Critical Care Medicine

Adult Critical Care

Angiotensin-Converting Enzyme N-Terminal Inactivation Alleviates Bleomycin-Induced Lung Injury

Li P, Xiao HD, Xu J, et al (Cedars-Sinai Med Ctr, Los Angeles, CA; Emory Univ, Atlanta, GA; et al) Am J Pathol 177:1113-1121, 2010^§

Abstract

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 (Figs 1, 2, and 8).

Figure 1 Evaluation of bleomycin-induced lung fibrosis. A and B: Bleomycin-induced lung injury in wild-type (WT) and N-KO mice 14 days after drug administration. Whole lung sections were stained with Masson’s trichrome (A) or H&E (B). These representative sections show focal inflammation and fibrosis in lungs from wild-type mice. In contrast, lungs from N-KO mice show a near-normal appearance. The line represents 5 mm. The lower panels are pictures of lesions taken at a higher magnification (the line is 20 μm). C: Lung histology was graded by a pathologist who was blinded to mouse genotype. Fibrosis was graded using a scale described by Ashcroft et al,²⁴ varying from 0 (normal lung) to 8 (total fibrosis). Inflammation was graded using the 0 (normal lung) to 4 (maximum inflammation) scale described by Sur et al.²⁵ The inactivation of the N-terminal catalytic site of ACE significantly reduced the lung injury scores for both fibrosis and inflammation (n = 10 per group; *P < 0.001). Editor’s Note: Please refer to original journal article for full references. (Reprinted from Li P, Xiao HD, Xu J, et al. Angiotensin-converting enzyme N-terminal inactivation alleviates bleomycin-induced lung injury. Am J Pathol. 2010;177:1113-1121, with permission from American Society for Investigative Pathology.)

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