The impact of alpha-1 antitrypsin augmentation therapy on neutrophil-driven respiratory disease in deficient individuals

Dunlea, Danielle M; Fee, Laura; McEnery, Tom; McElvaney, Noel G.; Reeves, Emer P.

doi:10.2147/jir.s156405

Cited by 27 publications

(21 citation statements)

References 128 publications

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“…SerpinA1 is an acute-phase protein, the most abundant serine proteinase inhibitor in human plasma, and, moreover, a potent regulator of neutrophil activation via both protease inhibitory and non-inhibitory functions [59]. Indeed, SerpinA1 can influence neutrophil chemotaxis preventing neutrophil activation independently to the proteinase role [60]. More specifically, two isoforms of Ser-pinA1, SerpinA1D and SerpinA1A, appeared upregulated, in higher levels, in SE2 and SE4, respectively, compared to SH and, moreover, compared to SC mice (Table 3).…”

Section: Discussionmentioning

confidence: 99%

Identification of the initial molecular changes in response to circulating angiogenic cells-mediated therapy in critical limb ischemia

et al. 2020

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Background: Critical limb ischemia (CLI) constitutes the most aggressive form of peripheral arterial occlusive disease, characterized by the blockade of arteries supplying blood to the lower extremities, significantly diminishing oxygen and nutrient supply. CLI patients usually undergo amputation of fingers, feet, or extremities, with a high risk of mortality due to associated comorbidities. Circulating angiogenic cells (CACs), also known as early endothelial progenitor cells, constitute promising candidates for cell therapy in CLI due to their assigned vascular regenerative properties. Preclinical and clinical assays with CACs have shown promising results. A better understanding of how these cells participate in vascular regeneration would significantly help to potentiate their role in revascularization. Herein, we analyzed the initial molecular mechanisms triggered by human CACs after being administered to a murine model of CLI, in order to understand how these cells promote angiogenesis within the ischemic tissues.

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Section: Discussionmentioning

confidence: 99%

Identification of the initial molecular changes in response to circulating angiogenic cells-mediated therapy in critical limb ischemia

et al. 2020

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“…Alpha-1 antitrypsin (AAT) is the archetypal member of the serpin superfamily produced mainly by hepatocytes and is the most abundant endogenous serine protease inhibitor in the blood. The predominant role of AAT is as a serine protease inhibitor, primarily inhibiting neutrophil elastase (NE), but also other proteases including cathepsin G and proteinase 3 (1). The structure of the AAT molecule is critical for its antiprotease activity and is comprised of 3 β-sheets (A, B and C), 9 α-helices and a reactive centre loop (RCL) at the C-terminal end (3).…”

Section: Introductionmentioning

confidence: 99%

Circulating Truncated Alpha-1 Antitrypsin Glycoprotein in Patient Plasma Retains Anti-Inflammatory Capacity

Reeves

Dunlea

McQuillan

et al. 2019

The Journal of Immunology

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Alpha-1 antitrypsin (AAT) is an acute phase protein that possesses immune regulatory and anti-inflammatory functions independent of anti-protease activity. AAT deficiency (AATD) is associated with early onset emphysema and chronic obstructive pulmonary disease. Of interest are the AATD nonsense mutations (termed Null or Q0) the majority of which arise from premature termination codons (PTC) in the messenger RNA coding-region. We have recently demonstrated that plasma from an AATD patient homozygous for the Null Bolton-allele (Q0bolton) contains AAT protein of truncated size. Although the potential to alleviate the phenotypic consequences of AATD by increasing levels of truncated protein holds therapeutic promise, protein functionality is key. The goal of this study was to evaluate the structural features and anti-inflammatory capacity of Q0bolton-AAT. A low abundance, truncated AAT protein was confirmed in plasma of a Q0bolton- AATD patient and was secreted by patient-derived iPSC-hepatic cells. Functional assays confirmed the ability of purified Q0bolton-AAT protein to bind neutrophil-elastase and to inhibit protease activity. Q0bolton-AAT bound interleukin-8 and leukotriene B4, comparable to control M-AAT, and significantly decreased leukotriene B4 induced neutrophil adhesion (P=0.04). Through a mechanism involving increased mRNA stability (P=0.007), ataluren treatment of HEK-293 significantly increased Q0bolton-AAT mRNA expression (P=0.03) and Q0bolton-AAT truncated protein secretion (P=0.04). Results support the rationale for treatment with pharmacological agents that augment levels of functional Q0bolton-AAT protein, thus offering a potential therapeutic option for AATD patients with rare mutations of similar theratype.

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“…Despite their important role in immune response in order to preserve the lung environment against microbial threats, their release following neutrophil accumulation and activation may lead to inflammation and lung matrix destruction [14]. Thus, the production and secretion of AAT is essential in the lung parenchyma to inhibit these NSPs and prevent alveolar tissues from destruction [16].…”

Section: Alpha 1-antitrypsinmentioning

confidence: 99%

“…AAT is the most abundant protease inhibitor in the circulation with around 5 days half-life and a circulation concentration varying between 1.2 to 2 g/L in a healthy individual [16]. This concentration can increase rapidly, up to 2-5 times, during acute phases of inflammation and infection following cytokine (interleukins 1 and 6) and tumor necrosis factor (TNFα) activation [16]. In addition to its major role into inflammation regulation, AAT has been also shown to be involved in angiogenesis and tumor growth processes [17].…”

Section: Alpha 1-antitrypsinmentioning

confidence: 99%

Alpha 1-Antitrypsin Deficiency: A Disorder of Proteostasis-Mediated Protein Folding and Trafficking Pathways

Karataş

Bouchecareilh

2020

IJMS

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Human cells express large amounts of different proteins continuously that must fold into well-defined structures that need to remain correctly folded and assemble in order to ensure their cellular and biological functions. The integrity of this protein balance/homeostasis, also named proteostasis, is maintained by the proteostasis network (PN). This integrated biological system, which comprises about 2000 proteins (chaperones, folding enzymes, degradation components), control and coordinate protein synthesis folding and localization, conformational maintenance, and degradation. This network is particularly challenged by mutations such as those found in genetic diseases, because of the inability of an altered peptide sequence to properly engage PN components that trigger misfolding and loss of function. Thus, deletions found in the ∆F508 variant of the Cystic Fibrosis (CF) transmembrane regulator (CFTR) triggering CF or missense mutations found in the Z variant of Alpha 1-Antitrypsin deficiency (AATD), leading to lung and liver diseases, can accelerate misfolding and/or generate aggregates. Conversely to CF variants, for which three correctors are already approved (ivacaftor, lumacaftor/ivacaftor, and most recently tezacaftor/ivacaftor), there are limited therapeutic options for AATD. Therefore, a more detailed understanding of the PN components governing AAT variant biogenesis and their manipulation by pharmacological intervention could delay, or even better, avoid the onset of AATD-related pathologies.

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The impact of alpha-1 antitrypsin augmentation therapy on neutrophil-driven respiratory disease in deficient individuals

Cited by 27 publications

References 128 publications

Identification of the initial molecular changes in response to circulating angiogenic cells-mediated therapy in critical limb ischemia

Identification of the initial molecular changes in response to circulating angiogenic cells-mediated therapy in critical limb ischemia

Circulating Truncated Alpha-1 Antitrypsin Glycoprotein in Patient Plasma Retains Anti-Inflammatory Capacity

Alpha 1-Antitrypsin Deficiency: A Disorder of Proteostasis-Mediated Protein Folding and Trafficking Pathways

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