584
U N I T 6
Respiratory Function
Etiology and Pathogenesis
Cystic fibrosis is caused by mutations in a single gene
on the long arm of chromosome 7 that encodes for the
cystic fibrosis transmembrane regulator (CFTR), which
functions as a chloride channel in epithelial cell mem-
branes.
49–51
Mutations in the
CFTR
gene render the epi-
thelial membrane relatively impermeable to the chloride
(Cl
–
) ion (Fig. 23-12).
The impact on impaired Cl
–
transport is relatively
tissue specific. In the sweat glands, the concentration
of sodium (Na
+
) and Cl
–
secreted into the lumen of the
gland remain unaffected, whereas the reabsorption of
Cl
–
through the CFTR and accompanying reabsorption
of Na
+
in the ducts of the gland fail to occur. This defect
accounts for the high concentration of NaCl in the sweat
of persons with CF.
50,51
In the normal airway epithelium,
Cl
–
is secreted into airway lumen through the CFTR. As
shown in Figure 23-12, in persons with CF, the transport
of Cl
–
into airway lumen is impaired. This ultimately
leads to a series of secondary events, including increased
absorption of Na
+
and water from the airways into the
blood. This lowers the water content of the mucocili-
ary blanket coating the respiratory epithelium, causing
it to become more viscid. The resulting dehydration of
the mucous layer leads to defective mucociliary function
and accumulation of viscid secretions that obstruct the
airways and predispose to recurrent pulmonary infec-
tions. Similar transport abnormalities and pathophysi-
ologic events take place in the pancreatic and biliary
ducts and in the vas deferens in males.
Manifestations
Respiratory manifestations of CF are caused by an
accumulation of viscid mucus in the bronchi, impaired
mucociliary clearance, and lung infections. Chronic
bronchiolitis and bronchitis are the initial lung manifes-
tations, but after months and years, structural changes
in the bronchial wall lead to bronchiectasis. In addi-
tion to airway obstruction, the basic genetic defect that
occurs with CF predisposes to chronic infection with
a surprisingly limited number of organisms, the most
common being
Pseudomonas aeruginosa, Burkholderia
cepacia, Staphylococcus aureus,
and
Haemophilus influ-
enzae.
48–51
Soon after birth, initial infection with bacte-
rial pathogens occurs and is associated with an excessive
neutrophilic inflammatory response that appears to
be independent of the infection itself. There is evidence
that the airway secretions in persons with CF provide a
favorable environment for harboring these organisms.
Pseudomonas aeruginosa,
in particular, has a propensity
to undergo mucoid transformation in this environment.
The complex polysaccharide produced by these organ-
isms provides a hypoxic environment and generates a
biofilm that protects
Pseudomonas
against antimicro-
bial agents. Pulmonary inflammation is another cause of
decline in respiratory function in persons with CF and
may precede the onset of chronic infection.
Exocrine pancreatic function is abnormal in more than
85% of affected children.
51
Steatorrhea, diarrhea, and
abdominal pain are common. In the newborn, meconium
ileus may cause intestinal obstruction, a fatal condition
if left untreated. The degree of pancreatic involvement
is highly variable. In some children, the defect is rela-
tively mild, and in others, the involvement is severe and
impairs intestinal absorption. In addition to exocrine
pancreatic insufficiency, hyperglycemia may occur, espe-
cially after 10 years of age, when approximately 8% of
persons with CF develop diabetes mellitus.
51
Diagnosis andTreatment
Early diagnosis and treatment are important in delaying
the onset and severity of chronic illness in children with
CF. Diagnosis is based on the presence of respiratory
and gastrointestinal manifestations typical of CF, a his-
tory of CF in a sibling, or a positive newborn screen-
ing test result. Confirmatory laboratory tests include
the sweat test and DNA tests for
CFTR
gene muta-
tions.
51
The
sweat test,
using pilocarpine iontophoresis
Chromosome 7
CFTR gene mutation
Respiratory tract
secretions
Airway epithelial
cell
Chronic airway obstruction
and bacterial infection
Neutrophil influx;
release of elastase and
inflammatory mediators
Development of chronic bronchitis,
bronchiectasis, respiratory failure
Development of a
microenvironment that is
protective of microbial agents
Abnormal thick and viscid
respiratory tract secretions
Defective mucociliary
clearance
Defective Cl - secretion with
excessive Na
+
and H
2
O absorption
H
2
O
Cl -
Na
+
FIGURE 23-12.
Pathogenesis of cystic fibrosis.
