Farivar Alexander S, Mackinnon-Patterson Brendan, Woolley Steven, Namkung Jane, Shimamoto Akira, Verrier Edward D, Mulligan Michael S
Department of Surgery, Division of Cardiothoracic Surgery, University of Washington Medical Center, 1959 NE Pacific Street, Seattle, WA 98195, USA.
J Heart Lung Transplant. 2004 Aug;23(8):985-92. doi: 10.1016/j.healun.2004.04.008.
Obliterative bronchiolitis (OB) is the main cause of late mortality among long-term survivors of lung transplantation. Although p38 kinase is functional in multiple acute inflammatory injury models, its role in chronic lung rejection is undefined. p38 regulates the expression of the cytokines tumor necrosis (TNF)-alpha and interleukin (IL)-1beta, 2 mediators involved in the development of OB in a tracheal transplant model. These studies assessed whether specific inhibition of p38 with FR167653 (FR) protects against the development of OB in rat tracheal allografts.
Rat airways were heterotopically transplanted from Brown-Norway donors into Lewis recipients, and animals were sacrificed on day 14 (6 per group). Treated animals received 10 mg/kg daily of FR intraperitoneally beginning either immediately or at day 7 after transplant. Allografts were assessed by computerized morphometry, and tracheas were processed for TNF-alpha mRNA and protein expression by quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry, respectively. Electrophoretic mobility shift assays evaluated nuclear factor kappa beta (NFkappaB) transactivation.
Control allografts averaged 61% occlusion and 98% loss of epithelium at 14 days, whereas FR administration reduced luminal occlusion to 28% (p < 0.001) and epithelial loss to 71% (p < 0.001). Delayed treatment beginning on day 7 slowed progression of disease, as tracheal occlusion averaged 44% and epithelial loss averaged 80%, both of which were significant (p < 0.05) improvements relative to 14-day controls. NFkappa transactivation (p < 0.004) and TNF-alpha mRNA and protein expression were reduced dramatically by FR at 14 days.
A specific p38 inhibitor, FR 167653, ameliorates obliterative airway disease in rat tracheal allografts via attenuated NFkappaB transactivation, which ultimately results in diminished TNF-alpha mRNA and protein expression.
闭塞性细支气管炎（OB）是肺移植长期存活者晚期死亡的主要原因。尽管p38激酶在多种急性炎症损伤模型中发挥作用，但其在慢性肺排斥反应中的作用尚不清楚。在气管移植模型中，p38调节细胞因子肿瘤坏死因子（TNF）-α和白细胞介素（IL）-1β的表达，这两种介质参与了OB的发生发展。这些研究评估了用FR167653（FR）特异性抑制p38是否能预防大鼠气管同种异体移植中OB的发生。
将大鼠气道从Brown-Norway供体异位移植到Lewis受体中，于第14天处死动物（每组6只）。治疗组动物在移植后立即或第7天开始每天腹腔注射10mg/kg的FR。通过计算机形态学评估同种异体移植，分别用定量逆转录聚合酶链反应和免疫组织化学法检测气管中TNF-α mRNA和蛋白表达。电泳迁移率变动分析评估核因子κB（NFκB）的反式激活。
对照组同种异体移植在14天时平均管腔闭塞率为61%，上皮丢失率为98%，而给予FR后管腔闭塞率降至28%（p<0.001），上皮丢失率降至71%（p<0.001）。从第7天开始延迟治疗减缓了疾病进展，气管闭塞平均为44%，上皮丢失平均为80%，相对于14天的对照组均有显著改善（p<0.05）。在第14天时，FR显著降低了NFκB的反式激活（p<0.004）以及TNF-α mRNA和蛋白表达。
特异性p38抑制剂FR 167653通过减弱NFκB的反式激活改善大鼠气管同种异体移植中的闭塞性气道疾病，最终导致TNF-α mRNA和蛋白表达减少。
