Neutrophil Extracellular XXXX -Related Extracellular Histones Cause Vascular Necrosis in Severe GN.

@entity9818 @entity8 @entity137 @entity26789 @entity39 @entity19 @entity633 @entity291 @entity52643
UNASSIGNED: Severe GN involves local neutrophil extracellular @entity52643 (NET) formation. We hypothesized a local cytotoxic effect of NET-related histone release in @entity39 GN. In vitro, histones from @entity291 thymus or histones released by neutrophils undergoing NETosis killed glomerular endothelial cells, podocytes, and parietal epithelial cells in a dose-dependent manner. Histone-neutralizing agents such as antihistone IgG, activated protein C, or heparin prevented this effect. Histone @entity137 on glomeruli ex vivo was @entity26789 dependent, and lack of @entity26789 attenuated histone-induced renal @entity9818 and @entity8 in mice. Anti-glomerular basement membrane GN involved NET formation and vascular @entity39 , whereas blocking NET formation by peptidylarginine inhibition or preemptive anti-histone IgG injection significantly reduced all aspects of GN (i.e., vascular @entity39 , podocyte loss, @entity633 , cytokine induction, recruitment or activation of glomerular leukocytes, and glomerular crescent formation). To evaluate histones as a therapeutic target, @entity19 with established GN were treated with three different histone-neutralizing agents. Anti-histone IgG, recombinant activated protein C, and heparin were equally effective in abrogating severe GN, whereas combination therapy had no additive effects. Together, these results indicate that NET-related histone release during GN elicits cytotoxic and immunostimulatory effects. Furthermore, neutralizing extracellular histones is still therapeutic when initiated in established GN.
