title: Anti-inflammatory and immunomodulatory properties of α1-antitrypsin without inhibition of elastase.
abstract: The rationale of α1-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-α (70% and 80%), and the neutrophil chemokine KC (CXCL1) (64% and 90%), respectively. Lung parenchyma TNF-α, 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-1β 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.
authors: Department of Respiratory Medicine, Institute of Pathology, Central Laboratory Animal Facility, and Institute for Laboratory Animal Science, Hannover Medical School, 30625 Hannover, Germany.
authors: Danny
authors: D
authors: Jonigk
authors: Mariam
authors: M
authors: Al-Omari
authors: Lavinia
authors: L
authors: Maegel
authors: Meike
authors: M
authors: Müller
authors: Nicole
authors: N
authors: Izykowski
authors: Jaewoo
authors: J
authors: Hong
authors: Kwangwon
authors: K
authors: Hong
authors: Soo-Hyun
authors: SH
authors: Kim
authors: Martina
authors: M
authors: Dorsch
authors: Ravi
authors: R
authors: Mahadeva
authors: Florian
authors: F
authors: Laenger
authors: Hans
authors: H
authors: Kreipe
authors: Armin
authors: A
authors: Braun
authors: Galit
authors: G
authors: Shahaf
authors: Eli C
authors: EC
authors: Lewis
authors: Tobias
authors: T
authors: Welte
authors: Charles A
authors: CA
authors: Dinarello
authors: Sabina
authors: S
authors: Janciauskiene
mesh_terms: D055371:Acute Lung Injury / Q000188:drug therapy / Q000235:genetics / Q000276:immunology; D000328:Adult; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity; D008168:Lung / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D011656:Pulmonary Emphysema / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D011994:Recombinant Proteins / Q000494:pharmacology; D000515:alpha 1-Antitrypsin / Q000494:pharmacology*; D019896:alpha 1-Antitrypsin Deficiency / Q000188:drug therapy / Q000235:genetics / Q000276:immunology
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D007155:Immunologic Factors; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D000515:alpha 1-Antitrypsin; D019272:Leukocyte Elastase
keywords: alpha 1-antitrypsin; immunomodulation; inflammation
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