Cystic fibrosis lung disease starts in the small airways: can we treat it more effectively?
The aims of this article are to summarize existing knowledge regarding the pathophysiology of small airways disease in cystic fibrosis (CF), to speculate about additional mechanisms that might play a role, and to consider the available or potential options to treat it. In the first section, we review the evidence provided by pathologic, physiologic, and imaging studies suggesting that obstruction of small airways begins early in life and is progressive. In the second section we discuss how the relationships between CF transmembrane conductance regulator (CFTR), ion transport, the volume of the periciliary liquid layer and airway mucus might lead to defective mucociliary clearance in small airways. In addition, we discuss how chronic endobronchial bacterial infection and a chronic neutrophilic inflammatory response increase the viscosity of CF secretions and exacerbate the clearance problem. Next, we discuss how the mechanical properties of small airways could be altered early in the disease process and how remodeling can contribute to small airways disease. In the final section, we discuss how established therapies impact small airways disease and new directions that may lead to improvement in the treatment of small airways disease. We conclude that there are many reasons to believe that small airways play an important role in the pathophysiology of (early) CF lung disease. Therapy should be aimed to target the small airways more efficiently, especially with drugs that can correct the basic defect at an early stage of disease.
Tiddens
Harm A W M
HA
Department of Pediatric Pulmonology and Allergology, Erasmus MC-Sophia, Rotterdam, the Netherlands. h.tiddens@erasmusmc.nl
Donaldson
Scott H
SH
Rosenfeld
Margaret
M
Paré
Peter D
PD
D000280:Administration, Inhalation; D000402:Airway Obstruction / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000503:physiopathology*; D056151:Airway Remodeling / Q000187:drug effects / Q000502:physiology; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D003550:Cystic Fibrosis / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism / Q000502:physiology; D003845:Deoxycytosine Nucleotides / Q000008:administration & dosage / Q000627:therapeutic use; D006801:Humans; D007223:Infant; D017136:Ion Transport / Q000502:physiology; D008353:Mannitol / Q000008:administration & dosage / Q000627:therapeutic use; D009079:Mucociliary Clearance / Q000187:drug effects; D009093:Mucus / Q000000981:diagnostic imaging / Q000502:physiology; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology; D018410:Pneumonia, Bacterial / Q000473:pathology; D011650:Pulmonary Alveoli / Q000000981:diagnostic imaging / Q000502:physiology / Q000503:physiopathology*; D011859:Radiography; D020545:Respiratory Mucosa / Q000187:drug effects / Q000503:physiopathology; D026941:Sodium Channel Blockers / Q000008:administration & dosage / Q000627:therapeutic use; D014529:Uridine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use; D055815:Young Adult
D000893:Anti-Inflammatory Agents; C505032:CFTR protein, human; D003845:Deoxycytosine Nucleotides; D026941:Sodium Channel Blockers; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D008353:Mannitol; C465279:denufosol tetrasodium; D014529:Uridine