Pulmonary Inflammation in Cystic Fibrosis: Impact of Innate Immunity and Estrogen

Cystic fibrosis (CF) is a multisystem disease, affecting many organs including the liver, intestines, respiratory and reproductive tracts, bone, heart, spleen, gall bladder, and pancreas (Table 1) [1]. It is the pulmonary manifestations that account for significant morbidity and mortality in patients with CF [2]. The CF transmembrane conductance regulator (CFTR) protein is central to CF disease. CFTR is a cyclic adenosine monophosphateactivated, adenosine triphosphate-binding cassette transporter protein (Figure 1). Expressed in submucosal glands and the apical membranes of epithelial cells in the liver, pancreas, intestines, reproductive tract, and lungs, the CFTR normally functions as a chloride channel. Individuals with CF have mutations in the CFTR gene. More than 1800 CFTR mutations have been identified to date. A subgroup of CFTR mutations are disease-causing and, as CF is an autosomal recessive disease, two alleles with such mutations are required to cause the disease. CFTR mutations can be grouped into six classes (I–VI) depending on whether they affect the expression, processing, or activity of CFTR, or a combination of these [3,4]. For example, the class III glycine to aspartic acid mutation at codon 551 (G551D) leads to a CFTR channel defect, whereas the class II deletion of phenylalanine mutation at codon 508 (ΔF508) results in a CFTR protein that is aberrantly folded and defectively processed in the endoplasmic reticulum. CFTR alleles with the ΔF508 mutation account for approximately 70% of mutated CFTR alleles worldwide; 64% of the Irish CF population is homozygous for ΔF508, while 94% carry the ΔF508 mutation on at least one chromosome [5].