Biomedical Engineering Reference
In-Depth Information
alveolar macrophages. This antiprotease provides the major defense against
proteolytic digestion of the lung by neutrophil serine proteases, such as neu-
trophil elastase, cathepsin G, and proteinase 3 (28). It has been known since
the early 1960s that individuals who have extremely low levels of
a
1
-AT have
an increased prevalence of emphysema (29). A genetic basis for
a
1
-AT defi-
ciency was demonstrated by the observation that the deficiency followed a
simple Mendelian pattern of inheritance and was usually associated with
the Z isoform of
a
1
-AT (30-32). The two most common deficiency variants
of
a
1
-AT, S and Z, result from point mutations in the
a
1
-AT gene (33-35)
and are named on the basis of their altered electrophoretic mobility on
isoelectric focusing gels compared with the normal M allele (36). Homozyg-
osity of the Z variant (which contains lysine rather than glutamic acid at
amino acid position 342) results in a severe deficiency that is characterized
by plasma
a
1-AT levels
10% of the normal M allele. Individuals with
the ZZ phenotype have a clearly accelerated rate of decline in lung function
(37), sometimes even in the absence of smoking (38). However, the homozy-
gous state is rare in the population (39) and thus can explain only a small
percentage of the genetic susceptibility to cigarette smoke.
Despite the strong association of the ZZ genotype with early-onset
COPD, the clinical course of the disease is highly variable (40), as is com-
mon with other genetic disorders. Exposure to cigarette smoke plays an
important role in determining this variability (41). Several large series of
AAT deficient individuals have clearly shown that PI Z subjects who smoke
cigarettes tend to develop more severe pulmonary impairment at an earlier
age than nonsmoking PI Z individuals (38,42,43). In addition, a follow-up
study of participants in the Swedish AAT Deficiency Register has shown
that the rate of decline in FEV
1
is significantly higher in PI Z current smo-
kers than in never smokers or exsmokers (41). Few studies have considered
whether factors other than smoking influence the development of lung dis-
ease. Black and Kueppers (44) studied 54 PI Z individuals and found signif-
icant variability in pulmonary function and clinical symptoms, especially
among nonsmoking PI Z individuals. Piitulainen et al. (45) studied more
than 200 nonsmoking PI Z subjects from the Swedish AAT Deficiency Reg-
ister; so, they were able to examine the impact of risk factors for reduced
pulmonary function without confounding by smoking. Not surprisingly,
increasing age was associated with reduced pulmonary function in these
nonsmoking PI Z subjects. Male sex, wheezing symptoms, and occupational
exposures to gas, fumes, or dust were also associated with reduced pulmon-
ary function. Subsequent analyses in this population suggested that agricul-
tural occupation and use of a kerosene heater were associated with reduced
FEV
1
levels; however, the generalizability of these findings may be limited as
only a small number of PI Z subjects had these exposures (46). Mayer et al.
(47) recently assessed occupational exposures as a potential contributor to
variable expression of lung disease in 128 PI Z subjects. They found that
