effect on TNF-a-driven inflammation. This effect
is mediated by preventing TNF-a from interacting
with its receptors on neutrophils and other cells. 18
In AATD, this results in increased degranulation
of neutrophils 19 and production of autoantibodies,
which can contribute significantly to the disease
state. 18 AATD patients receiving AAT therapy with
plasma-purified AAT show reduced TACE activity
and TNF-α signalling and normalised neutrophil
apoptosis. 20 In this regard, AAT also binds to
and inhibits caspase-3, thereby preventing lung
endothelial cell apoptosis. 21 AAT prolongs allograft
survival and modulates cellular immunity in mice
that have undergone pancreatic islet allograft. 22–25
The mechanism by which AAT protects islet cells is
unclear but AAT likely potentiates insulin secretion
and the effects of glucagon-like peptide-1 and
forskolin. Furthermore, AAT has been shown to
given that NE possesses the ability to damage every
component of the extracellular matrix. 7 Unopposed
NE also amplifies the inflammatory burden and
increases mucin secretion. 8,9 NE impairs host defence
further by cleaving complement receptors 10 and
CXCR1 receptors 11 on neutrophils and cleaving
complement 12 and immunoglobulins. 3 NE, when
in excess, cleaves anti-proteases 14,15 including AAT,
depriving the body not only of its anti-protease but
also of its anti-inflammatory effects. In these disease
states, the anti-NE effects of AAT are impeded
either by not enough AAT, as is found in AATD,
or inactivation of AAT at the site of inflammation.
Anti-inflammatory effects of AAT
In recent years, there has been increased awareness
of the anti-inflammatory properties of AAT. This
is of major interest in the study of lung disease
as many of these conditions are characterised by
neutrophil-dominated inflammation. AAT can
modulate interleukin (IL)-8-induced neutrophil
chemotaxis by binding IL-8 and preventing it from
interacting with its receptor on neutrophils. 16 The
glycosylation of AAT plays a pivotal role in this anti-
inflammatory effect as non-glycosylated AAT fails
to bind IL-8, and increased sialylation of AAT during
inflammation leads to increased IL-8 binding. AAT
also decreases neutrophil chemotaxis in response
to soluble immune complexes (sICs) through a
different mechanism. Neutrophil engagement of
sICs leads to increased tumour necrosis factor-alpha
(TNF-α)-converting enzyme (TACE) activity, with
release of the glycosylphosphatidylinositol anchored
Fc receptor (FcγRIIIB), necessary for chemotaxis.
AAT inhibits TACE activity, preventing the release
of membrane FcγRIIIB. 16 Another major contributor
to neutrophil chemotaxis in the lung is leukotriene
B4 (LTB4), which also increases neutrophil adhesion
and degranulation. NE can signal back to the
neutrophil causing increased production of LTB4
and upregulation of its receptor BLT1 on the
neutrophil membrane. AAT can bind LTB4, thereby
preventing neutrophil activation. 17 AAT also has an
The classic cause of AATD is the
autosomal, codominant, genetic
disorder of that name, which is
characterised by low circulating levels
of AAT due to a mutation of the
SERPINA1 gene
protect a diabetic cell line against TNF-α-mediated
apoptosis and to significantly reduce apoptosis
caused by a combination of TNF-α, IL-1β and
interferon (IFN)-γ. 26
FIGURE 1
AAT phenotype and risk of lung disease
2.5
2.0
1.5
1.0
0.5
0.0
MM
MS
AAT Phenotype
MZ
SS
Background
SZ
ZZ
High
Risk of lung disease
Deficiency of AAT: genetic and functional
The classic cause of AATD is the autosomal,
codominant, genetic disorder of that name, which
is characterised by low circulating levels of AAT
due to a mutation of the SERPINA1 gene. Healthy
individuals usually carry two copies of the non-
mutated M allele, which in homozygous individuals
leads to AAT plasma levels >1.04g/l or 20μM (Figure
1) and lung levels of approximately 4μM. 27,28 There
are at least 120 genetic deficiency variants of the
SERPINA1 gene with the Z (Glu342Lys) and
S (Glu264Val) mutations being the most common.
The Z mutation gives rise to the most severe
plasma deficiency and occurs in more than 95% of
individuals with AATD. Z homozygous individuals
have an AAT serum level of approximately 5μM
and an epithelial lining fluid level of approximately
0.5μM. 28 They have an increased risk of emphysema
due to low levels of AAT in the lung, leading to
loss of anti-NE protection. This risk is significantly
exacerbated by cigarette smoking. Loss of AAT
function can occur in other lung conditions, even
in the presence of normal AAT levels. In CF, there
is usually normal production of M-AAT by the liver
and indeed the serum and lung levels of AAT are
increased in CF. 29 However, the AAT on the airway
epithelial surface in CF is functionally inactive. 30
This is due mainly to cleavage by proteases such
as NE. This NE-driven proteolytic inactivation also
occurs in non-CF bronchiectasis 31 and pneumonia, 32
where this is an increased NE burden on the
respiratory epithelial surface, a powerful illustration
of disruption of the protease–anti-protease balance,
in this case by excess proteases. Emphysema usually
occurs in MM AAT individuals with normal serum
and lung levels of AAT. Carp et al were the first to
show evidence of oxidative inactivation of AAT in
the lungs of smokers with concomitant decreased
hospitalpharmacyeurope.com | 2019 | 7