Anti-inflammatory and immunomodulatory properties of alpha 1-antitrypsin without inhibition of elastase

• Published in: Proceedings of the National Academy of Sciences - PNAS 2013-09, Vol.110 (37), p.15007-15007
• Main Authors: Jonigk, Danny, Al-Omari, Mariam, Maegel, Lavinia, Mueller, Meike, Izykowski, Nicole, Hong, Jaewoo, Hong, Kwangwon, Kim, Soo-Hyun, Dorsch, Martina, Mahadeva, Ravi, Laenger, Florian, Kreipe, Hans, Braun, Armin, Shahaf, Galit, Lewis, Eli C, Welte, Tobias, Dinarello, Charles A, Janciauskiene, Sabina
• Format: Article
• Language: English
• ISSN: 0027-8424
• DOI: 10.1073/pnas.1309648110

The rationale of alpha 1-antitrypsin (AAT) augmentation therapy to treat progressive emphysema in AAT-deficient patients is based on inhibition of neutrophil elastase; however, the benefit of this treatment remains unclear. Here we show that clinical grade AAT (with elastase inhibitory activity) and a recombinant form of AAT (rAAT) without anti-elastase activity reduces lung inflammatory responses to LPS in elastase-deficient mice. WT and elastase-deficient mice treated with either native AAT or rAAT exhibited significant reductions in infiltrating neutrophils (23% and 68%), lavage fluid levels of TNF- alpha (70% and 80%), and the neutrophil chemokine KC (CXCL1) (64% and 90%), respectively. Lung parenchyma TNF- alpha , DNA damage-inducible transcript 3 and X-box binding protein-1 mRNA levels were reduced in both mouse strains treated with AAT; significantly lower levels of these genes, as well as IL-1 beta gene expression, were observed in lungs of AAT-deficient patients treated with AAT therapy compared with untreated patients. In vitro, LPS-induced cytokines from WT and elastase-deficient mouse neutrophils, as well as neutrophils of healthy humans, were similarly reduced by AAT or rAAT; human neutrophils adhering to endothelial cells were decreased by 60-80% (P < 0.001) with either AAT or rAAT. In mouse pancreatic islet macrophages, LPS-induced surface expression of MHC II, Toll-like receptor-2 and -4 were markedly lower (80%, P < 0.001) when exposed to either AAT or rAAT. Consistently, in vivo and in vitro, rAAT reduced inflammatory responses at concentrations 40- to 100-fold lower than native plasma-derived AAT. These data provide evidence that the anti-inflammatory and immunomodulatory properties of AAT can be independent of elastase inhibition.