The effect of N-acetylcysteine on nuclear factor-kappa B activation, interleukin-6, interleukin-8, and intercellular adhesion molecule-1 expression in patients with sepsis

R. L. Paterson, Helen Frances Galley, Nigel Robert Webster

Research output: Contribution to journalArticle

108 Citations (Scopus)

Abstract

Objective: Expression of inflammatory mediators is controlled in part at the transcriptional level via nuclear factor-kappaB. Inhibition of nuclear factor-kappaB activation may be beneficial in critically ill patients. N-acetylcysteine is an antioxidant that inhibits nuclear factor-kappaB activation in vitro. In this pilot study we investigated the effect of N-acetylcysteine on nuclear factor-kappaB activation and circulating cytokine and adhesion molecules in patients with sepsis.

Design: Prospective, randomized, double blind, placebo-controlled pilot trial.

Setting: Eight-bed intensive care unit in a university teaching hospital.

Patients: Twenty consecutive patients within 12 hrs of fulfilling the consensus criteria for sepsis.

Interventions: A bolus of 150 mg/kg N-acetylcysteine in 100 mL of 0.9% saline over 15 mins, then 50 mg/kg in 100 mL of 0.9% saline over 4 hrs as a loading dose, and then a maintenance infusion of 50 mg/kg in 200 mL of 0.9% saline over each 24-hr period for a total of 72 hrs, or an equivalent volume of saline.

Measurements and Main Results: Nuclear factor-kappaB activation was measured in mononuclear leukocytes using electrophoretic mobility shift assay, at baseline and 24, 48, 72, and 96 hrs later.

Activation decreased significantly in patients treated with N-acetylcysteine (p = .016) but not placebo and was significantly reduced at 72 hrs compared with both preinfusion values (p = .028) and patients receiving placebo (p = .01). Plasma interleukin-6, interleukin-8, and soluble intercellular adhesion molecule-1 concentrations were measured using enzyme immunoassay. Interieukin-6 concentrations were high initially and then decreased in all patients, regardless of whether they received N-acetylcysteine or placebo. Interleukin-8 decreased significantly only in those who received N-acetylcysteine (p = .0081). Soluble intercellular adhesion molecule-1 concentrations remained unchanged in all patients.

Conclusions: Administration of N-acetylcysteine results in decreased nuclear factor-kappaB activation in patients with sepsis, associated with decreases in interleukin-8 but not interieukin-6 or soluble intercellular adhesion molecule-1. These pilot data suggest that antioxidant therapy with N-acetylcysteine may be useful in blunting the inflammatory response to sepsis. Further studies are warranted.

Original languageEnglish
Pages (from-to)2574-2578
Number of pages4
JournalCritical Care Medicine
Volume31
Issue number11
DOIs
Publication statusPublished - 2003

Keywords

  • sepsis
  • nuclear factor-kappa B
  • N-acetylcysteine
  • interleukin-6
  • interleukin-8
  • intercellular adhesion molecule-1
  • antioxidant
  • glutathione
  • transcription factor
  • FACTOR-KAPPA-B
  • ACETYL-L-CYSTEINE
  • FULMINANT HEPATIC-FAILURE
  • HUMAN SEPTIC SHOCK
  • ORGAN FAILURE
  • DIMETHYL-SULFOXIDE
  • GENE-TRANSCRIPTION
  • LUNG INFLAMMATION
  • PLASMA CYTOKINE
  • DOUBLE-BLIND

Cite this

@article{75d0d21f697f4f819ea7c8104f5aeedb,
title = "The effect of N-acetylcysteine on nuclear factor-kappa B activation, interleukin-6, interleukin-8, and intercellular adhesion molecule-1 expression in patients with sepsis",
abstract = "Objective: Expression of inflammatory mediators is controlled in part at the transcriptional level via nuclear factor-kappaB. Inhibition of nuclear factor-kappaB activation may be beneficial in critically ill patients. N-acetylcysteine is an antioxidant that inhibits nuclear factor-kappaB activation in vitro. In this pilot study we investigated the effect of N-acetylcysteine on nuclear factor-kappaB activation and circulating cytokine and adhesion molecules in patients with sepsis.Design: Prospective, randomized, double blind, placebo-controlled pilot trial.Setting: Eight-bed intensive care unit in a university teaching hospital.Patients: Twenty consecutive patients within 12 hrs of fulfilling the consensus criteria for sepsis.Interventions: A bolus of 150 mg/kg N-acetylcysteine in 100 mL of 0.9{\%} saline over 15 mins, then 50 mg/kg in 100 mL of 0.9{\%} saline over 4 hrs as a loading dose, and then a maintenance infusion of 50 mg/kg in 200 mL of 0.9{\%} saline over each 24-hr period for a total of 72 hrs, or an equivalent volume of saline.Measurements and Main Results: Nuclear factor-kappaB activation was measured in mononuclear leukocytes using electrophoretic mobility shift assay, at baseline and 24, 48, 72, and 96 hrs later.Activation decreased significantly in patients treated with N-acetylcysteine (p = .016) but not placebo and was significantly reduced at 72 hrs compared with both preinfusion values (p = .028) and patients receiving placebo (p = .01). Plasma interleukin-6, interleukin-8, and soluble intercellular adhesion molecule-1 concentrations were measured using enzyme immunoassay. Interieukin-6 concentrations were high initially and then decreased in all patients, regardless of whether they received N-acetylcysteine or placebo. Interleukin-8 decreased significantly only in those who received N-acetylcysteine (p = .0081). Soluble intercellular adhesion molecule-1 concentrations remained unchanged in all patients.Conclusions: Administration of N-acetylcysteine results in decreased nuclear factor-kappaB activation in patients with sepsis, associated with decreases in interleukin-8 but not interieukin-6 or soluble intercellular adhesion molecule-1. These pilot data suggest that antioxidant therapy with N-acetylcysteine may be useful in blunting the inflammatory response to sepsis. Further studies are warranted.",
keywords = "sepsis, nuclear factor-kappa B, N-acetylcysteine, interleukin-6, interleukin-8, intercellular adhesion molecule-1, antioxidant, glutathione, transcription factor, FACTOR-KAPPA-B, ACETYL-L-CYSTEINE, FULMINANT HEPATIC-FAILURE, HUMAN SEPTIC SHOCK, ORGAN FAILURE, DIMETHYL-SULFOXIDE, GENE-TRANSCRIPTION, LUNG INFLAMMATION, PLASMA CYTOKINE, DOUBLE-BLIND",
author = "Paterson, {R. L.} and Galley, {Helen Frances} and Webster, {Nigel Robert}",
year = "2003",
doi = "10.1097/01.CCM.0000089945.69588.18",
language = "English",
volume = "31",
pages = "2574--2578",
journal = "Critical Care Medicine",
issn = "0090-3493",
publisher = "Lippincott Williams and Wilkins",
number = "11",

}

TY - JOUR

T1 - The effect of N-acetylcysteine on nuclear factor-kappa B activation, interleukin-6, interleukin-8, and intercellular adhesion molecule-1 expression in patients with sepsis

AU - Paterson, R. L.

AU - Galley, Helen Frances

AU - Webster, Nigel Robert

PY - 2003

Y1 - 2003

N2 - Objective: Expression of inflammatory mediators is controlled in part at the transcriptional level via nuclear factor-kappaB. Inhibition of nuclear factor-kappaB activation may be beneficial in critically ill patients. N-acetylcysteine is an antioxidant that inhibits nuclear factor-kappaB activation in vitro. In this pilot study we investigated the effect of N-acetylcysteine on nuclear factor-kappaB activation and circulating cytokine and adhesion molecules in patients with sepsis.Design: Prospective, randomized, double blind, placebo-controlled pilot trial.Setting: Eight-bed intensive care unit in a university teaching hospital.Patients: Twenty consecutive patients within 12 hrs of fulfilling the consensus criteria for sepsis.Interventions: A bolus of 150 mg/kg N-acetylcysteine in 100 mL of 0.9% saline over 15 mins, then 50 mg/kg in 100 mL of 0.9% saline over 4 hrs as a loading dose, and then a maintenance infusion of 50 mg/kg in 200 mL of 0.9% saline over each 24-hr period for a total of 72 hrs, or an equivalent volume of saline.Measurements and Main Results: Nuclear factor-kappaB activation was measured in mononuclear leukocytes using electrophoretic mobility shift assay, at baseline and 24, 48, 72, and 96 hrs later.Activation decreased significantly in patients treated with N-acetylcysteine (p = .016) but not placebo and was significantly reduced at 72 hrs compared with both preinfusion values (p = .028) and patients receiving placebo (p = .01). Plasma interleukin-6, interleukin-8, and soluble intercellular adhesion molecule-1 concentrations were measured using enzyme immunoassay. Interieukin-6 concentrations were high initially and then decreased in all patients, regardless of whether they received N-acetylcysteine or placebo. Interleukin-8 decreased significantly only in those who received N-acetylcysteine (p = .0081). Soluble intercellular adhesion molecule-1 concentrations remained unchanged in all patients.Conclusions: Administration of N-acetylcysteine results in decreased nuclear factor-kappaB activation in patients with sepsis, associated with decreases in interleukin-8 but not interieukin-6 or soluble intercellular adhesion molecule-1. These pilot data suggest that antioxidant therapy with N-acetylcysteine may be useful in blunting the inflammatory response to sepsis. Further studies are warranted.

AB - Objective: Expression of inflammatory mediators is controlled in part at the transcriptional level via nuclear factor-kappaB. Inhibition of nuclear factor-kappaB activation may be beneficial in critically ill patients. N-acetylcysteine is an antioxidant that inhibits nuclear factor-kappaB activation in vitro. In this pilot study we investigated the effect of N-acetylcysteine on nuclear factor-kappaB activation and circulating cytokine and adhesion molecules in patients with sepsis.Design: Prospective, randomized, double blind, placebo-controlled pilot trial.Setting: Eight-bed intensive care unit in a university teaching hospital.Patients: Twenty consecutive patients within 12 hrs of fulfilling the consensus criteria for sepsis.Interventions: A bolus of 150 mg/kg N-acetylcysteine in 100 mL of 0.9% saline over 15 mins, then 50 mg/kg in 100 mL of 0.9% saline over 4 hrs as a loading dose, and then a maintenance infusion of 50 mg/kg in 200 mL of 0.9% saline over each 24-hr period for a total of 72 hrs, or an equivalent volume of saline.Measurements and Main Results: Nuclear factor-kappaB activation was measured in mononuclear leukocytes using electrophoretic mobility shift assay, at baseline and 24, 48, 72, and 96 hrs later.Activation decreased significantly in patients treated with N-acetylcysteine (p = .016) but not placebo and was significantly reduced at 72 hrs compared with both preinfusion values (p = .028) and patients receiving placebo (p = .01). Plasma interleukin-6, interleukin-8, and soluble intercellular adhesion molecule-1 concentrations were measured using enzyme immunoassay. Interieukin-6 concentrations were high initially and then decreased in all patients, regardless of whether they received N-acetylcysteine or placebo. Interleukin-8 decreased significantly only in those who received N-acetylcysteine (p = .0081). Soluble intercellular adhesion molecule-1 concentrations remained unchanged in all patients.Conclusions: Administration of N-acetylcysteine results in decreased nuclear factor-kappaB activation in patients with sepsis, associated with decreases in interleukin-8 but not interieukin-6 or soluble intercellular adhesion molecule-1. These pilot data suggest that antioxidant therapy with N-acetylcysteine may be useful in blunting the inflammatory response to sepsis. Further studies are warranted.

KW - sepsis

KW - nuclear factor-kappa B

KW - N-acetylcysteine

KW - interleukin-6

KW - interleukin-8

KW - intercellular adhesion molecule-1

KW - antioxidant

KW - glutathione

KW - transcription factor

KW - FACTOR-KAPPA-B

KW - ACETYL-L-CYSTEINE

KW - FULMINANT HEPATIC-FAILURE

KW - HUMAN SEPTIC SHOCK

KW - ORGAN FAILURE

KW - DIMETHYL-SULFOXIDE

KW - GENE-TRANSCRIPTION

KW - LUNG INFLAMMATION

KW - PLASMA CYTOKINE

KW - DOUBLE-BLIND

U2 - 10.1097/01.CCM.0000089945.69588.18

DO - 10.1097/01.CCM.0000089945.69588.18

M3 - Article

VL - 31

SP - 2574

EP - 2578

JO - Critical Care Medicine

JF - Critical Care Medicine

SN - 0090-3493

IS - 11

ER -