anti-NE capacity. 33 Further studies have shown
that AAT is exquisitely sensitive to inactivation by
products of cigarette smoke, which render AAT
unable to inhibit NE. 34 A combination of low levels
of AAT, increased neutrophilic inflammation and
cigarette smoking is the ‘perfect storm’, which
results in the accelerated emphysema seen in AATD
individuals who smoke.
Effects in the liver and elsewhere
In most cases of AATD, the deficiency results
not from a failure of AAT production but from
a retention of AAT in the liver, with subsequent
systemic and local deficiencies, particularly in the
lung. The Z mutant of AAT (ZAAT) is retained within
the ER of hepatocytes as polymers. Misfolding
of mutant forms of AAT within the ER of AAT-
producing cells can lead to inflammatory effects
that contribute significantly to the liver disease
associated with this condition. 35 In order to cope
with the increased load of misfolded protein
within the ER, cellular disposal mechanisms
(ERAD pathway, autophagy) are activated. When
misfolded proteins accumulate within the ER, the
cell undergoes ‘ER stress’, which is characterised by
a number of intracellular responses including the
unfolded protein response, ER overload response,
and apoptosis. 36,37 Translational attenuation
(premature termination of the translation process)
occurs as an immediate response, reducing the load
of host protein synthesis in the ER and preventing
further accumulation of unfolded proteins. 38 Little
is known about the underlying mechanism but it
is thought to involve increased calcium leak from
a distended ER. 39 In AATD it is not clear whether
increased autophagy causes mitochondrial damage
or whether the mitochondria are directly damaged
by ZAAT accumulation in the ER. In any event,
apoptotic pathways are triggered in AATD cells. 40
Some studies have postulated a specific role for
activation of caspase-4, an ER-specific caspase 41
in AATD patients whereas others have shown that
while caspase-4 is activated, it is not essential for
ZAAT-induced apoptosis. These studies suggested
a central role for P-I-3 kinase and Bad with the
potential for the bile acid tauroursodeoxycholic acid
to target this pathway and promote cell survival
in ZAAT-expessing cells. 40 Other pro-apoptotic
pathways in AATD include the unopposed action of
TNF-a. 42 Inhibitors of apoptosis are upregulated in
References
1 Bergin DA et al. Alpha-1
antitrypsin: a potent anti-
inflammatory and potential
novel therapeutic agent. Arch
Immunol Ther Exp (Warsz)
2012;60(2):81–97.
2 Beatty K, Bieth J, Travis J.
Kinetics of association of serine
proteinases with native and
oxidized alpha-1-proteinase
inhibitor and alpha-1-
antichymotrypsin. J Biol Chem
1980;255(9):3931–4.
3 Carrell RW, Whisstock J,
Lomas DA. Conformational
changes in serpins and the
mechanism of alpha 1-antitrypsin
deficiency. Am J Respir Crit Care
Med 1994;150(6 Pt 2):S171–5.
Review. Erratum in: Am J Respir
Crit Care Med 1995;151(3 Pt
1):926.
4 Kolarich D et al. Biochemical,
molecular characterization,
and glycoproteomic analyses
of alpha(1)-proteinase
inhibitor products used for
replacement therapy. Transfusion
2006;46(11):1959–77.
5 Kolarich D et al.
Comprehensive glyco-
proteomic analysis of human
alpha1-antitrypsin and its
charge isoforms. Proteomics
2006;6(11):3369–80.
6 Huntington JA, Read, RJ,
Carrell RW. Structure of a
serpin-protease complex shows
inhibition by deformation. Nature
2000;407:923–26.
7 McElvaney NG, Crystal RG.
Proteases and lung injury. In:
Crystal RG et al (eds) The Lung:
Scientific Foundations. Raven
Press Inc, New York;1997:
2205–19.
8 Lundgren JD et al. The
effect of neutrophil proteinase
enzymes on the release of
mucus from feline and human
airway cultures. Respir Med
1994;88(7):511–18.
9 Kim KC et al. Human neutrophil
elastase releases cell surface
mucins from primary cultures
of hamster tracheal epithelial
cells. Proc Natl Acad Sci U S A
8 | 2019 | hospitalpharmacyeurope.com
1987;84(24):9304–8.
10 Berger M et al. Complement
receptor expression on
neutrophils at an inflammatory
site, the Pseudomonas-infected
lung in cystic fibrosis. J Clin
Invest 1989;84(4):1302–13.
11 Hartl D et al. Cleavage of
CXCR1 on neutrophils disables
bacterial killing in cystic
fibrosis lung disease. Nat Med
2007;13(12):1423–30.
12 Tosi MF, Zakem H, Berger M.
Neutrophil elastase cleaves C3bi
on opsonized pseudomonas as
well as CR1 on neutrophils to
create a functionally important
opsonin receptor mismatch.
J Clin Invest 1990;86:300–8.
13 Fick RB Jr et al. Proteins
of the cystic fibrosis
respiratory tract. Fragmented
immunoglobulin G opsonic
antibody causing defective
opsonophagocytosis. J Clin Invest
1984;74(1):236–48.
14 Weldon S et al. Decreased
levels of secretory leucoprotease
inhibitor in the Pseudomonas-
infected cystic fibrosis lung
are due to neutrophil elastase
degradation. J Immunol
2009;183(12):8148–56.
15 Guyot N et al. Elafin, an
elastase-specific inhibitor,
is cleaved by its cognate
enzyme neutrophil elastase in
sputum from individuals with
cystic fibrosis. J Biol Chem
2008;283(47):32377–85.
16 Bergin DA et al. α-1
Antitrypsin regulates human
neutrophil chemotaxis induced
by soluble immune complexes
and IL-8. J Clin Invest
2010;120(12):4236–50.
17 O’Dwyer CA et al. The BLT1
inhibitory function of alpha-1
antitrypsin augmentation
therapy disrupts leukotriene B4
neutrophil signaling. J Immunol
2015;195(8):3628–41.
18 Bergin DA et al. The
circulating proteinase inhibitor
α-1 antitrypsin regulates
neutrophil degranulation and
autoimmunity. Sci Transl Med
2014;6(217):217ra1.
19 Mócsai A et al. Kinase
pathways in chemoattractant-
induced degranulation of
neutrophils: the role of p38
mitogen-activated protein kinase
activated by Src family kinases.
J Immunol 2000;164(8):4321–31.
20 Hurley K et al. Alpha-1
antitrypsin augmentation therapy
corrects accelerated neutrophil
apoptosis in deficient individuals.
J Immunol 2014;193(8):3978–91.
21 Petrache I et al. Alpha-1
antitrypsin inhibits caspase-3
activity, preventing lung
endothelial cell apoptosis. Am
J Pathol 2006;169(4):1155–66.
22 Zhang B et al. Alpha1-
antitrypsin protects beta-cells
from apoptosis. Diabetes.
2007;56(5):1316–1323
23 Lewis EC et al. Alpha1-
antitrypsin monotherapy
prolongs islet allograft survival
in mice. Proc Natl Acad Sci U S A
2005;102(34):12153–8.
24 Molano RD et al. Prolonged
islet allograft survival by alpha-1
antitrypsin: the role of humoral