scholarly journals The Course of AαVal541 as a Proteinase 3 Specific Neo-Epitope after Alpha-1-Antitrypsin Augmentation in Severe Deficient Patients

2021 ◽  
Vol 22 (15) ◽  
pp. 8031
Author(s):  
Iris G. M. Schouten ◽  
Richard A. Mumford ◽  
Dirk Jan A. R. Moes ◽  
Pieter S. Hiemstra ◽  
Jan Stolk
Keyword(s):  
Plasma Level ◽  
Serine Proteases ◽  
Population Pharmacokinetic ◽  
Proteinase 3 ◽  
Healthy Controls ◽  
Population Pharmacokinetic Modeling ◽  
Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin

In alpha-1-antitrypsin deficiency (AATD), neutrophil serine proteases such as elastase and proteinase 3 (PR3) are insufficiently inhibited. A previous study in AATD patients showed a higher plasma level of the specific PR3-generated fibrinogen-derived peptide AαVal541, compared with healthy controls. Here, we analyzed the course of AαVal541 plasma levels during 4 weeks after a single iv dose of 240 mg/kg AAT in ten patients with genotype Z/Rare or Rare/Rare. To this end, we developed an immunoassay to measure AαVal541 in plasma and applied population pharmacokinetic modeling for AAT. The median AαVal541 plasma level before treatment was 140.2 nM (IQR 51.5–234.8 nM)). In five patients who received AAT for the first time, AαVal541 levels decreased to 20.6 nM (IQR 5.8–88.9 nM), and in five patients who already had received multiple infusions before, it decreased to 26.2 nM (IQR 22.31–35.0 nM). In 9 of 10 patients, AαVal541 levels were reduced to the median level of healthy controls (21.4 nM; IQR 16.7–30.1 nM). At 7–14 days after treatment, AαVal541 levels started to increase again in all patients. Our results show that fibrinopeptide AαVal541 may serve as a biochemical footprint to assess the efficacy of in vivo inhibition of PR3 activity in patients receiving intravenous AAT augmentation therapy.

scholarly journals A Novel Small Molecule Inhibits Intrahepatocellular Accumulation of Z-Variant Alpha 1-Antitrypsin In Vitro and In Vivo

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1586 ◽  
Author(s):  
Xiaojuan Zhang ◽  
Kien Pham ◽  
Danmeng Li ◽  
Ryan J. Schutte ◽  
David Hernandez Gonzalo ◽  
...  
Keyword(s):  
Liver Disease ◽  
Cell Model ◽  
Curative Therapy ◽  
Animal Models Of Disease ◽  
Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin ◽  
Models Of Disease

Alpha 1-antitrypsin deficiency (AATD) is the most common genetic cause of liver disease in children and is associated with early-onset chronic liver disease in adults. AATD associated liver injury is caused by hepatotoxic retention of polymerized mutant alpha 1-antitrypsin molecules within the endoplasmic reticulum. Currently, there is no curative therapy for AATD. In this study, we selected small molecules with the potential to bind mutant alpha 1-antitrypsin (Z-variant) to inhibit its accumulation in hepatocytes. We used molecular docking to select candidate compounds that were validated in cell and animal models of disease. A crystal structure of polymerized alpha 1-antitrypsin molecule was used as the basis for docking 139,735 compounds. Effects of the top scoring compounds were investigated in a cell model that stably expresses Z-variant alpha 1-antitrypsin and in PiZ mice expressing Z-variant human alpha 1-antitrypsin (Z-hAAT), encoded by SERPINA1*E342K. 4′,′5-(Methylenedioxy)-2-nitrocinnamic acid was predicted to bind cleaved alpha 1-antitrypsin at the polymerization interface, and observed to co-localize with Z-hAAT, increase Z-hAAT degradation, inhibit intracellular accumulation of Z-hAAT, and alleviate liver fibrosis.

Lung Function and CT Densitometry in Subjects with alpha-1-Antitrypsin Deficiency and Healthy Controls at 35 Years of Age

2014 ◽  
Vol 12 (2) ◽  
pp. 162-167 ◽  
Author(s):  
Eeva Piitulainen ◽  
Laura Cano Montero ◽  
Meltem Nystedt-Düzakin ◽  
Berend C. Stoel ◽  
Tomas Sveger ◽  
...  
Keyword(s):  
Lung Function ◽  
Healthy Controls ◽  
Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin

scholarly journals Plasma mitochondrial DNA is associated with extrapulmonary sarcoidosis

2019 ◽  
Vol 54 (2) ◽  
pp. 1801762
Author(s):  
Changwan Ryu ◽  
Caitlin Brandsdorfer ◽  
Taylor Adams ◽  
Buqu Hu ◽  
Dylan W. Kelleher ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
African Americans ◽  
Clinical Findings ◽  
Genomic Research ◽  
Healthy Controls ◽  
Tissue Remodelling ◽  
Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin Deficiency ◽  
Mechanistic Basis ◽  
Alpha 1 Antitrypsin

Sarcoidosis is an unpredictable granulomatous disease in which African Americans disproportionately experience aggressive phenotypes. Mitochondrial DNA (mtDNA) released by cells in response to various stressors contributes to tissue remodelling and inflammation. While extracellular mtDNA has emerged as a biomarker in multiple diseases, its relevance to sarcoidosis remains unknown. We aimed to define an association between extracellular mtDNA and clinical features of sarcoidosis.Extracellular mtDNA concentrations were measured using quantitative PCR for the human MT-ATP6 gene in bronchoalveolar (BAL) and plasma samples from healthy controls and patients with sarcoidosis from The Yale Lung Repository; associations between MT-ATP6 concentrations and Scadding stage, extrapulmonary disease and demographics were sought. Results were validated in the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis cohort.Relative to controls, MT-ATP6 concentrations in sarcoidosis subjects were robustly elevated in the BAL fluid and plasma, particularly in the plasma of patients with extrapulmonary disease. Relative to Caucasians, African Americans displayed excessive MT-ATP6 concentrations in the BAL fluid and plasma, for which the latter compartment correlated with significantly higher odds of extrapulmonary disease.Enrichments in extracellular mtDNA in sarcoidosis are associated with extrapulmonary disease and African American descent. Further study into the mechanistic basis of these clinical findings may lead to novel pathophysiologic and therapeutic insights.

scholarly journals The Emerging Role of Proteases in Alpha-1 Antitrypsin Deficiency and Beyond

2021 ◽  
pp. 00494-2021
Author(s):  
Aishath Fazleen ◽  
Tom Wilkinson
Keyword(s):  
Serine Proteases ◽  
Treatment Options ◽  
Disease Process ◽  
Cathepsin G ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Chronic Lung Diseases ◽  
Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin

Alpha-1 Antitrypsin Deficiency (AATD) has been historically under-recognised and under-diagnosed; recently it has begun to receive greater interest in terms of attempts at deeper elucidation of pathology and treatment options. However, the concept of disease phenotypes within AATD (emphysema, chronic bronchitis, bronchiectasis, or a combination of phenotypes) has not been proposed or studied. Of the 3 Neutrophil Serine Proteases (NSPs), Neutrophil Elastase (NE) was historically believed to be the sole contributor to disease pathology in AATD. Recently, Proteinase-3 (PR3) has been increasingly studied as an equal, if not greater, contributor to the disease process. Cathepsin G (CG), however, has not been extensively evaluated in this area. Matrix metalloproteinases (MMPs) have also been mentioned in the pathogenesis of AATD but have not been widely explored. This article considers the available evidence for differential protease activity in patients with AATD, including the contribution to distinct phenotypes of the disease. Due to limited literature in this area, extrapolations from studies of other chronic lung diseases with similar phenotypes, including chronic obstructive pulmonary disease (COPD) and bronchiectasis have been made. We consider a new framework of understanding defined by protease driven endotypes of disease which may lead to new opportunities for precision medicine.

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