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首页> 外文期刊>American Journal of Physiology >Low-dose carbon monoxide inhibits progressive chronic allograft nephropathy and restores renal allograft function
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Low-dose carbon monoxide inhibits progressive chronic allograft nephropathy and restores renal allograft function

机译：低剂量一氧化碳抑制进行性慢性同种异体肾病并恢复肾脏同种异体功能

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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). At day 60, CO (20 ppm) inhalation was initiated to recipients and continued until day 150 or animal death/Development of CAN was confirmed at day 60 with 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 on days 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-gamma and TNF-alpha at day 90. Expression of profibrotic TGF-beta/Smad was significantly suppressed with CO, together with downregulation of ERK-MAPK pathways. Continuous CO (20 ppm) treatment for days 0-30, days 30-60, or days 0-90, or daily 1-h CO (250 ppm) treatment for days 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.
机译：慢性同种异体肾病（CAN）代表随着纤维性炎症变化的肾脏同种异体移植功能的进行性恶化。 CAN，最近被重新分类为间质纤维化（IF）和肾小管萎缩（TA），尚无具体病因，是晚期同种异体肾移植丢失的主要原因，并且仍然是成功进行肾移植的重要有害因素。一氧化碳（CO）是血红素加氧酶途径的效应子产物，已知具有有效的抗炎和抗纤维化功能。我们假设即使在建立CAN后开始治疗，吸入CO也会抑制CAN的纤维炎性过程并恢复肾移植的功能。在短暂的他克莫司（0.5 mg / kg im，第0-6天）下，将Lewis大鼠的肾脏移植物原位移植到双肾切除的同种异体Brown Norway大鼠中。在第60天，向接受者开始吸入CO（20 ppm），并持续到第150天，或在第60天确认动物死亡/ CAN的发展，其肌酸酐清除率（CCr）降低，蛋白尿明显，以及TA，IF，和内膜动脉炎。空气处理过的对照接受者继续恶化，CCr进一步下降，尿蛋白排泄增加，死亡，中位生存期为82天。相反，当接受者在60-150天接受CO时，CAN的进展会减慢，这表明移植物的组织病理学显着改善，肾功能得以恢复，接受者的存活期提高至中位数> 150天。 CO在第90天时显着降低了IFN-γ和TNF-α的移植物内mRNA水平。CO显着抑制了原纤维化TGF-beta / Smad的表达，并下调了ERK-MAPK途径。在0-30天，30-60天或0-90天连续CO（20 ppm）处理，或在0-90天每天1h CO（250 ppm）连续1天（250 ppm）处理也显示出抑制CAN的功效。该研究表明，即使在诊断出CAN后开始治疗，CO仍能够抑制CAN的纤维炎性进程的进展，恢复肾脏的同种异体移植功能，并提高生存率。

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