Prolastin, a pharmaceutical preparation of purified human alpha 1-antitrypsin, blocks endotoxin-mediated cytokine release

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Abstract

Background: alpha 1-antitrypsin (AAT) serves primarily as an inhibitor of the elastin degrading proteases, neutrophil elastase and proteinase 3. There is ample clinical evidence that inherited severe AAT deficiency predisposes to chronic obstructive pulmonary disease. Augmentation therapy for AAT deficiency has been available for many years, but to date no sufficient data exist to demonstrate its efficacy. There is increasing evidence that AAT is able to exert effects other than protease inhibition. We investigated whether Prolastin, a preparation of purified pooled human AAT used for augmentation therapy, exhibits antibacterial effects. Methods: Human monocytes and neutrophils were isolated from buffy coats or whole peripheral blood by the Ficoll-Hypaque procedure. Cells were stimulated with lipopolysaccharide (LPS) or zymosan, either alone or in combination with Prolastin, native AAT or polymerised AAT for 18 h, and analysed to determine the release of TNF alpha, IL-1 beta and IL-8. At 2-week intervals, seven subjects were submitted to a nasal challenge with sterile saline, LPS ( 25 mu g) and LPS-Prolastin combination. The concentration of IL-8 was analysed in nasal lavages performed before, and 2, 6 and 24 h after the challenge. Results: In vitro, Prolastin showed a concentration-dependent (0.5 to 16 mg/ml) inhibition of endotoxin-stimulated TNF alpha and IL-1 beta release from monocytes and IL-8 release from neutrophils. At 8 and 16 mg/ml the inhibitory effects of Prolastin appeared to be maximal for neutrophil IL- 8 release (5.3-fold, p < 0.001 compared to zymosan treated cells) and monocyte TNFa and IL- 1 release (10.7- and 7.3-fold, p < 0.001, respectively, compared to LPS treated cells). Furthermore, Prolastin (2.5 mg per nostril) significantly inhibited nasal IL- 8 release in response to pure LPS challenge. Conclusion: Our data demonstrate for the first time that Prolastin inhibits bacterial endotoxin-induced pro-inflammatory responses in vitro and in vivo, and provide scientific bases to explore new Prolastin-based therapies for individuals with inherited AAT deficiency, but also for other clinical conditions.

Detaljer

Författare
Enheter & grupper
Externa organisationer
  • Skåne University Hospital
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Lungmedicin och allergi
Originalspråkengelska
TidskriftRespiratory Research
Volym6
Utgåva nummer12
StatusPublished - 2005
PublikationskategoriForskning
Peer review utfördJa

Relaterad forskningsoutput

Nita, I., 2009, Institutionen för kliniska vetenskaper, Lunds universitet. 167 s.

Forskningsoutput: AvhandlingDoktorsavhandling (sammanläggning)

Hollander, C., 2006, Department of Clinical Sciences, Lund University. 169 s.

Forskningsoutput: AvhandlingDoktorsavhandling (sammanläggning)

Visa alla (2)