Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Am J Pathol. 2010 Sep;177(3):1113-21. doi: 10.2353/ajpath.2010.081127. Epub 2010 Jul 22.
Bleomycin has potent anti-oncogenic properties for several neoplasms, but drug administration is limited by bleomycin-induced lung fibrosis. Inhibition of the renin-angiotensin system has been suggested to decrease bleomycin toxicity, but the efficacy of such strategies remains uncertain and somewhat contradictory. Our hypothesis is that, besides angiotensin II, other substrates of angiotensin-converting enzyme (ACE), such as the tetrapeptide N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP), play a significant role in controlling fibrosis. We studied bleomycin-induced lung injury in normotensive mice, termed N-KO and C-KO, which have point mutations inactivating either the N- or C-terminal catalytic sites of ACE, respectively. N-KO, but not C-KO mice, have a marked resistance to bleomycin lung injury as assessed by lung histology and hydroxyproline content. To determine the importance of the ACE N-terminal peptide substrate AcSDKP in the resistance to bleomycin injury, N-KO mice were treated with S-17092, a prolyl-oligopeptidase inhibitor that inhibits the formation of AcSDKP. In response to bleomycin injection, S-17092-treated N-KO mice developed lung fibrosis similar to wild-type mice. In contrast, the administration of AcSDKP to wild-type mice reduced lung fibrosis due to bleomycin administration. This study shows that the inactivation of the N-terminal catalytic site of ACE significantly reduced bleomycin-induced lung fibrosis and implicates AcSDKP in the mechanism of protection. These data suggest a possible means to increase tolerance to bleomycin and to treat fibrosing lung diseases.
博莱霉素对多种肿瘤具有强大的抗肿瘤特性，但由于博莱霉素引起的肺纤维化，其药物的使用受到限制。抑制肾素-血管紧张素系统已被建议可降低博莱霉素的毒性，但这些策略的疗效仍不确定，且存在一些矛盾。我们的假设是，除了血管紧张素 II 之外，血管紧张素转换酶 (ACE) 的其他底物，如四肽 N-乙酰丝氨酰-天冬氨酰-赖氨酰-脯氨酸 (AcSDKP)，在控制纤维化方面也起着重要作用。我们研究了 ACE 的 N 末端或 C 末端催化位点分别发生点突变的正常血压小鼠（分别称为 N-KO 和 C-KO）中的博莱霉素诱导的肺损伤。N-KO 小鼠，而不是 C-KO 小鼠，对博莱霉素肺损伤具有明显的抗性，如肺组织学和羟脯氨酸含量评估所示。为了确定 ACE N 末端肽底物 AcSDKP 在对博莱霉素损伤的抗性中的重要性，用脯氨酰寡肽酶抑制剂 S-17092 处理 N-KO 小鼠，该抑制剂可抑制 AcSDKP 的形成。在博莱霉素注射后，用 S-17092 处理的 N-KO 小鼠发展出类似于野生型小鼠的肺纤维化。相比之下，给予 AcSDKP 可减少因博莱霉素给药而引起的野生型小鼠的肺纤维化。这项研究表明，ACE 的 N 末端催化位点的失活显著降低了博莱霉素诱导的肺纤维化，并暗示 AcSDKP 参与了保护机制。这些数据表明，增加对博莱霉素的耐受性和治疗纤维化肺部疾病的一种可能方法。
