Jonigk, DannyDannyJonigkAl-Omari, MariamMariamAl-OmariMaegel, LaviniaLaviniaMaegelMüller, MeikeMeikeMüllerIzykowski, NicoleNicoleIzykowskiHong, JaewooJaewooHongHong, KwangwonKwangwonHongKim, Soo-HyunSoo-HyunKimDorsch, MartinaMartinaDorschMahadeva, RivaRivaMahadevaLaenger, FlorianFlorianLaengerKreipe, HansHansKreipeBraun, ArminArminBraunShahaf, GalitGalitShahafLewis, Eli C.Eli C.LewisWelte, TobiasTobiasWelteDinarello, Charles A.Charles A.DinarelloJanciauskiene, SabinaSabinaJanciauskiene2022-03-042022-03-042013https://publica.fraunhofer.de/handle/publica/23340110.1073/pnas.1309648110The rationale of alpha1-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-1beta gene expression, were observed in lungs of AAT-deficient patients treated with AAT thera py 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.enAlpha 1-antitrypsinImmunomodulationinflammation610505journal article