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.”
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