The effects of weekly augmentation therapy in patients with PiZZ α1-antitrypsin deficiency.
BACKGROUND
The major concept behind augmentation therapy with human α(1)-antitrypsin (AAT) is to raise the levels of AAT in patients with protease inhibitor phenotype ZZ (Glu342Lys)-inherited AAT deficiency and to protect lung tissues from proteolysis and progression of emphysema.


OBJECTIVE
To evaluate the short-term effects of augmentation therapy (Prolastin) on plasma levels of AAT, C-reactive protein, and chemokines/cytokines.


METHODS
Serum and exhaled breath condensate were collected from individuals with protease inhibitor phenotype ZZ AAT deficiency-related emphysema (n = 12) on the first, third, and seventh day after the infusion of intravenous Prolastin. Concentrations of total and polymeric AAT, interleukin-8 (IL-8), monocyte chemotactic protein-1, IL-6, tumor necrosis factor-α, vascular endothelial growth factor, and C-reactive protein were determined. Blood neutrophils and primary epithelial cells were also exposed to Prolastin (1 mg/mL).


RESULTS
There were significant fluctuations in serum (but not in exhaled breath condensate) levels of AAT polymers, IL-8, monocyte chemotactic protein-1, IL-6, tumor necrosis factor-α, and vascular endothelial growth factor within a week of augmentation therapy. In general, augmented individuals had higher AAT and lower serum levels of IL-8 than nonaugmented subjects. Prolastin added for 3 hours to neutrophils from protease inhibitor phenotype ZZ individuals in vitro reduced IL-8 release but showed no effect on cytokine/chemokine release from human bronchial epithelial cells.


CONCLUSIONS
Within a week, augmentation with Prolastin induced fluctuations in serum levels of AAT polymers and cytokine/chemokines but specifically lowered IL-8 levels. It remains to be determined whether these effects are related to the Prolastin preparation per se or to the therapeutic efficacy of augmentation with AAT.
Department of Internal Medicine, Division for Pulmonary Diseases, University Hospital Marburg, Marburg, Germany.
S T
ST
Schmid
J
J
Koepke
M
M
Dresel
A
A
Hattesohl
E
E
Frenzel
J
J
Perez
D A
DA
Lomas
E
E
Miranda
T
T
Greulich
S
S
Noeske
M
M
Wencker
H
H
Teschler
C
C
Vogelmeier
S
S
Janciauskiene
A R
AR
Koczulla
D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D001944:Breath Tests; D002097:C-Reactive Protein / Q000378:metabolism; D002478:Cells, Cultured; D018925:Chemokines / Q000097:blood; D016207:Cytokines / Q000097:blood; D004334:Drug Administration Schedule; D056947:Enzyme Replacement Therapy; D005260:Female; D005838:Genotype; D005858:Germany; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D010641:Phenotype; D011656:Pulmonary Emphysema / Q000097:blood / Q000188:drug therapy / Q000201:enzymology; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome; D000515:alpha 1-Antitrypsin / Q000008:administration & dosage* / Q000097:blood / Q000235:genetics; D019896:alpha 1-Antitrypsin Deficiency / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics
D015415:Biomarkers; D018925:Chemokines; D016207:Cytokines; C043392:SERPINA1 protein, human; D000515:alpha 1-Antitrypsin; D002097:C-Reactive Protein