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This Article Full Text Full Text (PDF) All Versions of this Article: 295/1/L178    most recent 00009.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Li, X. Articles by Uhal, B. D. PubMed PubMed Citation Articles by Li, X. Articles by Uhal, B. D.

Angiotensin converting enzyme-2 is protective but downregulated in human and experimental lung fibrosis

¹Department of Medicine, University of California at San Francisco, San Francisco, California; ²IDIBAPS, Universitat de Barcelona, Centro Investigaciones Biomédicas en Red de Enfermedades Respiratorias; ³Department of Physiology, Michigan State University, East Lansing, Michigan; and ⁴Servicio de Neumología, Hospital Clínic de Barcelona, Spain

Submitted 4 January 2008 ; accepted in final form 22 April 2008

Earlier work from this laboratory showed that local generation of angiotensin (ANG) II is required for the pathogenesis of experimental pulmonary fibrosis and that ANG peptides are expressed robustly in the lungs of patients with idiopathic pulmonary fibrosis (IPF). Angiotensin converting enzyme-2 (ACE-2) degrades the octapeptide ANG II to form the heptapeptide ANG1-7 and thereby limits ANG II accumulation. On this basis, we hypothesized that ACE-2 would be protective against experimental lung fibrogenesis and might be downregulated in human and experimental lung fibrosis. In lung biopsy specimens from patients with IPF, ACE-2 mRNA and enzyme activity were decreased by 92% (P < 0.01) and 74% (P < 0.05), respectively. ACE-2 mRNA and activity were also decreased similarly in the lungs of bleomycin-treated rats and C57-BL6 mice. In mice exposed to low doses of bleomycin, lung collagen accumulation was enhanced by intratracheal administration of either ACE-2-specific small interfering RNAs (siRNAs) or the peptide DX₆₀₀, a competitive inhibitor of ACE-2 (P < 0.05). Administration of either ACE-2 siRNA or DX₆₀₀ significantly increased the ANG II content of mouse lung tissue above the level induced by bleomycin alone. Coadministration of the ANG II receptor antagonist saralasin blocked the DX₆₀₀-induced increase in lung collagen. Moreover, purified recombinant human ACE-2, delivered to mice systemically by osmotic minipump, attenuated bleomycin-induced lung collagen accumulation. Together, these data show that ACE-2 mRNA and activity are severely downregulated in both human and experimental lung fibrosis and suggest that ACE-2 protects against lung fibrogenesis by limiting the local accumulation of the profibrotic peptide ANG II.

vasoactive peptides; peptidases; alveolar epithelium