Long-term treatment with oral N-acetylcysteine: Affects lung function but not sputum inflammation in cystic fibrosis subjects. A phase II randomized placebo-controlled trial

Conrad, Carol; Lymp, James; Thompson, Valeria; Dunn, Colleen; Davies, Zoe; Chatfield, Barbara A.; Nichols, David P.; Clancy, John; Vender, Robert L.; Egan, Marie E.; Quittell, Lynne M.; Michelson, Peter H.; Antony, Veena B.; Spahr, Jonathan E.; Rubenstein, Ronald C.; Moss, Richard B.; Herzenberg, Leonore A.; Goss, Christopher H.; Tirouvanziam, Rabindra

doi:10.1016/j.jcf.2014.08.008

Cited by 94 publications

(70 citation statements)

References 35 publications

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“…Corticosteroids [97] Ibuprofen* [92,[102][103][104] Antibacterials with anti-inflammatory properties Azithromycin* [109] Anti-PcrV antibody (KB-001A) [111] Modulators of intracellular signaling IL-10 [144] Interferon-γ (actimmune) [120] P38 MAPK inhibitor L-arginine [124] Parthenolide [145] Simvastatin [122] Synthetic triterpenoids (CDDO) [126] Thiazolidinediones/pioglitazone [116] Inhibitors of neutrophil influx Anti-IL-8 [146] Anti-IL-17 [ Anti-oxidants N-acetyl cysteine [139,140], β-carotene, glutathione, Omega-3 fatty acids Vitamin C, vitamin E [147] Anti-proteases α1-protease inhibitor (plasma derived and transgenic) [132] DMP-777 [148] EPI-hNE4 (Depalstat) [149] Monocyte/neutrophil elastase inhibitor [150] Recombinant secretory leukoprotease inhibitor [151] * Drugs recommended by CFF.…”

Section: Broad-based Anti-inflammatory Modulators Piroxicammentioning

confidence: 99%

“…The study was of short duration and not powered to detect changes in pulmonary function or other clinical outcome measures. A subsequent large randomized double-blind placebo controlled trial demonstrated that N-acetyl cysteine stabilized lung function but had no effect on neutrophil elastase activity or other inflammatory biomarkers [140]. N-acetyl cysteine is converted to cysteine, an essential precursor of glutathione synthesis.…”

Section: Inhibition Of Neutrophil Influx and Neutrophil Productsmentioning

confidence: 99%

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Inflammation in cystic fibrosis lung disease: Pathogenesis and therapy

Cantin

Hartl

Konstan

et al. 2015

Journal of Cystic Fibrosis

401

322

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Lung disease is the major cause of morbidity and mortality in patients with cystic fibrosis (CF). Although CF lung disease is primarily an infectious disorder, the associated inflammation is both intense and ineffective at clearing pathogens. Persistent high-intensity inflammation leads to permanent structural damage of the CF airways and impaired lung function that eventually results in respiratory failure and death. Several defective inflammatory responses have been linked to cystic fibrosis transmembrane conductance regulator (CFTR) deficiency including innate and acquired immunity dysregulation, cell membrane lipid abnormalities, various transcription factor signaling defects, as well as altered kinase and toll-like receptor responses. The inflammation of the CF lung is dominated by neutrophils that release oxidants and proteases, particularly elastase. Neutrophil elastase in the CF airway secretions precedes the appearance of bronchiectasis, and correlates with lung function deterioration and respiratory exacerbations. Anti-inflammatory therapies are therefore of particular interest for CF lung disease but must be carefully studied to avoid suppressing critical elements of the inflammatory response and thus worsening infection. This review examines the role of inflammation in the pathogenesis of CF lung disease, summarizes the results of past clinical trials and explores promising new anti-inflammatory options.

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Section: Broad-based Anti-inflammatory Modulators Piroxicammentioning

confidence: 99%

Section: Inhibition Of Neutrophil Influx and Neutrophil Productsmentioning

confidence: 99%

Inflammation in cystic fibrosis lung disease: Pathogenesis and therapy

Cantin

Hartl

Konstan

et al. 2015

Journal of Cystic Fibrosis

401

322

View full text Add to dashboard Cite

show abstract

“…Notably, the use of the oral antioxidant N-acetylcysteine showed beneficial effects in CF lung disease through reduction of NE activity, associated with increased or stable lung function Conrad et al, 2015). More specifically, therapies targeting neutrophil proteases using aerosolized protease inhibitors as AAT (α-1 antitrypsin) or SLPI were tested in clinical trials in CF patients.…”

Section: Neutrophil-based Targeting Strategies and Their Implicationmentioning

confidence: 99%

Neutrophils in cystic fibrosis

Laval

Ralhan

Hartl

2016

Biological Chemistry

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Cystic fibrosis (CF) lung disease is characterized by chronic infection and inflammation. Among inflammatory cells, neutrophils represent the major cell population accumulating in the airways of CF patients. While neutrophils provide the first defensive cellular shield against bacterial and fungal pathogens, in chronic disease conditions such as CF these short-lived immune cells release their toxic granule contents that cause tissue remodeling and irreversible structural damage to the host. A variety of human and murine studies have analyzed neutrophils and their products in the context of CF, yet their precise functional role and therapeutic potential remain controversial and incompletely understood. Here, we summarize the current evidence in this field to shed light on the complex and multi-faceted role of neutrophils in CF lung disease.

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“…However, clinical studies aiming to neutralize free NE activity in CF airways by the delivery of antiproteases, such as α-1 antitrypsin, showed modulated airway inflammation but failed to show convincing effects on lung function [25]. In contrast, the use of the oral antioxidant N -acetylcysteine, as a strategy to rebalance antioxidant deficiencies in CF, shows beneficial effects on lung function, but has no effect on neutrophilic inflammation [140]. Future studies are required to reconcile these findings and to further assess the therapeutic potential of antiprotease or antioxidant approaches in CF lung disease [24,141].…”

Section: Novel Therapeutic Conceptsmentioning

confidence: 99%

Current Concepts and Controversies in Innate Immunity of Cystic Fibrosis Lung Disease

et al. 2016

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Cystic fibrosis (CF) lung disease is characterized by chronic infection and inflammation. The inflammatory response in CF is dominated by the activation of the innate immune system. Bacteria and fungi represent the key pathogens chronically colonizing the CF airways. In response, innate immune pattern recognition receptors, expressed by airway epithelial and myeloid cells, sense the microbial threat and release chemoattractants to recruit large numbers of neutrophils into CF airways. However, neutrophils fail to efficiently clear the invading pathogens, but instead release harmful proteases and oxidants and finally cause tissue injury. Here, we summarize and discuss current concepts and controversies in the field of innate immunity in CF lung disease, facing the ongoing questions of whether inflammation is good or bad in CF and how innate immune mechanisms could be harnessed therapeutically.

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Long-term treatment with oral N-acetylcysteine: Affects lung function but not sputum inflammation in cystic fibrosis subjects. A phase II randomized placebo-controlled trial

Cited by 94 publications

References 35 publications

Inflammation in cystic fibrosis lung disease: Pathogenesis and therapy

Inflammation in cystic fibrosis lung disease: Pathogenesis and therapy

Neutrophils in cystic fibrosis

Current Concepts and Controversies in Innate Immunity of Cystic Fibrosis Lung Disease

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