**1. Introduction**

Cystic fibrosis (CF) is a multi-system disease resulting from mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). In excess of 1900 CF mutations have been identified thus far [1], leading to misfolding of the CFTR protein and defective chloride (Cl- ) transport across cell membranes. CF affects various organs including

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the pancreas, liver, and intestinal tract, but the most severe complications often occur in the lung. CF related symptoms, although variable among patients, are typically present early in life and increase in severity with age despite aggressive therapeutic intervention. CFTR absence or malfunction causes defective ion transport across the epithelium, reduction in pericillary liquid volume, and persistent mucus hypersecretion. As a consequence, mucus accumulates on the airway surface and leads to chronic bacterial infection, exacerbated airway inflammation, and lung injury. Pulmonary inflammation in the CF setting has been observed as early as infancy and there is evidence of structural lung disease present in children with CF as young as 10 weeks old, with 50%–70% of children presenting with bronchiectasis by 3–5 years [2-6]. Additional studies have shown neutrophil-dominated airway inflammation in children with CF [7, 8], and with increasing age elevated levels of proinflammatory mediators including interleukin (IL)-8 [9], tumour necrosis factor-alpha (TNF-alpha) [10], and leukotriene B4 (LTB4) [11] serve to escalate the chronic neutrophil presence in the pulmonary circulation. Indeed, key studies have demonstrated that neutrophil-released granule proteins, particularly neutrophil elastase (NE), play a crucial pathological role (Figure 1) [12, 13]. In the healthy lung, neutrophils represent approximately 1% of the inflammatory cells; however, they account for 60–70% of the total cell count in CF bronchial lavage fluid [14, 15] and ~25% of CF children were positive for free NE activity in airway samples at 3 months old [16].

**Figure 1.** The potential effects of active NE in CF. Neutrophil elastase (NE) has the potential to cleave structural mole‐ cules and antiproteases causing an anti-protease imbalance and also activate enzymes and receptors that play a crucial pathological role in CF. Abbreviations used: NE, neutrophil elastase; SLPI, secretory leukocyte protease inhibitor; TIMPs, tissue inhibitors of metalloproteinases; MMP, metalloproteinase; TACE, tumour necrosis factor-alpha-convert‐ ing enzyme; TLRs, toll-like receptors; EGFR, epidermal growth factor receptor; PAR, protease activated receptors.

Despite advances in our understanding of the molecular and cellular basis of CF, there persists an enigma as to why recruited neutrophils fail to eradicate bacterial infections in the lung. Support for the hypothesis that a genetic defect gives rise to dysregulated neutrophil responses in CF is shown by a study demonstrating upregulation of genes coding for both chemokines and proteins involved in signal transduction in CF [17]. A recent study has demonstrated that CXC chemokine receptors 1/2 (CXCR1/CXCR2) haplotypes in CF modulate antibacterial neutrophil functions against *P. aeruginosa* [18]. In addition, CF circulating neutrophils display an altered toll-like receptor (TLR) expression when compared to blood neutrophils from healthy subjects, including reduced expression of TLR2 [19, 20]. A recently published study identified IFRD1 (interferon-related developmental regulator 1), a histone-deacetylasedependent transcriptional co-regulator expressed during terminal neutrophil differentiation, as a genetic modifier of CF disease severity. Neutrophils isolated from IFRD1 deficient mice exhibited impaired oxidative burst, bacterial clearance, and cytokine production leading to excessive bacterial burden and chronic infection of the lung [21]. Furthermore, levels of IFRD in bronchial epithelial cells with the *∆F508* mutation were significantly reduced but could be rescued by treatment with glutathione suggesting down-regulation of IFRD1 expression in response to oxidative stress [22].

The focus of this chapter is on new research authenticating the CF neutrophil as a key player in disease pathogenesis. Studies published in the previous 10 years specifying intrinsic abnormalities due to a lack of CFTR function, along with reports indicating reprogrammed cell activity secondary to chronic bacterial infection and inflammation will be discussed. Our review of the literature was carried out using the MEDLINE database (from 2005 to the year 2015), Google Scholar, and The Cochrane Library databases using several appropriate generic terms.
