Peng Chung-Kan, Huang Kun-Lun, Lan Chou-Chin, Hsu Yu-Juei, Wu Geng-Chin, Peng Chia-Hui, Wu Chin-Pyng, Chan Khee-Siang
Division of Pulmonary and Critical Care, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China.
Institute of Undersea and Hyperbaric Medicine, National Defense Medical Center, Taipei, Taiwan, Republic of China.
PLoS One. 2017 Mar 14;12(3):e0171736. doi: 10.1371/journal.pone.0171736. eCollection 2017.
Lung ischemia reperfusion injury (LIRI) is one of important complications following lung transplant and cardiopulmonary bypass. Although patients on hemodialysis are still excluded as lung transplant donors because of the possible effects of renal failure on the lungs, increased organ demand has led us to evaluate the influence of chronic kidney disease (CKD) on LIRI. A CKD model was induced by feeding Sprague-Dawley rats an adenine-rich (0.75%) diet for 2, 4 and 6 weeks, and an isolated rat lung in situ model was used to evaluate ischemia reperfusion (IR)-induced acute lung injury. The clinicopathological parameters of LIRI, including pulmonary edema, lipid peroxidation, histopathological changes, immunohistochemistry changes, chemokine CXCL1, inducible nitric oxide synthase (iNOS), proinflammatory and anti-inflammatory cytokines, heat shock protein expression, and nuclear factor-κB (NF-κB) activation were determined. Our results indicated that adenine-fed rats developed CKD as characterized by increased blood urea nitrogen and creatinine levels and the deposition of crystals in the renal tubules and interstitium. IR induced a significant increase in the pulmonary arterial pressure, lung edema, lung injury scores, the expression of CXCL1 mRNA, iNOS level, and protein concentration of the bronchial alveolar lavage fluid (BALF). The tumor necrosis factor-α levels in the BALF and perfusate; the interleukin-10 level in the perfusate; and the malondialdehyde levels in the lung tissue and perfusate were also significantly increased by LIRI. Counterintuitively, adenine-induced CKD significantly attenuated the severity of lung injury induced by IR. CKD rats exhibited increased heat shock protein 70 expression and decreased activation of NF-κB signaling. In conclusion, adenine-induced CKD attenuated LIRI by inhibiting the NF-κB pathway.
肺缺血再灌注损伤（LIRI）是肺移植和体外循环后重要的并发症之一。尽管由于肾衰竭可能对肺部产生影响，接受血液透析的患者仍被排除在肺移植供体之外，但器官需求的增加促使我们评估慢性肾脏病（CKD）对LIRI的影响。通过给Sprague-Dawley大鼠喂食富含腺嘌呤（0.75%）的饮食2、4和6周来诱导建立CKD模型，并使用离体大鼠肺原位模型评估缺血再灌注（IR）诱导的急性肺损伤。测定了LIRI的临床病理参数，包括肺水肿、脂质过氧化、组织病理学变化、免疫组化变化、趋化因子CXCL1、诱导型一氧化氮合酶（iNOS）、促炎和抗炎细胞因子、热休克蛋白表达以及核因子-κB（NF-κB）激活情况。我们的结果表明，喂食腺嘌呤的大鼠出现了CKD，其特征为血尿素氮和肌酐水平升高以及肾小管和间质中晶体沉积。IR导致肺动脉压、肺水肿、肺损伤评分、CXCL1 mRNA表达、iNOS水平以及支气管肺泡灌洗液（BALF）蛋白浓度显著增加。LIRI还使BALF和灌注液中的肿瘤坏死因子-α水平、灌注液中的白细胞介素-10水平以及肺组织和灌注液中的丙二醛水平显著升高。与预期相反，腺嘌呤诱导的CKD显著减轻了IR诱导的肺损伤严重程度。CKD大鼠热休克蛋白70表达增加，NF-κB信号激活降低。总之，腺嘌呤诱导的CKD通过抑制NF-κB途径减轻了LIRI。
