Low-dose carbon monoxide inhibits progressive chronic allograft nephropathy and restores renal allograft function.
Low-dose carbon monoxide inhibits progressive chronic allograft nephropathy and restores renal allograft function.
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低剂量一氧化碳可抑制进行性慢性同种异体移植肾病并恢复同种异体移植肾功能。
DOI：
10.1152/ajprenal.90728.2008
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发表时间：
2009
期刊：
影响因子：
--
通讯作者：
Murase,Noriko
中科院分区：
文献类型：
--
作者：
Nakao,Atsunori;Faleo,Gaetano;Nalesnik,MichaelA;Seda-Neto,Joao;Kohmoto,Junichi;Murase,Noriko
慢性移植肾肾病（CAN）是指移植肾功能进行性恶化伴纤维炎性改变。CAN是导致移植肾失功的主要原因之一，目前被重新分类为间质纤维化（IF）和肾小管萎缩（TA），其病因不明。一氧化碳（CO）是血红素加氧酶途径的效应副产物，具有抗炎、抗纤维化作用。我们假设吸入CO可以抑制CAN的纤维炎症过程，恢复移植肾功能，即使在CAN建立后开始治疗。将刘易斯大鼠肾移植物原位移植到双侧肾切除的同种异体Brown Norway大鼠中，给予短暂的他克莫司（0.5 mg/kg im，第0-6天）。第60天开始吸入CO（20 ppm），持续至第150天或动物死亡。在第60天，CAN的发展被证实为肌酐清除率（CCr）降低，显著的蛋白尿，以及TA、IF和内膜动脉炎的组织病理学发现。空气处理对照组受者病情继续恶化，CCr进一步下降，尿蛋白排泄增加，死亡，中位生存期为82天。相比之下，当受体在第60-150天接受CO时，CAN的进展减慢，显示移植物组织病理学显著改善，肾功能恢复，受体生存期延长至中位数>150天。在第90天，CO显著降低了移植物内IFN-γ和TNF-α的mRNA水平。CO可显著抑制促纤维化TGF-β/Smad的表达，同时下调ERK-MAPK通路。连续CO（20 ppm）处理0-30天、30-60天、0-90天或每天1小时CO（250 ppm）处理0-90天也显示出抑制CAN的效果。该研究表明，CO能够抑制CAN的纤维炎症过程的进展，恢复肾移植物功能，并提高生存率，即使在CAN诊断后开始治疗。
Chronic allograft nephropathy (CAN) represents progressive deterioration of renal allograft function with fibroinflammatory changes. CAN, recently reclassified as interstitial fibrosis (IF) and tubular atrophy (TA) with no known specific etiology, is a major cause of late renal allograft loss and remains a significant deleterious factor of successful renal transplantation. Carbon monoxide (CO), an effector byproduct of heme oxygenase pathway, is known to have potent anti-inflammatory and antifibrotic functions. We hypothesized that inhaled CO would inhibit fibroinflammatory process of CAN and restore renal allograft function, even when the treatment was initiated after CAN was established. Lewis rat kidney grafts were orthotopically transplanted into binephrectomized allogenic Brown Norway rats under brief tacrolimus (0.5 mg/kg im,days 0–6). Atday 60, CO (20 ppm) inhalation was initiated to recipients and continued untilday 150or animal death. Development of CAN was confirmed atday 60with decreased creatinine clearance (CCr), significant proteinuria, and histopathological findings of TA, IF, and intimal arteritis. Air-treated control recipients continued to deteriorate with further declines of CCr and increases of urinary protein excretion and died with a median survival of 82 days. In contrast, progression of CAN was decelerated when recipients received CO ondays 60–150, showing markedly improved graft histopathology, restored renal function, and improved recipient survival to a median of >150 days. CO significantly reduced intragraft mRNA levels for IFN-γ and TNF-α atday 90. Expression of profibrotic TGF-β/Smad was significantly suppressed with CO, together with downregulation of ERK-MAPK pathways. Continuous CO (20 ppm) treatment fordays 0–30,days 30–60, ordays 0–90, or daily 1-h CO (250 ppm) treatment fordays 0–90, also showed efficacy in inhibiting CAN. The study demonstrates that CO is able to inhibit progression of fibroinflammatory process of CAN, restore renal allograft function, and improve survival even when the treatment is started after CAN is diagnosed.
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DOI：
10.1016/j.bbrc.2006.03.058
发表时间：
2006-05-12
影响因子：
3.1
作者：
Lee, BS;Heo, J;Chung, HT
通讯作者：
Chung, HT
ERK、p38 和 Smad 信号通路差异调节近端肾小管上皮细胞中的转化生长因子-β1 自诱导。
影响因子：
6
作者：
M. Zhang;D. Fraser;A. Phillips
通讯作者：
A. Phillips
影响因子：
56.9
作者：
VERMA, A;HIRSCH, DJ;SNYDER, SH
通讯作者：
SNYDER, SH
影响因子：
6
作者：
Nakao, A;Kimizuka, K;Murase, N
通讯作者：
Murase, N
慢性同种异体移植肾病：转化生长因子-β 和骨形态发生蛋白-7 产生的上皮内信号
影响因子：
8.8
作者：
J. Tyler;H. Robertson;T. Booth;Alastair D. Burt;John A. Kirby
通讯作者：
John A. Kirby