The effects of weekly augmentation therapy in patients with PiZZ &amp;alpha;1-antitrypsin deficiency

Schmid, Severin; Koepke, Janine; Dresel, M; Hattesohl, Akira; Frenzel, Eileen; Pérez, José María Hernández; Lomas, DA; Miranda, Elena; Greulich, Timm; Noeske, Sarah; Wencker, Marion; Teschler, Helmut; Vogelmeier, Claus; Janciauskiene, Sabina; Koczulla, AR

doi:10.2147/copd.s34560

Cited by 10 publications

(8 citation statements)

References 38 publications

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“…Some studies have suggested that replacement therapy may reduce airway inflammation. 49 – 51 However, Olfert et al 52 found that replacement therapy reduces the concentration of TNF-alpha, but has no effect on IL-6, IL1B, or C-reactive protein. In our study, 4 severe and 2 mild emphysema AATD patients received augmentation therapy every 15 days.…”

Section: Limitationsmentioning

confidence: 99%

Gene and miRNA expression profiles in PBMCs from patients with severe and mild emphysema and PiZZ alpha1-antitrypsin deficiency

Esquinas¹,

Janciauskiene²,

Gonzalo³

et al. 2017

COPD

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IntroductionCOPD has complex etiologies involving both genetic and environmental determinants. Among genetic determinants, the most recognized is a severe PiZZ (Glu342Lys) inherited alpha1-antitrypsin deficiency (AATD). Nonetheless, AATD patients present a heterogeneous clinical evolution, which has not been completely explained by sociodemographic or clinical factors. Here we performed the gene expression profiling of blood cells collected from mild and severe COPD patients with PiZZ AATD. Our aim was to identify differences in messenger RNA (mRNA) and microRNA (miRNA) expressions that may be associated with disease severity.Materials and methodsPeripheral blood mononuclear cells from 12 COPD patients with PiZZ AATD (6 with severe disease and 6 with mild disease) were used in this pilot, high-throughput microarray study. We compared the cellular expression levels of RNA and miRNA of the 2 groups, and performed functional and enrichment analyses using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene-ontology (GO) terms. We also integrated the miRNA and the differentially expressed putative target mRNA. For data analyses, we used the R statistical language R Studio (version 3.2.5).ResultsThe severe and mild COPD–AATD groups were similar in terms of age, gender, exacerbations, comorbidities, and use of augmentation therapy. In severe COPD–AATD patients, we found 205 differentially expressed genes (DEGs) (114 upregulated and 91 downregulated) and 28 miRNA (20 upregulated and 8 downregulated) compared to patients with mild COPD–AATD disease. Of these, hsa-miR-335-5p was downregulated and 12 target genes were involved in cytokine signaling, MAPK/mk2, JNK signaling cascades, and angiogenesis were much more highly expressed in severe compared with mild patients.ConclusionsDespite the small sample size, we identified downregulated miRNA (hsa-miR-335) and the activation of pathways related to inflammation and angiogenesis on comparing patients with severe vs mild COPD–AATD. Nonetheless, our findings warrant further validation in large studies.

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Section: Limitationsmentioning

confidence: 99%

Gene and miRNA expression profiles in PBMCs from patients with severe and mild emphysema and PiZZ alpha1-antitrypsin deficiency

Esquinas¹,

Janciauskiene²,

Gonzalo³

et al. 2017

COPD

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“…This finding is in accordance with a previous study demonstrating a reduction of MMP-9 on weekly treatment with augmentation therapy [ 52 ]. In addition to the effects on MMP-9, we previously found that Prolastin therapy significantly reduces serum levels of IL-8 [ 16 ] as well as the levels of TNF, IL-1, IL-6, MCP-1 in experimental models in vitro and in vivo [ 16 , 53 , 54 ].…”

Section: Discussionmentioning

confidence: 99%

“…Previously we have measured plasma levels of A1AT polymers, cytokines (IL-1β, IL-6, and TNFα), chemokines (IL-8 and MCP-1) and VEGF in patients undergoing weekly augmentation therapy- just before intravenous A1AT (Prolastin) infusion, as well as one and three days after therapy. Our results revealed significant fluctuations in plasma cytokine and A1AT polymer concentrations, pointing out that potentially unacknowledged immunologic properties are carried out by weekly infusion of A1AT [ 16 ].…”

Section: Introductionmentioning

confidence: 88%

“…Purified human plasma pooled A1AT (Prolastin, Grifols) was used for in vitro experiments. To remove high molecular mass proteins, specifically IgA [ 16 , 23 , 24 ] Prolastin was first diluted in phosphate-buffered saline (PBS) and repurified by ultrafiltration using a centricon-100 kDa and centricon-30 kDa cutoff. The IgA-free preparation of A1AT was subjected to quantitative analysis using bicinchoninic acid assay (BCA assay, Pierce BCA Protein Assay Kit, Thermo Scientific) and to qualitative evaluation using Western blot analysis with specific anti-A1AT and anti-IgA antibody.…”

Section: Methodsmentioning

confidence: 99%

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Therapy with Plasma Purified Alpha1-Antitrypsin (Prolastin®) Induces Time-Dependent Changes in Plasma Levels of MMP-9 and MPO

et al. 2015

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The common Z mutation (Glu342Lys) of α1-antitrypsin (A1AT) results in the polymerization and intracellular retention of A1AT protein. The concomitant deficiency of functional A1AT predisposes PiZZ subjects to early onset emphysema. Clinical studies have implied that, among the biomarkers associated with emphysema, matrix metalloproteinase 9 (MMP-9) is of particular importance. Increased plasma MMP-9 levels are proposed to predict the decline of lung function as well as greater COPD exacerbations in A1AT deficiency-associated emphysema. The aim of the present study was to investigate the effect of A1AT therapy (Prolastin) on plasma MMP-9 and myeloperoxidase (MPO) levels. In total 34 PiZZ emphysema patients were recruited: 12 patients without and 22 with weekly intravenous (60 mg/kg body weight) A1AT therapy. The quantitative analysis of A1AT, MMP-9 and MPO was performed in serum and in supernatants of blood neutrophils isolated from patients before and after therapy. Patients with Prolastin therapy showed significantly lower serum MMP-9 and MPO levels than those without therapy. However, parallel analysis revealed that a rapid infusion of Prolastin is accompanied by a transient elevation of plasma MMP-9 and MPO levels. Experiments with freshly isolated blood neutrophils confirmed that therapy with Prolastin causes transient MMP-9 and MPO release. Prolastin induced the rapid release of MMP-9 and MPO when added directly to neutrophil cultures and this reaction was associated with the presence of IgA in A1AT preparation. Our data support the conclusion that changes in plasma levels of MMP-9 and MPO mirror the effect of Prolastin on blood neutrophils.

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“…Polymeric α 1 -antitrypsin is found within the Periodic Acid Schiff (PAS) positive inclusion bodies in hepatocytes ( Ekeowa et al, 2010; Eriksson et al, 1986; Miranda et al, 2010 ). Polymers of α 1 -antitrypsin are also present in the circulation of PiZZ individuals ( Janciauskiene et al, 2002; Schmid et al, 2012; Tan et al, 2014 ) and have been detected in the lung, kidney and skin ( Elliott et al, 1998; Gross et al, 2009; Lawless et al, 2004; Mahadeva et al, 2005; Morris et al, 2011; Paakko et al, 1996; Venembre et al, 1994 ). The structure of the polymers that form within hepatocytes has been the subject of much debate.…”

Section: Introductionmentioning

confidence: 99%

Characterising the association of latency with α1-antitrypsin polymerisation using a novel monoclonal antibody

Tan

Pérez

Mela

et al. 2015

The International Journal of Biochemistry & Cell Biology

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α1-Antitrypsin is primarily synthesised in the liver, circulates to the lung and protects pulmonary tissues from proteolytic damage. The Z mutant (Glu342Lys) undergoes inactivating conformational change and polymerises. Polymers are retained within the hepatocyte endoplasmic reticulum (ER) in homozygous (PiZZ) individuals, predisposing the individuals to hepatic cirrhosis and emphysema. Latency is an analogous process of inactivating, intra-molecular conformational change and may co-occur with polymerisation. However, the relationship between latency and polymerisation remained unexplored in the absence of a suitable probe. We have developed a novel monoclonal antibody specific for latent α1-antitrypsin and used it in combination with a polymer-specific antibody, to assess the association of both conformers in vitro, in disease and during augmentation therapy. In vitro kinetics analysis showed polymerisation dominated the pathway but latency could be promoted by stabilising monomeric α1-antitrypsin. Polymers were extensively produced in hepatocytes and a cell line expressing Z α1-antitrypsin but the latent protein was not detected despite manipulation of the secretory pathway. However, α1-antitrypsin augmentation therapy contains latent α1-antitrypsin, as did the plasma of 63/274 PiZZ individuals treated with augmentation therapy but 0/264 who were not receiving this medication (p < 10−14). We conclude that latent α1-antitrypsin is a by-product of the polymerisation pathway, that the intracellular folding environment is resistant to formation of the latent conformer but that augmentation therapy introduces latent α1-antitrypsin into the circulation. A suite of monoclonal antibodies and methodologies developed in this study can characterise α1-antitrypsin folding and conformational transitions, and screen methods to improve augmentation therapy.

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The effects of weekly augmentation therapy in patients with PiZZ α1-antitrypsin deficiency

Cited by 10 publications

References 38 publications

Gene and miRNA expression profiles in PBMCs from patients with severe and mild emphysema and PiZZ alpha1-antitrypsin deficiency

Gene and miRNA expression profiles in PBMCs from patients with severe and mild emphysema and PiZZ alpha1-antitrypsin deficiency

Therapy with Plasma Purified Alpha1-Antitrypsin (Prolastin®) Induces Time-Dependent Changes in Plasma Levels of MMP-9 and MPO

Characterising the association of latency with α1-antitrypsin polymerisation using a novel monoclonal antibody

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