Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in a single gene encoding the glycoprotein CF transmembrane conductance regulator (CFTR) that is mostly (but not only) expressed in excretory epithelia (Davis et al., 1996; Tirouvanziam et al., 2006).

In CF, lung disease is the principal factor on morbidity and mortality (Dauletbaev et al., 2009), but the patients often suffer of serious gastrointestinal problems, called distal intestinal obstruction syndrome (DIOS), a peculiar condition of CF (Lillibridge et al., 1967; Gracey et al., 1969; The Leeds Method of Management, 2008; Hedsund et al., 2012). 

CFTR is a transmembrane channel which is primarily involved in Cl- ions transport, but it also regulates other ion channels (Vasu et al., 2011). The impairment in the structure of this channel causes defects in the transport of Cl- outside the cell, which in turn causes, in the respiratory tract, accumulation of a thick, under-hydrated mucus due to hyper-absorption of sodium chloride and reduced periciliary water and anion transport, leading to reduced mucociliary clearance, airway bacterial colonization and inflammation characterized by an intense airway neutrophil influx (Vasu et al., 2011). The neutrophil influx, the consequent inflammation and their effector oxidative processes are believed to represent major factors in CF respiratory tract disease (Meyer, 2004; Tirouvanziam et al., 2006).

The neutrophils also release, actively or upon death, massive amounts of effector molecules, including elastase, TNF-α and IL-8, which perpetuate tissue damage and neutrophil recruitment and contribute to create a more favorable environment for opportunistic pathogens, which in turn cause more oxidative stress (Schwarzer et al., 2008; Dauletbaev et al., 2009). Furthermore, the organism is unable of countering the imbalance in redox state because of the malabsorption of dietary antioxidants in the gut caused by the disease itself and the inability of cells bearing mutant CFTR proteins to efflux glutathione (GSH) (Kogan et al., 2003; Tirouvanziam et al., 2006). A common gastrointestinal comorbidity is estimated to occur in  2.4% - 21.9% of the patients, depending on the severity of the phenotype (Dray et al., 2004). It occurs basically for the same reason of the CF lung disease: insufficient hydration of mucus and debris at mucosal surfaces because of abnormal transepithelial electrolyte and water transport in the absence of CFTR activity. In the intestine them fuse with intestinal content to form obstructing mucofeculant impactions (Walker et al., 2006). 

The current anti-inflammatory therapies for CF lung disease such as oral corticosteroids,  azithromycin or high-dose ibuprofen are only partially effective and they have extensive adverse effects (Dauletbaev et al., 2009; Tirouvanziam et al., 2006). Recently, n-acetylcysteine (brand name PharmaNAC) has received attention as a potential treatment for these symptoms due to its known efficacy as a mucolytic, anti-inflammatory, antioxidant and its ability to reduce the microbial flora in the lungs (Riise et al., 1994; Tirouvanziam et al., 2006; Dauletbaev et al., 2009; Suk et al., 2011), moreover, it seems that NAC is able to activate chloride movement in epithelial cells expressing the mutant protein (Brown et al., 1997; Köttgen et al., 1996) and it has also been used for the treatment of gastrointestinal problems in CF patients (The Leeds Method of Management, 2008; Gracey et al., 1969; Lillibridge et al., 1967).

NAC is known to be used to replenish the cysteine and GSH that are lost due to acetaminophen toxicity (Atkuri et al., 2007). It acts as a cysteine pro-drug and GSH precursor, it is chemically similar to cysteine, but the presence of the acetyl moiety reduces the reactivity of the thiol compared to cysteine. NAC is much less toxic, less susceptible to oxidation, and more soluble in water (Atkuri et al., 2007) than L-cysteine.

NAC can be orally delivered and it is readily taken up in the stomach and gut where the low pH of stomach makes the neutral species of NAC easily absorbed (Noszál et al., 2000). It is subsequently sent to the liver through the portal vein where it is converted in cysteine (Cotgreave I.A., 1997) and then into intermediates to glutathione (GSH). The oral administration of NAC at doses up to 8,000 mg/day is not known to cause adverse effects (De Rosa et al., 2000).

The two most recent clinical trials about the role of NAC for the treatment of CF, one of them sponsored by BioAdvantex Pharma (Tirouvanziam et al., 2006), have focused on the systemic redox imbalance, thought to be the most important issue, and the role of NAC as an antioxidant and a GSH prodrug. This redox imbalance can affect particularly neutrophils, given their low basal level of intracellular GSH (Kinnula et al., 2002), leading to abnormal apoptosis (Tirouvanziam et al., 2006).

Tirouvanziam and colleagues, during a phase I clinical trial, hypothesized that orally delivering high doses of oral NAC ( 900 mg per dose, three times daily) could improve GSH levels within the circulating neutrophils, more than the aerosolized formulation, therefore decreasing apoptosis and further oxidative stress and also possibly inhibit recruitment of neutrophils to CF airways and their subsequent dysfunction. After four weeks of treatment, even if FEV1 and FVC them-selves did not change over the short period of this trial, they proved that NAC at high doses is completely safe, and it was able to reduce the count of neutrophils in the airways as well as elastase activity, moreover, the GSH levels in blood neutrophils were higher at the end of this short-term treatment. All of these parameters are know to be impaired in CF (Tirouvanziam et al., 2006).

These studies add to other performed about the potential role of NAC for treatment of pulmonary diseases such as COPD and chronic bronchitis (Dekhuijzen and van Beurden, 2006; Gerrits et al., 2003; Grandjean et al., 2000; Stey et al., 2000) indicating NAC as a promising and safe molecule.

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