<p class="first" id="P3">Immune cell death caused by neutrophil extracellular traps
(NETs), referred to as
NETosis, can contribute to the pathogenesis of endotoxemia and organ damage. Although
the mechanisms by which infection induces NETosis and how that leads to organ dysfunction
remain largely unknown, NET formation is often found following citrullination of histone
H3 (CitH3) by peptidylarginine deiminase (PAD). We hypothesized that lipopolysaccharide
(LPS)-induced activation of PAD and subsequent CitH3-mediated NET formation increase
endothelial permeability and pulmonary dysfunction and, therefore, that inhibition
of PAD could mitigate damage and improve survival in lethal endotoxemia. Here, we
showed that treatment with YW3-56, a PAD2/PAD4 inhibitor, significantly diminished
PAD activation, blocked LPS-induced pulmonary vascular leakage, alleviated acute lung
injury, and improved survival in a mouse model of lethal LPS-induced endotoxemia.
We found CitH3 in the bloodstream 30 min after intraperitoneal injection of LPS (35
mg/kg) into mice. Additionally, CitH3 production was induced in cultured neutrophils
exposed to LPS, and NETs derived from these LPS-treated neutrophils increased the
permeability of endothelial cells. However, YW3-56 exposure reduced CitH3 production
and NET formation by neutrophils following LPS exposure. Moreover, treatment with
YW3-56 decreased the levels of circulating CitH3 and abolished neutrophil activation
and NET formation in the lungs of mice with endotoxemia. These data suggest a novel
mechanism by which PAD-NET-CitH3 can play a pivotal role in pulmonary vascular dysfunction
and the pathogenesis of lethal endotoxemia.
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