Inhibition of inducible nitric oxide synthase ameliorates functional and histological changes of acute lung allograft rejection.
Inhibition of inducible nitric oxide synthase ameliorates functional and histological changes of acute lung allograft rejection.
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抑制诱导型一氧化氮合酶可改善急性肺同种异体移植排斥的功能和组织学变化。
DOI：
10.1097/00007890-199704270-00008
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发表时间：
1997
期刊：
影响因子：
6.2
通讯作者：
Patterson,GA
中科院分区：
文献类型：
--
作者：
Worrall,NK;Boasquevisque,CH;Botney,MD;Misko,TP;Sullivan,PM;Ritter,JH;FergusonJr,TB;Patterson,GA
背景。我们最近证明，抑制诱导型一氧化氮合酶（iNOS）可改善严重的急性肺同种异体移植排斥反应。本研究采用大鼠肺移植模型来确定(1)未修饰急性排斥反应组织学进展过程中iNOS表达的时间过程和细胞定位；(2)抑制iNOS是否能防止同种异体移植肺的气体交换功能受损和/或改善急性排斥反应的组织学改变。方法与结果。在轻度、中度和重度急性排斥反应期间，同种异体移植肺中iNOS mRNA和酶活性均有表达，而在轻度急性排斥反应组织学改变前，正常、同种异体移植或同种异体移植肺中iNOS mRNA和酶活性均无表达。异体移植物中iNOS的表达导致血清亚硝酸盐/硝酸盐水平升高，表明体内一氧化氮（NO）的产生增加。原位杂交显示iNOS mRNA在浸润性炎症细胞中表达，而在同种异体移植物实质细胞中不表达。同种异体移植物的气体交换明显受损，选择性iNOS抑制剂氨基胍可以阻止这种现象（同种异体移植物、同种异体移植物和氨基胍处理的同种异体移植物的PaO 2分别为566±19、76±22和504±105 mmHg， P< 0.0002）。氨基胍还能显著改善组织排斥反应评分。(1) iNOS的表达和NO的产生增加发生在急性排斥反应的早期阶段，持续在未修饰的排斥反应过程中，并且局限于浸润性炎症细胞，而不局限于同种异体移植物实质细胞；(2)氨基胍改善急性排斥反应的组织学和功能改变；(3)通过iNOS mRNA、蛋白或无创血清亚硝酸盐/硝酸盐水平检测NO生成增加，可能作为急性同种异体移植排斥反应的早期标志。
Background.We recently demonstrated that inhibition of inducible nitric oxide synthase (iNOS) ameliorated severe acute lung allograft rejection. This study used a rat lung transplant model to determine (1) the time course and cellular localization of iNOS expression during the histological progression of unmodified acute rejection and (2) whether inhibition of iNOS prevented impaired gas exchange function of the allograft lung and/or ameliorated the histological changes of acute rejection.Methods and Results.iNOS mRNA and enzyme activity were expressed in allograft lungs during mild, moderate, and severe acute rejection, but not in normal, isograft, or allograft lungs before histological changes of mild acute rejection. iNOS expression in allografts resulted in elevated serum nitrite/nitrate levels, indicative of increased in vivo nitric oxide (NO) production. In situ hybridization demonstrated iNOS mRNA expression in infiltrating inflammatory cells, but not in allograft parenchymal cells. Allografts had significantly impaired gas exchange, which was prevented with the selective iNOS inhibitor aminoguanidine (PaO 2 of 566±19, 76±22, and 504±105 mmHg for isograft, allograft, and aminoguanidine-treated allograft, respectively; P< 0.0002). Aminoguanidine also significantly improved the histological rejection scores.Conclusions.(1) iNOS expression and increased NO production occurred during the early stages of acute rejection, persisted throughout the unmodified rejection process, and localized to infiltrating inflammatory cells, but not allograft parenchymal cells;(2) aminoguanidine ameliorated the histological and functional changes of acute rejection; and (3) increased NO production, detected by the presence of iNOS mRNA, protein, or noninvasively by measuring serum nitrite/nitrate levels, may serve as an early marker of acute allograft rejection.