Alpha-1 Antitrypsin: A Potent Anti-Inflammatory and Potential Novel Therapeutic Agent

Bergin, David A.; Hurley, Killian; McElvaney, Noel G.; Reeves, Emer P.

doi:10.1007/s00005-012-0162-5

Cited by 119 publications

(105 citation statements)

References 167 publications

(154 reference statements)

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“…Thus, inhibition of NE has consistently been the objective in the development of therapeutic strategies for these patients. However, the broad anti-inflammatory and immunomodulating properties of AAT (7,8,23) raise the question whether elastase inhibition accounts for the spectrum of biological activities of AAT. Here, we compared in vitro and in vivo anti-inflammatory effects of clinical grade AAT with elastase inhibitory activity to a form of recombinant AAT that does not inhibit elastase.…”

Section: Discussionmentioning

confidence: 99%

Anti-inflammatory and immunomodulatory properties of α1-antitrypsin without inhibition of elastase

Jonigk

Al-Omari²,

Maegel

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

222

148

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The rationale of α1-antitrypsin (AAT) augmentation therapy to treat progressive emphysema in AAT-deficient patients is based on inhibition of neutrophil elastase; however, the benefit of this treatment remains unclear. Here we show that clinical grade AAT (with elastase inhibitory activity) and a recombinant form of AAT (rAAT) without anti-elastase activity reduces lung inflammatory responses to LPS in elastase-deficient mice. WT and elastasedeficient mice treated with either native AAT or rAAT exhibited significant reductions in infiltrating neutrophils (23% and 68%), lavage fluid levels of TNF-α (70% and 80%), and the neutrophil chemokine KC (CXCL1) (64% and 90%), respectively. Lung parenchyma TNF-α, DNA damage-inducible transcript 3 and X-box binding protein-1 mRNA levels were reduced in both mouse strains treated with AAT; significantly lower levels of these genes, as well as IL-1β gene expression, were observed in lungs of AAT-deficient patients treated with AAT therapy compared with untreated patients. In vitro, LPS-induced cytokines from WT and elastasedeficient mouse neutrophils, as well as neutrophils of healthy humans, were similarly reduced by AAT or rAAT; human neutrophils adhering to endothelial cells were decreased by 60-80% (P < 0.001) with either AAT or rAAT. In mouse pancreatic islet macrophages, LPS-induced surface expression of MHC II, Toll-like receptor-2 and -4 were markedly lower (80%, P < 0.001) when exposed to either AAT or rAAT. Consistently, in vivo and in vitro, rAAT reduced inflammatory responses at concentrations 40-to 100-fold lower than native plasma-derived AAT. These data provide evidence that the anti-inflammatory and immunomodulatory properties of AAT can be independent of elastase inhibition.is the prototypic member of the serpin superfamily and one of the most abundant serine protease inhibitors in the circulation (1). As an acute-phase protein, AAT is thought to play an important role in limiting host-tissue injury triggered by proteases, particularly neutrophil elastase (NE). The clinical relevance of AAT is highlighted in individuals with inherited deficiency in circulating AAT, who have increased susceptibility to early-onset pulmonary emphysema, liver and pancreatic diseases, and in rare cases to panniculitis and vasculitis (2). It has been assumed that in AAT-deficiency the protease/antiprotease balance is shifted toward NE, which leads to extensive tissue damage, particularly in causing emphysema. Therefore, augmentation of circulating AAT was introduced 25 y ago to treat emphysema patients with severe PiZZ (Glu342Lys) AAT deficiency (3). Because clinical trials of AAT augmentation therapy use historical data as controls, the benefit of AAT therapy for PiZZ patients remains under debate (4-6), although in most cases therapy offers disease stabilization. The uncertainty surrounding the efficacy of augmentation therapy also reflects the incomplete understanding of the properties of the AAT protein, which can be affected by the isolation methods from plasma.Although the a...

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Section: Discussionmentioning

confidence: 99%

Anti-inflammatory and immunomodulatory properties of α1-antitrypsin without inhibition of elastase

Jonigk

Al-Omari²,

Maegel

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

222

148

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“…However, aside from its primary role as an antiprotease, AAT has gained attention due to emerging evidence of its ability to exert a range of immunomodulatory properties affecting a number of immune and structural cells of the airways (71). Studies have shown that native AAT may modulate immune cell function of neutrophils (72)(73)(74)(75), monocytes (71,76), and T cells (77), and the results of this study are analogous to data demonstrating the inhibitory effect of AAT on IL-8-and TNF-a-induced neutrophil responses (28,29). Moreover, this study elucidates what we think to be a novel role for AAT and has uncovered the ability of AAT to inhibit adhesion and degranulation signaling events involving AAT/LTB 4 complex formation, consequently inhibiting LTB 4 -BLT1 interaction.…”

Section: Discussionmentioning

confidence: 99%

“…Of relevance to our findings, Griese et al (31) have reported a reduction in airway levels of IL-8 and LTB 4 in individuals with CF treated with aerosolized AAT and suggested the use of AAT outside of the context of AATD. Indeed, the therapeutic potential of AAT in clinical conditions not associated with AATD includes CF, COPD, and RA (71).…”

Section: Discussionmentioning

confidence: 99%

The BLT1 Inhibitory Function of α-1 Antitrypsin Augmentation Therapy Disrupts Leukotriene B4 Neutrophil Signaling

O’Dwyer

O’Brien

Wormald

et al. 2015

The Journal of Immunology

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Leukotriene B4 (LTB4) contributes to many inflammatory diseases, including genetic and nongenetic forms of chronic obstructive pulmonary disease. α-1 Antitrypsin (AAT) deficiency (AATD) is characterized by destruction of lung parenchyma and development of emphysema, caused by low AAT levels and a high neutrophil burden in the airways of affected individuals. In this study we assessed whether AATD is an LTB4-related disease and investigated the ability of serum AAT to control LTB4 signaling in neutrophils. In vitro studies demonstrate that neutrophil elastase is a key player in the LTB4 inflammatory cycle in AATD, causing increased LTB4 production, and associated BLT1 membrane receptor expression. AATD patients homozygous for the Z allele were characterized by increased neutrophil adhesion and degranulation responses to LTB4. We demonstrate that AAT can bind LTB4 and that AAT/LTB4 complex formation modulates BLT1 engagement and downstream signaling events, including 1,4,5-triphosphate production and Ca2+ flux. Additionally, treatment of ZZ-AATD individuals with AAT augmentation therapy decreased plasma LTB4 concentrations and reduced levels of membrane-bound neutrophil elastase. Collectively, these results provide a mechanism by which AAT augmentation therapy impacts on LTB4 signaling in vivo, and not only reinforces the utility of this therapy for resolving inflammation in AATD, but supports useful future clinical applications in treatment of other LTB4-related diseases.

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“…AAT protects tissues from proteases released from inflammatory cells. It also exhibits proteaseindependent antiinflammatory activities against these cells and against the soluble effectors they release [176,177] . Unlike immunosuppressive drugs, AAT helps the immune system to disting uish between desired responses against authentic threats and unwanted responses fueled by positive feedback loops [178] , thereby transforming devastating inflammation into beneficial immune tolerance.…”

Section: Controlling Inflammationmentioning

confidence: 99%

Survival of encapsulated islets: More than a membrane story

Barkai¹,

Rotem²,

Vos³

2016

WJT

114

109

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Alpha-1 Antitrypsin: A Potent Anti-Inflammatory and Potential Novel Therapeutic Agent

Cited by 119 publications

References 167 publications

Anti-inflammatory and immunomodulatory properties of α1-antitrypsin without inhibition of elastase

Anti-inflammatory and immunomodulatory properties of α1-antitrypsin without inhibition of elastase

The BLT1 Inhibitory Function of α-1 Antitrypsin Augmentation Therapy Disrupts Leukotriene B4 Neutrophil Signaling

Survival of encapsulated islets: More than a membrane story

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