Origins of cystic fibrosis lung disease.
At 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). At the clinical level, we know that chronic bacterial airway infection, prominent neutrophilic inflammation, mucus-obstructed airways, and progressive bronchiectasis characterize advanced cystic fibrosis lung disease, which causes most cystic fibrosis morbidity and mortality. Between those two extremes, how loss of CFTR-mediated chloride and bicarbonate transport leads to chronic airway infection has remained uncertain.
Over the past two decades, investigators have studied people with cystic fibrosis, who have disease causing CFTR mutations, at progressively earlier time points. We have learned that, by 3 years of age, bronchiectasis is present in nearly one in three children with cystic fibrosis, although the host defense defects that trigger infection continue to be debated. Even before symptom onset, pulmonary inflammation and infection are often present, although which comes first has been uncertain. As early as 3 months of age, most babies with cystic fibrosis have abnormal chest X-ray computed tomography (CT), although the relative contribution of inflammation, airway remodeling or other factors remains undefined. Moving to even earlier time points might reveal the origins of cystic fibrosis lung disease and thereby change clinical practice.
Indeed, simply knowing that disease begins before symptoms has been a factor driving cystic fibrosis centers to intervene early, and the outcomes have been encouraging. Understanding the initial host defense defects in cystic fibrosis airways could suggest novel preventions and treatments and the means to assess disease status and efficacy of therapeutics. Implementation of universal newborn cystic fibrosis screening and potential new therapeutics that target CFTR, further emphasize the need to elucidate the origins of this disease. However, access to newborn organs and tissue and the invasive in vivo and ex vivo experimental interventions required to elucidate the pathogenesis are impossible in humans.
Lack of an animal model that mirrors human cystic fibrosis has hindered progress in discovering the origins of cystic fibrosis lung disease. Mice with CFTR mutations fail to develop respiratory disease like that in humans. In contrast, recently generated animal models develop lung disease that mimics human cystic fibrosis. In this review, we focus primarily on the newborn time period because this time window is key to discovering origins of cystic fibrosis airway disease.