Low-dose carbon monoxide inhalation prevents development of chronic allograft nephropathy.
Low-dose carbon monoxide inhalation prevents development of chronic allograft nephropathy.
复制标题
吸入低剂量一氧化碳可预防慢性同种异体移植肾病的发展。
DOI：
10.1152/ajprenal.00026.2005
复制
发表时间：
2006
期刊：
影响因子：
--
通讯作者：
Murase,Noriko
中科院分区：
文献类型：
--
作者：
Neto,JoaoSeda;Nakao,Atsunori;Toyokawa,Hideyoshi;Nalesnik,MichaelA;Romanosky,AnnaJeanine;Kimizuka,Kei;Kaizu,Takashi;Hashimoto,Naoki;Azhipa,Olga;Stolz,DonnaB;Choi,AugustineMK;Murase,Noriko
慢性移植肾肾病（CAN）是晚期移植肾失功的主要原因。一氧化碳（CO）是血红素加氧酶代谢血红素的产物，已知其对各种应激具有保护作用。我们假设CO可以减少慢性纤维炎症过程，保护肾移植物免受CAN的影响。将刘易斯肾移植物原位移植到双侧肾切除的Brown-Norway大鼠中，短期使用他克莫司。移植后将受体保持在室内空气中或暴露于20 ppm的CO中30天。在第30天和第80天观察吸入CO的疗效。在整个实验过程中，同种异体移植肾功能保持正常，肌酐清除率为1.5 ml/min。空气对照组移植肾功能逐渐恶化，到第80天肌酐清除率下降至0.2 ± 0.1 ml/min，并伴有大量蛋白尿。CO治疗的动物具有显著更好的肌酐清除率（1.3 ± 0.2 ml/min），伴有最小的蛋白尿。组织学检查显示，在暴露于空气的移植物的发展进行性CAN，而CO处理的移植物有最小的肾小管萎缩和间质纤维化，可忽略的IV型胶原沉积。体外分析表明，CO处理的收件人有显着减少T细胞增殖对供体肽通过间接同种异体识别途径和更少的抗供体IgG抗体相比，空气控制。与空气处理的同种异体移植物相比，CO处理的同种异体移植物中趋化因子（受活化调节的正常T细胞表达和分泌、巨噬细胞炎性蛋白-1 α、趋化因子受体（CCR 1、CXCR 3、CXCR 5）、IL-2和细胞间粘附分子-1）的mRNA水平显著降低。此外，空气处理的同种异体移植物中的血流量减少与CO。总之，吸入低浓度的CO有效地消除了与CAN相关的慢性纤维炎性变化，并改善了长期的肾移植功能。
Chronic allograft nephropathy (CAN) is the primary cause for late kidney allograft loss. Carbon monoxide (CO), a product of heme metabolism by heme oxygenases, is known to impart protection against various stresses. We hypothesized that CO could minimize the chronic fibroinflammatory process and protect kidney allografts from CAN. Lewis kidney grafts were orthotopically transplanted into binephrectomized Brown-Norway rats under short-course tacrolimus. Recipients were maintained in room air or exposed to CO at 20 parts/million for 30 days after transplant. Efficacy of inhaled CO was studied atday 30andday 80. Isografts maintained normal kidney function throughout the experiment with creatinine clearance of ∼1.5 ml/min. Renal allograft function in air controls progressively deteriorated, and creatinine clearance declined to 0.2 ± 0.1 ml/min byday 80with substantial proteinuria. CO-treated animals had significantly better creatinine clearance (1.3 ± 0.2 ml/min) with minimal proteinuria. Histological examination revealed the development of progressive CAN in air-exposed grafts, whereas CO-treated grafts had minimal tubular atrophy and interstitial fibrosis, with negligible collagen IV deposition. In vitro analyses revealed that CO-treated recipients had significantly less T cell proliferation against donor peptides via the indirect allorecognition pathway and less anti-donor IgG antibodies compared with air controls. Intragraft mRNA levels for chemokines (regulated on activation normal T cell expressed and secreted, macrophage inflammatory protein-1α, chemokine receptors (CCR1, CXCR3, CXCR5), IL-2, and intercellular adhesion molecule-1 were significantly decreased in CO-treated than in air-treated allografts. Furthermore, reduction of blood flow in air-treated allografts was prevented with CO. In conclusion, inhaled CO at a low concentration efficiently abrogates chronic fibroinflammatory changes associated with CAN and improves long-term renal allograft function.