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Inactivation of the N-terminal of ACE reduces bleomycin-induced lung fibrosis
  1. S Haque
  1. Correspondence to S Haque, Foundation Year 2 Doctor, King George Hospital, Essex, IG3 8YB, UK; shariahhaque{at}doctors.org.uk

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This study examined bleomycin-induced lung injury in normotensive mice, termed N-KO and C-KO, which have point mutations inactivating the N- or C-terminal catalytic sites of angiotensin converting enzyme (ACE), respectively. N-KO, but not C-KO mice, exhibited a marked resistance to bleomycin-induced lung injury and fibrosis, as assessed by lung histology and hydroxyproline content (46% increase in hydroxyproline content in C-KO lungs compared with 6.9% in N-KO lungs, p<0.001). Furthermore, the N-KO mice showed enhanced survival when exposed to a dose of bleomycin lethal to wild-type mice. The importance of the tetrapeptide N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP), an ACE N-terminal substrate, was demonstrated when N-KO mice were treated with S-17092, a prolyl-oligopeptidase inhibitor that reduces the concentration of AcSDKP. These mice developed lung fibrosis similar to wild-type mice in response to bleomycin injection. Conversely, the administration of AcSDKP to wild-type mice reduced bleomycin-induced lung fibrosis, as assessed by lung hydroxyproline content (7.7 μg/mg in mice given AcSDKP compared with 12.47 μg/mg in mice given saline, p<10-4).

These results show that the inactivation of the N-terminal of ACE significantly reduces bleomycin-induced lung fibrosis and implicates AcSDKP as a mediator of this protection. A novel means to increase tolerance to bleomycin and to treat fibrosing lung diseases is thus proposed.

Li P, Xiao HD, Xu J, et al. Angiotensin-converting enzyme N-terminal inactivation alleviates bleomycin-induced lung injury. Am J Pathol 2010;177:1113–21.

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