COPD with emphysema is characterized by persistent inflammation causing lung damage independently if the patient carriers normal (PiMM) or deficient (PiZZ, Glu342Lys) variant of alpha1-antitrypsin. Our aim was to compare plasma inflammatory biomarker profiles and blood neutrophil (NEU) transcriptome in PiMM and PiZZ COPD patients and to elucidate the impact of augmentation therapy (AATat) on PiZZ COPD. When compared to general COPD (n=67), patients with PiZZ (n=44) demonstrated significantly higher plasma levels of alpha2-macroglobulin (A2MG) and macrophage inflammatory protein-1 alpha (MIP-1?/CCL3) but lower levels of IFN-?, IL-4, IL-13, and VEGF. On the other hand, PiZZ patients treated with AATat had significantly lower levels of plasma A2MG, GRO?, IL-8, and IL-13 as compared to PiZZ non-treated. Blood NEU RNA-seq data revealed that male and female neutrophils cluster into distinct subsets based on their gene expression profiles. After gender correction, we found 27 differentially expressed genes between NEU of non-smokers PiZZ vs PiMM COPD while only ZNF682 (Zinc Finger Protein 682) and TMEM218 (Transmembrane Protein 218) were significantly lower in PiZZ patients with AATat vs without therapy. Altogether, we show that plasma levels of A2MG are higher in PiZZ than in PiMM COPD patients, and that AATat lowers A2GM, IL-8, and IL-13 levels in PiZZ. The transcriptome of PiZZ NEU isolated one week after AATat shows a similar profile to PiZZ NEU without therapy.

Grants:2015/17/B/NZ5/01370 and 2018/29/B/NZ5/02346