CYSTIC FIBROSIS: NEUTROPHIL-DRIVEN LUNG INFLAMMATION

Cystic fibrosis (CF) is the most frequent recessive genetic disease in Caucasians, affecting 1 in 2,500 individuals. Although the genetic defect in CF causes malfunction in many organs and tissues, it is most often respiratory distress that results in hospitalization or life threatening events. Treatment of this lung inflammation is, therefore, a key to CF patient well-being and longevity. Respiratory distress in CF is related to persistent lung infection and overwhelming lung tissue damage caused by both the infectious organism and the immune response, particularly an overwhelming and dysfunctional response by neutrophils.

In the chronic phase of CF, patients show increased neutrophil count in blood, and massive and persistent neutrophil migration into airways, possibly compounded by the inability of neutrophils to leave the airways (Figure 1). CF airway neutrophils actively release destructive enzymes known as proteases and generate potent oxidizing chemicals such as hydrogen peroxide and hypochlorous acid (a relative of household bleach), which severely damage nearby lung tissue. CF airway neutrophils also extend their lifespan and communicate with other cells to trigger a chronic inflammatory feedback loop.

 

 

Figure 1 Caption: Neutrophils in Cystic Fibrosis Airway Tissue

Pink areas are normal tissue. Each blue dot is a neutrophil. The ring structure in upper right is a small airway tube (bronchiole). Reference: Elizur et al., Chest 2008 v133, no.2, 489-495.

Evidence of the central role that live neutrophils play in CF airway pathology has been part of a total rethinking of the neutrophil itself. This movement has dispelled several persistent misconceptions of the neutrophil that are still found in text books.
The new thinking on the neutrophils in CF airways is that:

• Inflammation in CF airways occurs right around birth, with a clear tendency for infiltration and persistence of over-activated neutrophils in airways in response to mild infections;
  
  
• CF airway neutrophils are competent as immune cells. They establish conditions in CF airways that kill most bacteria. However, these conditions permit growth of resistant bacteria, such as Pseudomonas aeruginosa, a common and dangerous pathogenic microbe;
  
  
• Neutrophils change their behavior upon migration into CF airways, where they live for extended periods and even generate new biochemical materials; and
  
  
• It is live, not dead or dying, CF airway neutrophils that actively release damaging proteases and oxidases which, among other factors, are responsible for chronic airway damage. This means that the process is potentially treatable.

Taken together, the recent scientific evidence demonstrates that live, reprogrammed neutrophils are front and center in the pathology of CF airway disease. “Smart” drugs for CF will target the dysfunctional states, while preserving the beneficial bacterial killing and normal immune signaling activities of CF airway neutrophils.

For more about Cystic Fibrosis, please visit the Cystic Fibrosis Foundation.

 

 

References:

Neutrophilic inflammation as a major determinant in the progression of cystic fibrosis. Tirouvanziam R. Drug News Perspect 2006; 19:609-614. PMID: 17299603

Inflammatory mechanisms and treatment of obstructive airway diseases with neutrophilic bronchitis. Simpson JL et al. Pharmacol Ther 2009; 124:86-95. PMID: 19555716