Effect of N-acetylcysteine on neutrophil activation markers in healthy volunteers: In vivo and in vitro study

Sadowska, Anna; Manuel-y-Keenoy, Begoña; Vertongen, Tim; Schippers, Glenn; Radomska-Leśniewska, Dorota M.; Heytens, Elke; Backer, Wilfried A. De

doi:10.1016/j.phrs.2005.11.003

Cited by 34 publications

(36 citation statements)

References 46 publications

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“…In contrast, NAC was less effective in preventing elastase release. In this sense, we only appreciated a significant reduction at 10 m M , the highest concentration assayed, which was also in accordance with previous studies [47]. Recent studies have shown that NAC may ameliorate lung emphysema induced by elastase or cigarette smoke in animal models [49,50], which indicates that an active antioxidant therapy could be useful to ameliorate the emphysema progression in humans.…”

Section: Discussionsupporting

confidence: 92%

“…The NAC dose needed to inhibit ROS generation is controversial. Some authors found an increase in glutathione content in neutrophils only after 10 m M NAC [47], and others reported that NAC at 100–200 µ M in vitro inhibits ROS generation [48]. Our findings relative to oxidative stress and chemotaxis are in accordance with other studies and might have pharmacological significance, since a 100-µ M concentration of NAC is enough to inhibit both processes in vitro.…”

Section: Discussionsupporting

confidence: 91%

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Neutrophil Activation in Severe, Early-Onset COPD Patients versus Healthy Non-Smoker Subjects in vitro: Effects of Antioxidant Therapy

Milara¹,

Juan²,

Peiró³

et al. 2011

Respiration

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Background: Neutrophils and oxidative stress have been implicated in the pathogenesis of COPD. Severe, early-onset COPD is characterized by a rapid decline in the lung function at an early age; however, nothing is known about neutrophil activation in COPD patients. Objectives: The aim of this study was to evaluate peripheral blood neutrophil activation in severe, early-onset COPD patients versus healthy non-smokers and the effect of N-acetyl-L-cysteine (NAC) on neutrophil activation in vitro. Methods: Neutrophils were isolated from 15 severe, early-onset COPD patients and 15 age-matched healthy subjects and stimulated with N-formyl- Met-Leu-Phe (fMLP) in the presence or absence of NAC (10 µM to 10 mM). Neutrophil chemotaxis, elastase release, reactive oxygen species (ROS), intracellular thiols and apoptosis were measured by Boyden chamber, spectrofluorometry, CMFDA and H₂DCF-DA dyes and by annexin V-FITC, respectively. Results: Chemotaxis of peripheral blood neutrophils from COPD patients in response to fMLP was 30% more increased than that observed in healthy subjects. Elastase release in response to fMLP was 2-fold higher in neutrophils from COPD patients versus healthy subjects. Intracellular thiol levels were 30% lower in COPD and ROS was approximately 30% higher in COPD versus healthy neutrophils. Spontaneous apoptosis showed no differences in both groups of patients and fMLP-induced apoptosis was higher in COPD. Pre-treatment with the antioxidant NAC effectively attenuated neutrophil chemotaxis, elastase release and ROS as well as effectively increased thiol levels in COPD. Conclusions: Neutrophils in severe, early-onset COPD patients are highly activated and this is alleviated by NAC in vitro.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 91%

Neutrophil Activation in Severe, Early-Onset COPD Patients versus Healthy Non-Smoker Subjects in vitro: Effects of Antioxidant Therapy

Milara¹,

Juan²,

Peiró³

et al. 2011

Respiration

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“…The two molecules are induced in radiationinduced pulmonary fibrosis and the radiation-induced increases of VCAM-1 and ICAM-1 are reversed by administration of manganese superoxide dismutase (49,50). Treatment of bronchoalveolar macrophages obtained from patients with IPF or other interstitial lung disease with N-acetylcysteine, an agent used in the treatment of IPF (51), caused a decrease in ICAM-1 expression (52), and a reduction of neutrophil activation and IL-8 expression (53,54), potentially suggesting that many of the changes in the peripheral blood are driven by the same mechanistic theme. The source of ICAM-1 and VCAM-1 in the blood remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Peripheral Blood Proteins Predict Mortality in Idiopathic Pulmonary Fibrosis

Richards

Kaminski

Baribaud³

et al. 2012

Am J Respir Crit Care Med

335

287

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Rationale: Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease of unknown etiology with a variable and unpredictable course. Objectives: The aim of this study was to identify and validate plasma proteins that are predictive of outcome in IPF. Methods: Plasma samples were available for 241 patients with IPF (140 derivation and 101 validation). In the derivation cohort, concentrations of 92 proteins were analyzed using a multiplex beadbased immunoassay and concentrations of matrix metalloproteinase (MMP)-7, MMP-1, and surfactant protein D were assessed by ELISA. In the validation cohort concentrations of intercellular adhesion molecule (ICAM)-1, IL-8, and vascular cell adhesion molecule (VCAM)-1 were assessed by bead-based multiplex assay, and S100A12 and MMP-7 by ELISA. Associations of biomarkers with mortality, transplant-free survival, and disease progression were tested in the derivation and validation cohorts using nonparametric methods of survival analysis and the Cox proportional hazards model, and an integrated risk prediction score was derived and tested. Measurements and Main Results: High concentrations of MMP-7, ICAM-1, IL-8, VCAM-1, and S100A12 predicted poor overall survival, poor transplant-free survival, and poor progression-free survival in the derivation cohort. In the independent validation cohort high concentrations of all five were predictive of poor transplant-free survival; MMP-7, ICAM-1, and IL-8 of overall survival; and ICAM-1 of poor progression-free survival. The personal clinical and molecular mortality prediction index derived in the derivation cohort was highly predictive of mortality in the validation cohort. Conclusions: Our results suggest that plasma proteins should be evaluated as a tool for prognosis determination in prioritization of patients for lung transplantation and stratification in drug studies.

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“…Assuming that most of the nonprotein SH content in biological samples is GSH [45,46] and that NAC is a GSH precursor, our findings are in agreement with the data reported by Haddad and Land [47] and Haddad and Harb [48], who have demonstrated that NAC increases the GSH/GSSG ratio. In fact, a significant body of evidence suggests that NAC decreases expression of pro-inflammatory molecules by inhibiting NF-jB and MAPK pathways by redox mechanisms [22,47,[49][50][51][52]. Accordingly, in-vivo GSH depletion activates NF-jB and MAPK pathways in liver and kidney [53], and increases the LPS-induced release of IL-1b, IL-6, IL-8 and TNF-a in different cell cultures [54,55].…”

Section: Discussionmentioning

confidence: 99%