Origins of cystic fibrosis lung disease.

A t the basic level, we know the genetic cause of cystic fibrosis: it is an autosomal recessive disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR).1,2 At the clinical level, we know that chronic bacterial airway infection, prominent neutrophilic inflammation and mucus in airways, and progressive bronchiectasis characterize advanced cystic fibrosis lung disease, which causes most morbidity and death in people with cystic fibrosis.2 Between those two extremes, the way in which loss of CFTR-mediated chloride and bicarbonate transport leads to chronic airway infection has remained uncertain. Over the past two decades, investigators have conducted studies involving people with cystic fibrosis (defined as persons who carry known disease-causing CFTR mutations) at progressively earlier time points. We have learned that bronchiectasis is present in nearly one in three children with cystic fibrosis by 3 years of age,3 although the host-defense defects that trigger infection continue to be debated.4-10 Even before the onset of symptoms, pulmonary inflammation and infection are often present, although which condition comes first has been uncertain.11,12 Findings on chest computed tomography (CT) are abnormal in most babies with cystic fibrosis as early as 3 months of age,13 although the relative contribution of inflammation, airway remodeling, and other factors remains undefined. Studies involving children at even earlier ages might reveal the origins of cystic fibrosis lung disease and thereby change clinical practice. Indeed, simply knowing that disease begins before symptoms develop has been a factor driving cystic fibrosis centers to intervene early, and the outcomes have been encouraging.14 Understanding the initial host-defense defects in the airways of people with cystic fibrosis could suggest new preventions and treatments, as well as the means to assess disease status and the efficacy of therapeutic agents. Additional reasons to elucidate the origins of this disease are the implementation of universal screening to detect cystic fibrosis in newborns and potential new therapeutic agents that target CFTR.15-17 However, access to organs and tissue in newborns is extremely limited, and the invasive in vivo and ex vivo experimental interventions required to elucidate the pathogenesis most often cannot be performed in humans. The lack of an animal model that mirrors cystic fibrosis in humans has hindered progress in discovering the origins of the lung disease.18 Respiratory disease such as that in humans does not develop in mice with cftr mutations. However, lung disease that mimics that in humans with cystic fibrosis occurs in other recently generated animal models. In this review, we focus primarily on the newborn period, because this time window is key to discovering the origins of cystic fibrosis airway disease.