Divergente Effekte der Substitutionstherapie auf polymorph-nukleäre Granulozyten beim hereditären α1-Antitrypsinmangel
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Philipps-Universität Marburg
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Abstract
Background: α1-antitrypsin (AAT) is a ubiquitary present acute-phase protein which occupies an important immunomodulatory role besides its function as antiprotease protein. Based on the relatively decreased serum concentrations patients with α1-antitrypsin deficiency (AATD) feature levels below the protective antiprotease threshold. In the long-run, these patients frequently develop a progressive panacinary lung-emphysema, similar to chronic obstructive pulmonary disease, as well as a systemic inflammation. As main-producers of the tissue-degrading proteases, polymorph-nuclear granulocytes (PMNs) are in the spotlight of the emphysematic modification. Further effects of these cells are being investigated in the latest studies in order to complete the picture of the pathophysiologic process. So far, the only specific therapy is the weekly substitution therapy. Due to insufficient data on the clinical efficacy, substitution therapy is still in the focus of academic discussion.
Aim: The purpose of this study was to investigate the effects of substitution therapy with Prolastin® on the activation of PMNs derived from patients with AATD. In reverse, we attempted to observe the impact of the high, inflammatory capability on the infused AAT.
Methods: The PMN-markers of degranulation, matrix metalloproteinase 9 (MMP-9) and myeloperoxidase (MPO) were analysed in the sera of 22 AATD-patients with verified PI*ZZ genotype. Sera were taken directly before (pre), two hours (post) and three days after infusion (day 3). In one patient, markers were consequently followed up for the duration of one week. Additionally, the different AAT-fractions in the sera of the patients were determined. In order to monitor the direct effects of Prolastin® and oxidized AAT, PMNs from eight AATD-patients were isolated directly before and two hours after infusion for ex vivo experiments. Subsequently, the cells were stimulated for four hours with Prolastin® and chemically oxidized AAT (oxAATc), respectively. The effects were measured via the release of MMP-9, MPO and Interleukin-8 as wells as the neutrophil adhesion. All investigations were compared with the values of non-substituted patients and healthy probands, respectively.
Results: Substituted patients exhibited a short-term activation of PMNs in terms of a infusion-concomitant degranulation of MMP-9 and MPO two hours after infusion. Both markers were under the levels of non-substituted patients on day 3. Furthermore, MMP-9 and MPO levels dropped below the basic value (pre substitution) on day 3, although this was only statistically significant in the case of MPO. The weekly-timecourse confirmed the trend of low PMN activity in the middle of the week. Further serum analyses displayed a complexation and oxidation of the infused AAT, also apparent in the the weekly-timecourse. In ex vivo experiments we observed an increased activity of PMNs after stimulation with Prolastin® and oxAATc in terms of a degranulation of MMP-9, MPO and IL-8. Prolastin® and oxAATc themselves displayed no differences among each other. Neutrophil adhesion was not altered by the stimulation of Prolastin® and oxAATc.
Conclusion: The degranulation of MMP-9 and MPO suggests an infusion-related, short-term activation of PMNs. However, the relevant decline up to day 3 and beyond indicates a sustained anti-inflammatory effect of substitution therapy. So far, reasons for the short-term activation of PMNs have not been fully elucidated, but the results imply pleiotropic effects of substitution therapy with Prolastin®. Infused AAT appears to be oxidated after infusion in the environment of systemic inflammation and to form higher-molecular complexes. Despite that, oxAAT has no additional disease-modifying, immunologic effects on PMNs in their pathophysiologic role, disregarding the loss of the antiprotease function and in comparison with Prolastin®.
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Created: 2015Issued: 2015-09-10
Faculty
Medizin
Publisher
Philipps-Universität Marburg
Language
ger
Data types
DoctoralThesis
Keywords
Neutrophile GranulozytenMyeloperoxidasesystemische Inflammationimmunologic effectsMetalloproteinaseCOPDantitrypsin deficiencySubstitutionstherapiepolymorph nuclear granulocytes
DFG-subjects
Antitrypsin GranulozytEntzündungObstruktive VentilationsstörungPeroxidaseLungeSubstitutionAugmentation
DDC-Numbers
610
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Dresel, Marc: Divergente Effekte der Substitutionstherapie auf polymorph-nukleäre Granulozyten beim hereditären α1-Antitrypsinmangel. : Philipps-Universität Marburg 2015-09-10. DOI: https://doi.org/10.17192/z2015.0511.