Inducible nitric oxide synthase in neutrophils and endothelium contributes to ischemic brain injury in mice.
Inducible nitric oxide synthase in neutrophils and endothelium contributes to ischemic brain injury in mice.
复制标题
DOI：
10.4049/jimmunol.1400918
复制
发表时间：
2014-09-01
期刊：
影响因子：
--
通讯作者：
Anrather J
中科院分区：
文献类型：
--
作者：
Garcia-Bonilla L;Moore JM;Racchumi G;Zhou P;Butler JM;Iadecola C;Anrather J
诱导型一氧化氮合酶（inducible Nitric oxide synthase, iNOS）产生的一氧化氮参与缺血性脑损伤，但表达iNOS的细胞类型和介导组织损伤的机制尚不清楚。为了研究iNOS在常驻脑细胞和浸润缺血脑的外周白细胞中的相对贡献，我们使用大脑中动脉闭塞3天后测定梗死体积的骨髓（BM）嵌合小鼠。与自体移植iNOS - / -小鼠（24±3 mm3, n=10, p<0.01）相比，移植iNOS+/+ BM的iNOS - / -小鼠表现出更大的梗死（44±2 mm3, n=13; Mean±SE），提示血源性白细胞参与了损伤。此外，iNOS - / - BM移植的iNOS+/+小鼠出现大面积梗死（39±6 mm3, n=13），与自体移植的iNOS+/+小鼠（39±4 mm3, n=14）相似，表明驻留的脑细胞也发挥了作用。流式细胞术和细胞分选显示iNOS在中性粒细胞和内皮细胞中高表达，而在小胶质细胞中不表达。令人惊讶的是，缺血后iNOS在移植了iNOS - / - BM的iNOS+/+小鼠的内皮细胞和移植了iNOS+/+ BM的iNOS - / -小鼠的白细胞中表达增强，这表明内皮细胞中的iNOS抑制白细胞中iNOS的表达，反之亦然。为了提供中性粒细胞介导脑损伤的独立证据，在脑卒中后24小时将中性粒细胞分离并转移到小鼠体内。与嵌合小鼠的结果一致，将中性粒细胞iNOS+/+而不是iNOS - /−转移到iNOS - /−小鼠中会增加梗死体积。研究结果表明，中性粒细胞和内皮细胞中的iNOS均可介导组织损伤，并将这些细胞类型确定为脑卒中损伤的推定治疗靶点。
Nitric oxide produced by inducible nitric oxide synthase (iNOS) contributes to ischemic brain injury, but the cell types expressing iNOS and mediating tissue damage have not been elucidated. To examine the relative contribution of iNOS in resident brain cells and peripheral leukocytes infiltrating the ischemic brain, we used bone marrow (BM) chimeric mice in which the middle cerebral artery was occluded and infarct volume was determined 3 days later. iNOS−/− mice engrafted with iNOS+/+ BM exhibited larger infarcts (44±2 mm3; n=13; Mean±SE) compared to autologous transplanted iNOS−/− mice (24±3 mm3; n=10; p<0.01), implicating blood-borne leukocytes in the damage. Furthermore, iNOS+/+ mice transplanted with iNOS−/− BM had large infarcts (39±6 mm3; n=13), similar to those of autologous transplanted iNOS+/+ mice (39±4 mm3; n=14), indicating the resident brain cells also play a role. Flow cytometry and cell sorting revealed that iNOS is highly expressed in neutrophils and endothelium, but not microglia. Surprisingly, post-ischemic iNOS expression was enhanced in the endothelium of iNOS+/+ mice transplanted with iNOS−/− BM, and in leukocytes of iNOS−/− mice with iNOS+/+ BM, suggesting that endothelial iNOS suppresses iNOS expression in leukocytes and vice-versa. To provide independent evidence that neutrophils mediate brain injury, neutrophils were isolated and transferred to mice 24 hours after stroke. Consistent with the result in chimeric mice, transfer of iNOS+/+, but not iNOS−/−, neutrophils into iNOS−/−mice increased infarct volume. The findings establish that iNOS both in neutrophils and endothelium mediates tissue damage and identify these cell types as putative therapeutic targets for stroke injury.
登录
查看更多内容
影响因子：
37.8
作者：
Go AS;Mozaffarian D;Roger VL;Benjamin EJ;Berry JD;Blaha MJ;Dai S;Ford ES;Fox CS;Franco S;Fullerton HJ;Gillespie C;Hailpern SM;Heit JA;Howard VJ;Huffman MD;Judd SE;Kissela BM;Kittner SJ;Lackland DT;Lichtman JH;Lisabeth LD;Mackey RH;Magid DJ;Marcus GM;Marelli A;Matchar DB;McGuire DK;Mohler ER 3rd;Moy CS;Mussolino ME;Neumar RW;Nichol G;Pandey DK;Paynter NP;Reeves MJ;Sorlie PD;Stein J;Towfighi A;Turan TN;Virani SS;Wong ND;Woo D;Turner MB;American Heart Association Statistics Committee and Stroke Statistics Subcommittee
通讯作者：
American Heart Association Statistics Committee and Stroke Statistics Subcommittee
影响因子：
4.4
作者：
Forman, LJ;Liu, P;Wong, PYK
通讯作者：
Wong, PYK
DOI：
10.1152/ajpgi.1998.275.3.g592
发表时间：
1998-09-01
影响因子：
4.5
作者：
Binion, DG;Fu, SD;Wilson, KT
通讯作者：
Wilson, KT
影响因子：
12.7
作者：
Forster, C;Clark, HB;Iadecola, C
通讯作者：
Iadecola, C
影响因子：
8.3
作者：
Becker, K;Kindrick, D;Winn, R
通讯作者：
Winn, R