Anti-inflammatory and immunomodulatory properties of α1-antitrypsin without inhibition of elastase.
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.
['Jonigk|Danny|D|', 'Al-Omari|Mariam|M|', 'Maegel|Lavinia|L|', 'Müller|Meike|M|', 'Izykowski|Nicole|N|', 'Hong|Jaewoo|J|', 'Hong|Kwangwon|K|', 'Kim|Soo-Hyun|SH|', 'Dorsch|Martina|M|', 'Mahadeva|Ravi|R|', 'Laenger|Florian|F|', 'Kreipe|Hans|H|', 'Braun|Armin|A|', 'Shahaf|Galit|G|', 'Lewis|Eli C|EC|', 'Welte|Tobias|T|', 'Dinarello|Charles A|CA|', 'Janciauskiene|Sabina|S|']
D055371:Acute Lung Injury D000328:Adult D000818:Animals D000893:Anti-Inflammatory Agents D016207:Cytokines D004195:Disease Models, Animal D005260:Female D015870:Gene Expression D006801:Humans D007155:Immunologic Factors D019272:Leukocyte Elastase D008070:Lipopolysaccharides D008168:Lung D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D018345:Mice, Knockout D008875:Middle Aged D009504:Neutrophils D011656:Pulmonary Emphysema D011994:Recombinant Proteins D000515:alpha 1-Antitrypsin D019896:alpha 1-Antitrypsin Deficiency
alpha 1-antitrypsin immunomodulation inflammation