Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
FASEB J. 2019 Dec;33(12):13660-13668. doi: 10.1096/fj.201901231R. Epub 2019 Oct 8.
Olfactomedin-4 (OLFM4) identifies a subset of neutrophils conserved in both mouse and man, associated with worse outcomes in several inflammatory conditions. We investigated the role of OLFM4-positive neutrophils in murine intestinal ischemia/reperfusion (IR) injury. Wild-type (WT) C57Bl/6 and OLFM4 null mice were subjected to intestinal IR injury and then monitored for survival or tissues harvested for further analyses. intestinal barrier function was determined functional assay of permeability to FITC-dextran. OLFM4 null mice had a significant 7-d survival benefit and less intestinal barrier dysfunction compared with WT. Early after IR, WT mice had worse mucosal damage on histologic examination. Experiments involving adoptive transfer of bone marrow demonstrated that the mortality phenotype associated with OLFM4-positive neutrophils was transferrable to OLFM4 null mice. After IR injury, WT mice also had increased intestinal tissue activation of NFκB and expression of iNOS, 2 signaling pathways previously demonstrated to be involved in intestinal IR injury. In combination, these experiments show that OLFM4-positive neutrophils are centrally involved in the pathologic pathway leading to intestinal damage and mortality after IR injury. This may provide a therapeutic target for mitigation of intestinal IR injury in a variety of common clinical situations.-Levinsky, N. C., Mallela, J., Opoka, A., Harmon, K., Lewis, H. V., Zingarelli, B., Wong, H. R., Alder, M. N. The olfactomedin-4 positive neutrophil has a role in murine intestinal ischemia/reperfusion injury.
嗅鞘蛋白 4（OLFM4）鉴定出在小鼠和人类中均保守的中性粒细胞亚群，与几种炎症状态下的不良结局相关。我们研究了 OLFM4 阳性中性粒细胞在小鼠肠道缺血/再灌注（IR）损伤中的作用。野生型（WT）C57Bl/6 和 OLFM4 敲除小鼠接受肠道 IR 损伤，然后监测其存活或采集组织进行进一步分析。肠道屏障功能通过 FITC-右旋糖酐的功能渗透性测定来确定。与 WT 相比，OLFM4 敲除小鼠具有显著的 7 天生存获益和较少的肠道屏障功能障碍。IR 后早期，WT 小鼠在组织学检查中具有更严重的黏膜损伤。涉及骨髓过继转移的实验表明，与 OLFM4 阳性中性粒细胞相关的死亡率表型可转移到 OLFM4 敲除小鼠。IR 损伤后，WT 小鼠的肠道组织 NFκB 激活和 iNOS 表达也增加，这两种信号通路先前被证明与肠道 IR 损伤有关。综合这些实验表明，OLFM4 阳性中性粒细胞在导致 IR 损伤后肠道损伤和死亡的病理途径中起核心作用。这可能为减轻各种常见临床情况下的肠道 IR 损伤提供治疗靶点。-Levinsky, N. C., Mallela, J., Opoka, A., Harmon, K., Lewis, H. V., Zingarelli, B., Wong, H. R., Alder, M. N. 嗅鞘蛋白 4 阳性中性粒细胞在小鼠肠道缺血/再灌注损伤中的作用。
