Angiotensin-Converting Enzyme N-Terminal Inactivation Alleviates Bleomycin-Induced Lung Injury
Angiotensin-Converting Enzyme N-Terminal Inactivation Alleviates Bleomycin-Induced Lung Injury
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DOI：
10.2353/ajpath.2010.081127
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发表时间：
2010-09-01
影响因子：
6
通讯作者：
Fuchs, Sebastien
中科院分区：
文献类型：
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作者：
Li, Ping;Xiao, Hong D.;Fuchs, Sebastien
博莱霉素对几种肿瘤有很强的抗肿瘤作用，但博莱霉素引起的肺纤维化限制了药物的使用。抑制肾素-血管紧张素系统被认为可以减少博莱霉素的毒性，但这种策略的效果仍然不确定，而且有些矛盾。我们的假设是，除了血管紧张素II，血管紧张素转换酶(ACE)的其他底物，如四肽N-乙酰-丝氨酸-天冬氨酰-赖氨酸(AcSDKP)，在控制纤维化方面起着重要作用。我们研究了博莱霉素诱导的正常血压小鼠的肺损伤，称为N-KO和C-KO，它们分别具有点突变，使ACE的N-末端或C-末端催化位点失活。根据肺组织学和羟脯氨酸含量的评估，N-KO而不是C-KO小鼠对博莱霉素肺损伤具有显著的抵抗力。为了确定血管紧张素转换酶N端肽底物AcSDKP在抗博莱霉素损伤中的重要性，用抑制AcSDKP形成的Pro基寡肽酶抑制剂S-17092对N-KO小鼠进行了治疗。作为对博莱霉素注射的反应，S-17092处理的N-KO小鼠出现了与野生型小鼠相似的肺纤维化。相反，野生型小鼠服用AcSDKP可减少博莱霉素引起的肺纤维化。本研究表明血管紧张素转换酶N端催化位点的失活显著减轻了博莱霉素诱导的肺纤维化，提示AcSDKP具有保护作用。这些数据提示了一种可能的方法来提高对博莱霉素的耐受性和治疗纤维化肺部疾病。(Am J Pathol2010,177：1113-1121；DOI：10.2353/ajpath.2010.081127)
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. (Am J Pathol 2010, 177:1113-1121; DOI: 10.2353/ajpath.2010.081127)