Pharmacological Strategies for the Treatment of the Basic Defect in Cystic Fibrosis

Abstract

Cystic fibrosis (CF), a common, lethal inherited disease of Caucasians, is a systemic exocrine disorder associated with a dysfunctional chloride channel that restricts or prevents the movement of chloride ions across the apical membrane of epithelial cells [1]. This results in elevated sodium and chloride levels in sweat and airway surface fluid, and in the abnormal composition and hydration of mucus [1–4]. Clinical presentations of the disease are widely heterogeneous, but patients commonly show a predisposition to chronic and fatal lung colonisation by bacterial pathogens such as P. aeruginosa and S. aureus [5]. Although there are important gastroenterological manifestations contributing to morbidity and mortality, the lung involvement is the primary cause of 95% of the mortality [6]. Infants who die from meconium ileus shortly after birth do not have macroscopic lung disease although histological abnormalities can be detected within a few days of life [7]. Lung disease develops over the first few years of life and leads to death, on average in the third decade, from chronic suppurative lung disease [8]. Since the CF gene was discovered in 1989 [9, 10], enormous progress has been made in the understanding of the basic defect and the changes that occur in CF. However, there is still much debate about how different genotypes, infection and inflammatory responses interact, and the exact process by which the genetically determined defect leads to extensive damage and irreversible failure of the lungs is not yet clear.