Origins of Cystic Fibrosis Lung Disease — NEJM (NEJM 2015; 372: 351-62) is a good read.  The authors note that the basic defect in Cystic Fibrosis (CF), the loss of the cystic fibrosis transmembrane conductance regulator (CFTR), has been recognized for a long time.  However, the connection between this defect and the progressive lung disease/inflammation has remained uncertain.

Now, new animal models have provided a wealth of information that closes the knowledge gap.

Here are the key points:

• CF affects the lungs very early: Bronchiectasis is present in nearly one in three children with CF by 3 years of age and CT scans are abnormal in most babies with CF as early as 3 months of age.
• Infection precedes inflammation: “During the first hours after birth, piglets with CF show no evidence of inflammation in their airways…yet,…they fail to eradicate bacteria as well…[which] can initiate a cascade of airway inflammation and airway remodeling.”
• There are multiple “hits” on the airways.  While many have suggested that increased sodium leads to a ‘dehydrated’ state, this does not seem to be correct.
• More recent studies point to loss of bicarbonate secretion as a crucial factor.  This results in a reduced pH which in turn leaves the lungs more vulnerable to infection.  Lower acidity reduces the effectiveness of a “complex soup of antimicrobial peptides, proteins, and lipids in airway-surface liquid.”
• Poor mucociliary transport, “which guards the lungs by trapping invading pathogens and particulates in mucus,” is another important “hit” on the lungs.

Implications:

• CF needs to be diagnosed early and treated early
• Improving even one of these defects in host defenses is likely to be beneficial.
• Animal models remain important in understanding pathophysiology.  They allow “investigating the disease at its genesis and before the onset of secondary manifestations.”

Related blog posts:

• Breaking down lung defenses in Cystic Fibrosis …
• Ivacaftor for Cystic Fibrosis | gutsandgrowth