Tanaka Satona, Chen-Yoshikawa Toyofumi F, Kajiwara Moto, Menju Toshi, Ohata Keiji, Takahashi Mamoru, Kondo Takeshi, Hijiya Kyoko, Motoyama Hideki, Aoyama Akihiro, Masuda Satohiro, Date Hiroshi
Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Department of Pharmacy, Kyushu University Hospital, Fukuoka, Japan; Department of Research and Development of Next Generation Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
Ann Thorac Surg. 2016 Nov;102(5):1717-1724. doi: 10.1016/j.athoracsur.2016.05.037. Epub 2016 Jul 25.
Ischemia/reperfusion injury (IRI) remains a significant complication after lung transplantation. Endothelial damage and inflammation contribute to its development. Imatinib has been reported to regulate vascular permeability by maintaining endothelial junctions and showing antiinflammatory effects through inhibition of the Abl kinases. We hypothesized that imatinib could have a protective effect against IRI.
Male Lewis rats were heparinized and underwent left thoracotomy, and the left hilum was clamped for 90 minutes followed by reperfusion for 120 minutes. Imatinib mesylate (50 mg/kg) and a solvent were administered intraperitoneally 20 minutes before ischemia in the imatinib group and the vehicle group, respectively (n = 7 in each group). After reperfusion, lung function, lung wet to dry weight (W/D) ratio, and histologic findings were obtained. The expression of vascular endothelial cadherin (VEC), the phosphorylation level of CrkL (pCrkL) (an exclusive target of Abl kinases), and the cytokine level were evaluated using lung tissue lysate. The imatinib concentrations of plasma and lungs after reperfusion were measured in this hilar clamp model (n = 7).
In the imatinib group, lung function was improved with a lower W/D ratio. Perivascular edema and neutrophil infiltration were ameliorated. The imatinib group demonstrated maintained expression of VEC, inhibition of pCrkL, and a significantly higher level of interleukin (IL)-10. The imatinib concentration in both lungs showed a strong correlation with plasma concentration.
In a rat IRI model, imatinib attenuated lung injury by an antipermeability and antiinflammatory effect. The delivery and function of imatinib in the lung was also confirmed in this model.
缺血/再灌注损伤（IRI）仍是肺移植术后的一个重要并发症。内皮损伤和炎症促成了其发展。据报道，伊马替尼可通过维持内皮连接来调节血管通透性，并通过抑制Abl激酶发挥抗炎作用。我们推测伊马替尼可能对IRI具有保护作用。
雄性Lewis大鼠肝素化后行左胸切开术，左肺门阻断90分钟，随后再灌注120分钟。伊马替尼组和溶剂对照组分别在缺血前20分钟腹腔注射甲磺酸伊马替尼（50 mg/kg）和溶剂（每组n = 7）。再灌注后，测定肺功能、肺湿干重（W/D）比及组织学结果。使用肺组织裂解液评估血管内皮钙黏蛋白（VEC）的表达、CrkL（Abl激酶的唯一靶点）的磷酸化水平（pCrkL）及细胞因子水平。在该肺门阻断模型中测定再灌注后血浆和肺组织中的伊马替尼浓度（n = 7）。
在伊马替尼组中，肺功能得到改善，W/D比降低。血管周围水肿和中性粒细胞浸润减轻。伊马替尼组VEC表达得以维持，pCrkL受到抑制，白细胞介素（IL）-10水平显著升高。肺组织中伊马替尼浓度与血浆浓度呈强相关。
在大鼠IRI模型中，伊马替尼通过抗通透性和抗炎作用减轻了肺损伤。该模型还证实了伊马替尼在肺组织中的递送及功能。
