**1. Introduction**

### **1.1. Oxidative stress pathways in cystic fibrosis**

Colonization of the respiratory tract by bacterial pathogens in the mucus of CF patients leads to a sustained inflammatory response characterized by massive influx of polymorphonuclear neutrophils and the activation of macrophages, eosinophils, monocytes and lymphocytes. An integral part of this inflammation is the production and release of free radicals such as superoxide (O2-) and hydroxide (OH-), which can induce oxidative stress. In fact, elevated levels of proinflammatory cytokines, especially interleukins (IL-1β, IL-6, IL-8), tumour necrosis factor-α and potent neutrophil chemoattractants found in bronchoalveolar lavage, are

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involved in the production of pro-oxidants leading to apoptosis and tissular damage. Con‐ versely, the production of immunosuppressive cytokine IL-10 with anti-inflammatory properties is reduced or even suppressed [1].

Thus, the severe and recurrent respiratory inflammation ultimately leads to excessive activated neutrophils and macrophages, which contribute to the generation of free radicals. Further‐ more, defects in the Cystic Fibrosis Transmembrane Regulator (CFTR) can directly affect transport and glutathione homeostasis, while maldigestion and malabsorption related to exocrine pancreatic insufficiency impair the absorption of fat-soluble vitamins and antioxi‐ dants. It has been suggested that the chloride channel CFTR also regulates glutathione, disturbing the balance between pro- and anti-oxidants and promoting oxidative stress, which may play an important role in Cystic Fibrosis Related Diabetes, a serious complication associated with a dramatic increase in morbidity and mortality [2].

Although the cause of CF is well established, the pathogenesis of this progressive multisyste‐ mic disease is not yet fully understood. In fact, the broad spectrum of phenotypes and severity in CF patients that carry the same combination of mutations suggests additional environmental or genetic factors.

The CFTR dysfunction in the pancreas causes exocrine pancreatic insufficiency in almost 90% of patients with CF. This leads to fat malabsorption, which explains the difficulty to gain or at least maintain weight, and the high incidence of fat-soluble-vitamins and antioxidant (vita‐ mins A, E, and D and carotenoids) deficiency, and also essential-fatty-acids deficiency. Obviously, the reduced availability of dietary antioxidants may further increase oxidative stress in CF patients, which apparently plays an important role in multiorgan pathophysiology of CF.

Consequently, the products of lipid peroxidation, which are markers of oxidative stress, have been detected in exhaled breath condensate, as well as in blood and urine of CF patients. Thus products of lipid peroxidation are unstable molecules that can reach distant sites to exert various effects, including activation of the fibroblast cells in the presence of inflammation, which further increases oxidative stress [3].
