State of the art: why do the lungs of patients with cystic fibrosis become infected and why can't they clear the infection?

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.

Figure 1

Impact of mutant cystic fibrosis transmembrane conductance regulator (CFTR) on cellular physiology. 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). Defects in CFTR also lead to increased sodium absorption through the epithelial sodium channel (ENaC) and decreased chloride secretion. Water follows its concentration gradient and results in decreased depth of airway surface liquid. Bacterial persistence is promoted by alterations in airway wall architecture, impaired host defense mechanisms, an excessive inflammatory response, and adaptations made by the bacteria to the microenvironment of the cystic fibrosis airway.

Figure 2

Schematic Representation of the mucociliary escalator in the non-cystic fibrosis and cystic fibrosis (CF) airways. In the non-CF airway (Fig. 2A), where the depth of the periciliary fluid is normal, islands of mucus float on top and are propelled upward toward the mouth by the coordinated beating of cilia. In the CF airway (Fig 2B), the mucus is poorly hydrated and hypoxic. Because of the decreased depth of the periciliary fluid, the abnormal mucus is plastered down upon the cilia, thus inhibiting normal ciliary beating. Eventually the bacteria present in the airway become trapped in the mucus and adapt to the local environment. In the case of P. aeruginosa, this includes production of mucoid exopolysaccharide (MEP) and organization into a biofilm.

Figure 3

Adverse effects of elastase on host defense mechanisms and inflammation. In the cystic fibrosis airway, the concentration of elastase exceeds the concentration of inhibitors of elastase by several hundred to several thousand fold. While the vast majority of elastase is produced by the neutrophil, a small but significant amount is derived from bacteria. In addition to causing structural damage directly, elastase stimulates the production of pro-inflammatory mediators such as IL-8, which further induces neutrophil influx. Elastase also impairs mucociliary clearance by direct effects on ciliary function and by stimulating increased mucus production. Elastase inhibits opsonophagocytosis by cleaving the Fc portion of immunoglobulin G and complement receptors on both the neutrophil (CR1) and P. aeruginosa (C3bi), resulting in an opsonin-receptor mismatch.