Short term effects of alpha1-antitrypsin substitution therapy on the degranulation of neutrophil granulocytes

Introduction: Alpha-1-antitrypsin-deficiency (AATD) is a hereditary, co-dominant condition which results in low levels of circulating alpha-1-antitrypsin (A1AT), unbalanced protease activity and frequent development of emphysema. The concept behind substitution therapy with human plasma A1AT is to normalize the concentration in blood and tissue and thereby protecting the lungs from progressive destruction by proteases.

Aims: To better understand the influence of weekly augmentation therapy on polymorphnuclear neutrophils (PMNs) function we examined direct effects on chemokine release and degranulation of matrix metallopeptidase-9 (MMP-9) and myeloperoxidase (MPO).

Methods: PMNs were isolated from peripheral blood of ten AATD-patients (PI-ZZ, mean age 55±8.7; FEV1 [%] 38.1±14.33) pre and two hours post substitution infusion. The release of IL-8, MMP-9 and MPO was quantified in neutrophil supernatants via ELISA. Standard inflammation markers as well as MMP-9, MPO and the tissue inhibitor of metalloproteinase-1 (TIMP-1) were evaluated in patient sera.

Results: PMN-stimulation experiments displayed no differences on chemokine release or degranulation between pre and post substitution infusion. Two hours after substitution we measured increased MMP-9 (p=0.002) and MPO (p=0.0034) concentrations in sera of patients, whereas TIMP-1 decreased drastically (p=0.002). IL-8 levels in sera of these patients were within normal range and no changes were detectable due to substitution.

Conclusions: We conclude that elevated MMP-9 and MPO concentrations after substitution depend on rapid degranulation of PMNs whereas the decline in TIMP-1 concentration possibly depends on a feedback loop.