Abstract
Cystic Fibrosis (CF) lung disease, which is characterized by airway obstruction, chronic bacterial infection, and an excessive inflammatory response, is responsible for most of the morbidity and mortality. Early in life, CF patients become infected with a limited spectrum of bacteria, especially P. aeruginosa. New data now indicate that decreased depth of periciliary fluid and abnormal hydration of mucus, which impede mucociliary clearance, contribute to initial infection. Diminished production of the antibacterial molecule nitric oxide, increased bacterial binding sites (e.g., asialo GM-1) on CF airway epithelial cells, and adaptations made by the bacteria to the airway microenvironment, including the production of virulence factors and the ability to organize into a biofilm, contribute to susceptibility to initial bacterial infection. Once the patient is infected, an overzealous inflammatory response in the CF lung likely contributes to the host's inability to eradicate infection. In response to increased IL-8 and leukotriene B4 production, neutrophils infiltrate the lung where they release mediators, such as elastase, that further inhibit host defenses, cripple opsonophagocytosis, impair mucociliary clearance, and damage airway wall architecture. The combination of these events favors the persistence of bacteria in the airway. Until a cure is discovered, further investigations into therapies that relieve obstruction, control infection, and attenuate inflammation offer the best hope of limiting damage to host tissues and prolonging survival.
Highlights
Cystic fibrosis (CF) is an autosomal recessive disease caused by lack of function of a cAMP-regulated chloride channel, called CFTR, which normally resides at the apical surface of many epithelial cell types
Structural damage to the lung allows for mechanical retention of secretions and retention of bacteria We have argued here that inflammation in the CF lung occurs in excess compared to the response mounted by non-CF individuals, and that it is ineffective against the bacteria
The lungs of patients with CF are vulnerable to bacterial infection, and once the infection becomes established, it is not eradicated despite prolonged and vigorous antibiotic and airway clearance therapy
Summary
Cystic fibrosis (CF) is an autosomal recessive disease caused by lack of function of a cAMP-regulated chloride channel, called CFTR (for the cystic fibrosis transmembrane conductance regulator), which normally resides at the apical surface of many epithelial cell types. Mutant CFTR promotes initial bacterial infection by upregulating epithelial cell adhesion molecules for bacteria such as asialo-GM1 and by decreasing production of innate host defense molecules such as nitric oxide (NO). All the factors, which serve to retain bacteria in the CF lung, overwhelm the defenses of the lung, even the phagocytic defenses, and the bacterial signals for inflammation persist At this point, the excessive inflammatory response becomes deleterious and even promotes continuing infection. Most patients with CF acquire this organism, develop a vigorous and persistent neutrophilic inflammatory response, and settle into a vicious cycle of airway obstruction, infection, and excess inflammation that results in lung destruction, further damage to the clearance processes, and additional vulnerability to infection or phenotypic transformation of the P. aeruginosa into a biofilm, which is impossible to eradicate despite the most vigorous antibiotic therapy. Many patients with bronchiectasis of non-CF etiology survive well into adulthood or even old age, whereas such survival is rare in patients with CF
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