Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 37, Pages 15007-15012Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1309648110
Keywords
alpha 1-antitrypsin; inflammation; immunomodulation
Categories
Funding
- Fundacion Federico
- Deutsche Forschungsgemeinschaft [SFB 587, A18, JO743/2-1]
- Deutsches Zentrum fur Lungenforschung
- Hannover Biomedical Research School Graduate School
- Integriertes Forschungs- und Behandlungszentrum Transplantation [01EO0802]
- Cambridge National Institute of Health Research Biomedical Research Institute
- National Institutes of Health [AI-15614, AR-45584, CA-04 6934]
- National Research Foundation Grant WCU [R33-2008-000-10022-0]
- Korea Healthcare Technology Research and Development Project [A100460]
- Israel Science Foundation
- Korea Health Promotion Institute [A100460] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
- National Research Foundation of Korea [R33-2008-000-10022-0] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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The rationale of alpha 1-alpha ntitrypsin (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.
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