聚（ADP）核糖合成酶抑制可减轻大鼠气管同种异体移植中的闭塞性气道疾病。
Poly (ADP) ribose synthetase inhibition reduces obliterative airway disease in rat tracheal allografts.
作者信息
Farivar Alexander S, Woolley Steven M, Naidu Babu V, Fraga Charles H, Byrne Karen, Thomas Robert, Salzman Andrew L, Szabo Csaba S, Mulligan Michael S
机构信息
Department of Surgery, Division of Cardiothoracic Surgery, University of Washington Medical Center, 1959 NE Pacific Street, Seattle, WA 98195, USA.
出版信息
J Heart Lung Transplant. 2004 Aug;23(8):993-1002. doi: 10.1016/j.healun.2003.08.009.
BACKGROUND
Obliterative bronchiolitis (OB) is the major long-term complication affecting lung transplant recipients, and is characterized pathologically by chronic inflammatory and fibroproliferative airway disease. Based on studies revealing anti-inflammatory and anti-apoptotic properties of poly (ADP)-ribose synthetase (PARS) inhibitors, we hypothesized that their administration would be protective in a heterotopic model of experimental OB.
METHODS
We transplanted rat tracheas from Brown-Norway donors into Lewis recipients, and treated 2 groups with a novel PARS inhibitor, INO-1001. One group received 14 days of treatment, whereas a second received delayed treatment beginning on Day 7 post-transplant. Tracheas were analyzed by light microscopy and computerized morphometry. Effects on cytokine transcription, nuclear transcription factor activation and cellular death were assessed by in situ hybridization for tumor necrosis factor-alpha (TNF-alpha), electromobility shift assays for nuclear factor-kappaB (NF-kappaB) and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assays, respectively.
RESULTS
PARS inhibition significantly decreased luminal obstruction (p < 0.001) and enhanced preservation of epithelial lining (p < 0.001) at 14 days post-transplant. Day 7 controls confirmed the development of an obstructive lesion in the lumen, averaging 28% occlusion. Delayed treatment (beginning on Day 7) arrested (p < 0.001) progression of the established lesion. Allograft airways treated with INO-1001 demonstrated attenuated NF-kappaB nuclear translocation, reduced transcription of TNF-alpha mRNA, and decreased cellular death on TUNEL and caspase 3 staining.
CONCLUSIONS
PARS inhibition is anti-inflammatory, protects against experimental OB, and is associated with enhanced preservation of respiratory epithelium and decreased cellular death. Delayed treatment with INO-1001 arrests progression of the lesion developed by Day 7. These studies suggest that activation of PARS plays a critical role in the development of airway obliterative disease.
背景
闭塞性细支气管炎（OB）是影响肺移植受者的主要长期并发症，其病理特征为慢性炎症和纤维增生性气道疾病。基于揭示聚（ADP）-核糖合成酶（PARS）抑制剂具有抗炎和抗凋亡特性的研究，我们推测给予该抑制剂在实验性OB的异位模型中具有保护作用。
方法
我们将来自Brown-Norway供体的大鼠气管移植到Lewis受体中，并用新型PARS抑制剂INO-1001治疗两组。一组接受14天的治疗，而另一组在移植后第7天开始接受延迟治疗。通过光学显微镜和计算机形态学分析气管。分别通过肿瘤坏死因子-α（TNF-α）的原位杂交、核因子-κB（NF-κB）的电泳迁移率变动分析和末端脱氧核苷酸转移酶介导的dUTP缺口末端标记（TUNEL）分析评估对细胞因子转录、核转录因子激活和细胞死亡的影响。
结果
移植后14天，PARS抑制显著降低管腔阻塞（p < 0.001）并增强上皮内衬的保存（p < 0.001）。第7天的对照组证实管腔内出现阻塞性病变，平均阻塞率为28%。延迟治疗（从第7天开始）阻止了（p < 0.001）已形成病变的进展。用INO-1001治疗的同种异体移植气道显示NF-κB核转位减弱、TNF-α mRNA转录减少以及TUNEL和半胱天冬酶3染色显示细胞死亡减少。
结论
PARS抑制具有抗炎作用，可预防实验性OB，并且与增强呼吸道上皮的保存和减少细胞死亡有关。用INO-1001进行延迟治疗可阻止第7天形成的病变进展。这些研究表明PARS的激活在气道闭塞性疾病的发展中起关键作用。
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