RT Journal Article
SR Electronic
T1 Cell cycle-dependence of ACE-2 explains downregulation in Idiopathic pulmonary fibrosis
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP erj00156-2012
DO 10.1183/09031936.00015612
A1 D Uhal, Bruce
A1 Dang, MyTrang
A1 Dang, Vinh
A1 Llatos, Roger
A1 Cano, Esteban
A1 Abdul-Hafez, Amal
A1 Markey, Jonathan
A1 Piasecki, Christopher C.
A1 Molina-Molina, Maria
YR 2012
UL http://erj.ersjournals.com/content/early/2012/10/25/09031936.00015612.abstract
AB Alveolar epithelial type II cells, a major source of angiotensin converting enzyme-2 in the adult lung, are normally quiescent but actively proliferate in lung fibrosis and downregulate this protective enzyme. It was therefore hypothesized that angiotensin converting enzyme-2 expression might be related to cell cycle progression. To test this hypothesis, angiotensin converting enzyme-2 mRNA, protein and enzymatic were examined in fibrotic human lung and in the AEC cells lines A549 and MLE-12 studied at postconfluent (quiescent) versus subconfluent (proliferating) densities. Angiotensin converting enzyme-2 mRNA, immunoreactive protein and enzymatic activity were all high in quiescent cells, but were severely downregulated or absent in actively proliferating cells. Upregulation of enzyme in cells that were progressing to quiescence was completely inhibited by the transcription blocker actinomycin D or by SP600125, an inhibitor of c-Jun N-Terminal Kinase. In lung biopsy specimens obtained from patients with Idiopathic Pulmonary Fibrosis, immunoreactive enzyme was absent in alveolar epithelia that were positive for proliferation markers, but was robustly expressed in alveolar epithelia devoid of proliferation markers. These data explain the loss of angiotensin converting enzyme-2 in lung fibrosis and demonstrate cell cycle-dependent regulation of this protective enzyme by a JNK-mediated transcriptional mechanism.