Effects of oxidant stress on inflammation and survival of iNOS knockout mice after marrow transplantation.
Effects of oxidant stress on inflammation and survival of iNOS knockout mice after marrow transplantation.
复制标题
氧化应激对 iNOS 敲除小鼠骨髓移植后炎症和存活的影响。
DOI：
10.1152/ajplung.2001.281.4.l922
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发表时间：
2001
期刊：
影响因子：
--
通讯作者：
Haddad,IY
中科院分区：
文献类型：
--
作者：
Yang,S;Porter,VA;Cornfield,DN;Milla,C;Panoskaltsis-Mortari,A;Blazar,BR;Haddad,IY
在骨髓移植（BMT）后特发性肺炎综合征模型中，注射同种异体T细胞诱导一氧化氮（·NO），添加环磷酰胺（Cy）产生超氧化物（O·）和一种组织损伤的硝化氧化剂。我们假设·NO和O·平衡是bmt后生存和炎症的主要决定因素。给予供体骨髓和脾脏T细胞（BMS）的诱导型一氧化氮合酶（iNOS）缺失突变小鼠（−/−）与匹配的BMS对照组相比，表现出更高的存活率。iNOS(−/−)BMS小鼠在bmt后第7天获得的支气管肺泡灌洗液含有较少的肿瘤坏死因子-α和干扰素-γ，表明·NO刺激了促炎细胞因子的产生。然而，尽管炎症抑制和硝基酪氨酸染色降低，iNOS（−/−）小鼠同时给予供体T细胞和Cy (BMS + Cy)，比iNOS充足的BMS + Cy小鼠更早死亡。iNOS(−/−)BMS + Cy小鼠的肺泡巨噬细胞不产生·NO，但通过细胞内荧光探针2 ',7 ' -二氯荧光素的氧化来评估其持续产生强氧化剂。我们得出结论，·NO会放大T细胞依赖性炎症，而Cy的添加会加剧·NO依赖性死亡率。然而，在cy诱导的氧化应激过程中，缺乏·NO会降低T细胞受体小鼠的存活率，这很可能是由于产生了不依赖·NO的有毒氧化剂。
In a model of idiopathic pneumonia syndrome after bone marrow transplantation (BMT), injection of allogeneic T cells induces nitric oxide (·NO), and the addition of cyclophosphamide (Cy) generates superoxide (O·) and a tissue-damaging nitrating oxidant. We hypothesized that ·NO and O· balance are major determinants of post-BMT survival and inflammation. Inducible nitric oxide synthase (iNOS) deletional mutant mice (−/−) given donor bone marrow and spleen T cells (BMS) exhibited improved survival compared with matched BMS controls. Bronchoalveolar lavage fluids obtained onday 7post-BMT from iNOS(−/−) BMS mice contained less tumor necrosis factor-α and interferon-γ, indicating that ·NO stimulated the production of proinflammatory cytokines. However, despite suppressed inflammation and decreased nitrotyrosine staining, iNOS(−/−) mice given both donor T cells and Cy (BMS + Cy) died earlier than iNOS-sufficient BMS + Cy mice. Alveolar macrophages from iNOS(−/−) BMS + Cy mice did not produce ·NO but persisted to generate strong oxidants as assessed by the oxidation of the intracellular fluorescent probe 2′,7′-dichlorofluorescin. We concluded that ·NO amplifies T cell-dependent inflammation and addition of Cy exacerbates ·NO-dependent mortality. However, the lack of ·NO during Cy-induced oxidant stress decreases survival of T cell-recipient mice, most likely by generation of ·NO-independent toxic oxidants.