Developmental Paradigm for Early Features of Cystic Fibrosis

Abstract

Cystic fibrosis (CF) is a progressive disease in which the lung is perceived to be normal at birth and is injured by recurrent infection. However, there is increasing evidence that the lung is functionally and structurally abnormal prior to the appearance of clinical infection. The cystic fibrosis transmembrane regulator (CFTR) is highly expressed in fetal tissues, and this review examines the role of CFTR in regulatory cascades during lung development. Early changes in the CF lung are examined from a perspective of disrupted fetal development, explaining a number of paradoxes seen with the disease.

Dysregulation of TIM-3–Galectin-9 Pathway in the Cystic Fibrosis Airways

“…Furthermore, constitutive upregulation of this receptor and its ligand may reflect a proinflammatory state in CF bronchial epithelial cells (50,51). Increased TIM-3 and galectin-9 expression in the lung may explain the early neutrophil airway infiltration observed in CF newborns (52) and in aseptic CF animal models (5). Of clinical relevance, we demonstrated that both TIM-3 and galectin-9 undergo rapid proteolytic degradation by serine proteases in CF BAL, which could impact on the previously described role of galectin-9, inducing resolution of inflammation via apoptosis of immune cells (32,53).…”

“…Several mechanisms have been proposed to explain how CFTR mutations lead to chronic lung disease in CF including altered ion transport across the airway epithelium, dehydration of the airway surface layer (3), and increased production of proinflammatory cytokines in the CF airway, arguably caused by constitutive NF-kB activation (4). Regardless of the initial cause, hyperinflammation in the CF lung occurs early and continues throughout life (5). This inflammatory state is further amplified by bacterial infections, in particular, Pseudomonas aeruginosa (6,7).…”

Lentivirus vector‐mediated gene transfer to the developing bronchiolar airway epithelium in the fetal lamb

“…Obstacles include difficulty in achieving efficient gene delivery to mature airway epithelium, the need to target self-renewing airway epithelium progenitor cells if repeated vector re-administration is to be avoided, and evidence of structural and functional abnormality in the CF airway at birth [9][10][11]. Targeting gene therapy to the CF lung during fetal development offers the theoretical prospect of circumventing these barriers, but also introduces substantial technical and safety challenges.…”

Cystic Fibrosis and Formes Frustes of CFTR-Related Disease

“…There is now compelling evidence that the clearance and composition of ASL is compromised in CF [22]. A paradox in CF is that CFTR gene expression levels are low in the airways compared to other epithelia (table 2) [23, 24]. Despite this there appears to be a significant impact on transepithelial airway ion transport and this appears to be the fundamental defect in CF.…”