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

Abstract

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.

The Multifaceted Effects of Alpha1-Antitrypsin on Neutrophil Functions

“…In support of this hypothesis, excessive neutrophil infiltration into the lung correlates with increased MMP-9 production ( Narasaraju et al, 2011 ), and MMP-9 was suggested as a biomarker to predict decline of lung function in patients with AATD ( Omachi et al, 2011 ). By contrast, serum MMP-9 levels seem to be lower in AATD patients receiving AAT therapy than in those without it ( Koepke et al, 2015 ).…”

Point Mutation of a Non-Elastase-Binding Site in Human α1-Antitrypsin Alters Its Anti-Inflammatory Properties

“…Interestingly, proteases outside the serine-protease family are also inhibited by hAAT, albeit to a lesser extent. These include metalloproteases [e.g., MMP-9 ( 15 – 17 ), ADAMTS-4 ( 18 ), and cysteine-proteases (e.g., caspase-3) ( 19 , 20 )], suggesting that some functions of the molecule may extend beyond the specificity conferred by the primary sequence of the RCL. As such, it has been proposed that the globular surface of hAAT may contain significant functional attributes.…”

The concentration of matrix metalloproteinase 9 in the tumor and peritumoral tissue as prognostic marker in breast cancer patients

“…Concentration of total MMP-9 (human MMP-9 assay measures the 92 kDa Pro-MMP-9 and the 82 kDa active MMP-9) was detected by the immune/sandwich ELISA method according to the kit procedure (Human MMP-9, R&D Systems). The method is based on the measurement of total MMP-9 amount, the enzyme included in degradation of extracellular matrix which could be in active form or preform 27 . After determination, the total protein concentration, supernatants of peritumoral and carcinoma tissue were used as the samples for the total MMP-9 concentration.…”