Alpha1‐antitrypsin binds hemin and prevents oxidative activation of human neutrophils: putative pathophysiological significance.

Janciauskiene, Sabina; Tumpara, Srinu; Wiese, Malgorzata; Wrenger, Sabine; Vijayan, Vijith; Gueler, Faikah; Chen, Rongjun; Madyaningrana, Kukuh; Mahadeva, Ravi; Welte, Tobias; Immenschuh, Stephan; Chorostowska‐Wynimko, Joanna

A1AT as a physiologically relevant scavenger of hemin. Heme is a ubiquitous compound of human tissues, and it is involved in cellular physiology and metabolism. Once released from the cell, free heme oxidizes to the ferric state (hemin). High levels of hemin can cause oxidative stress and inflammation if not neutralized immediately by specialized scavenger proteins. Human alpha1‐antitrypsin (A1AT), an acute‐phase glycoprotein and important inhibitor of neutrophil proteases, is also a hemin‐binding protein. A short‐term exposure of freshly isolated human blood neutrophils to 4 µM hemin results in cell spreading, surface expression of filament protein, vimentin, free radical production, expression of heme oxygenase‐1 (HO‐1), release of IL‐8, and enhanced neutrophil adhesion to human endothelial cells. Consequently, the phosphorylation of protein kinase C (PKC) occurs after 25 min. Under the same experimental conditions, addition of 1 mg/ml A1AT markedly reduces or abolishes neutrophil‐activating effects of hemin and prevents PKC phosphorylation. In a mouse model of acute kidney injury (AKI) plus injection of hemin, monotherapy with 4 mg/mouse A1AT significantly lowered serum levels of free hemin at 2 h after surgery. Moreover, a tendency toward lower AKI scores, reduced infiltration of neutrophils, and lower levels of serum chemokine [CXCL1/keratinocyte‐derived chemokine (KC)] was observed. Our findings highlight A1AT as a potential serum scavenger of hemin and suggest that the commercial preparations of human plasma A1AT might prove to be useful therapeutics in conditions associated with hemolysis.

PROTEIN kinase C; NEUTROPHILS; HEMIN; ACUTE kidney failure; VASCULAR cell adhesion molecule-1; ENDOTHELIAL cells

Journal of Leukocyte Biology, 2017, Vol 102, Issue 4, p1127

0741-5400

Academic Journal

10.1189/jlb.3A0317-124R