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 ANGII to form the heptapeptide ANG 1-7 and thereby limits ANGII 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 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 ANGII content of mouse lung tissue above the level induced by bleomycin alone. Coadministration of the ANGII 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 ANGII.