Oxidized low density lipoprotein suppresses activation of NFκB in macrophages via a pertussis toxin-sensitive signaling mechanism. J Biol Chem. 1995;2703475- 3478
Link to Article
Mulsch  ASchray-Utz  BMordvintcev  PIHauschildt  SBusse  R Diethyldithiocarbamate inhibits induction of macrophage NO synthase. FEBS Lett. 1993;321215- 218
Link to Article
Brisseau  GFKresta  ASchouten  D  et al.  Unilamellar liposomes modulate secretion of tumor necrosis factor by lipopolysaccharide-stimulated macrophages. Antimicrob Agents Chemother. 1994;382671- 2675
Link to Article
Xiao  BGBail  XFZhang  GXHedlund  GLink  H Linomide-mediated protection of oligodendrocytes is associated with inhibition of nitric oxide production and IL-1β expression in Lewis rat glial cells. Neurosci Lett. 1998;24917- 20
Link to Article
Arnush  MHeitmeier  MRScarim  ALMarino  MHManning  PTCorbett  JA IL-1 produced and released endogenously within human islets inhibits beta cell function. J Clin Invest. 1998;102516- 526
Link to Article

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The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
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For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
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