Beneficial Role of Neutrophils Through Function of Lactoferrin After Intracerebral Hemorrhage.
Beneficial Role of Neutrophils Through Function of Lactoferrin After Intracerebral Hemorrhage.
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DOI：
10.1161/strokeaha.117.020544
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发表时间：
2018-05
期刊：
影响因子：
8.3
通讯作者：
Aronowski J
中科院分区：
文献类型：
--
作者：
Zhao X;Ting SM;Sun G;Roy-O'Reilly M;Mobley AS;Bautista Garrido J;Zheng X;Obertas L;Jung JE;Kruzel M;Aronowski J
Intracerebral hemorrhage (ICH) is a devastating disease with a 30-day mortality of approximately 50%. There are no effective therapies for ICH. ICH results in brain damage in two major ways; through the mechanical forces of extravasated blood and then through toxicity of the intraparenchymal blood components including hemoglobin/iron. Lactoferrin (LTF) is an iron-binding protein, uniquely abundant in polymorphonuclear neutrophils (PMNs). After ICH, circulating blood PMNs enter the ICH-afflicted brain where they release LTF. By virtue of sequestrating iron, LTF may contribute to hematoma detoxification. ICH in mice was produced using intra-striatal autologous blood injection. PMNs were depleted with intraperitoneal administration of anti-Ly-6G antibody. Treatment of mouse brain cell-cultures with lysed RBC or iron was used as in-vitro model of ICH. LTF mRNA was undetectable in the mouse brain, even after ICH. Unlike mRNA, LTF protein increased in ICH-affected hemispheres by 6h, peaked at 24–72h, and remained elevated for at least a week after ICH. At the single cell level, LTF was detected in PMNs in the hematoma-affected brain at all timepoints after ICH. We also found elevated LTF in the plasma after ICH, with a temporal profile similar to LTF changes in the brain. Importantly, recombinant mouse LTF (mrLTF) reduced the cytotoxicity of lysed RBC and FeCl3 to brain cells in culture. Ultimately, in an ICH model, systemic administration of mrLTF (at 3h, 24h and 48h after ICH) reduced brain edema and ameliorated neurological deficits caused by ICH. mrLTF retained the benefit in reducing behavioral deficit even with 24h treatment delay. Interestingly, systemic depletion of PMNs at 24h after ICH worsened neurological deficits, suggesting that PMN infiltration into the brain at later stages after ICH could be a beneficial response. LTF delivered to the ICH-affected brain by infiltrating PMNs may assist in hematoma detoxification and represent a powerful potential target for the treatment of ICH.
