Nuclear localization of leukotriene A4 hydrolase in type II alveolar epithelial cells in normal and fibrotic lung

Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Health System, Ann Arbor, Michigan Submitted 10 November 2004 ; accepted in final form 30 March 2005 Leukotriene A 4 (LTA 4 ) hydrolase catalyzes the final step in leukotriene B 4 (LTB 4 ) synthesis. In addition to its role in LTB 4 synthesis, the enzyme possesses aminopeptidase activity. In this study, we sought to define the subcellular distribution of LTA 4 hydrolase in alveolar epithelial cells, which lack 5-lipoxygenase and do not synthesize LTA 4 . Immunohistochemical staining localized LTA 4 hydrolase in the nucleus of type II but not type I alveolar epithelial cells of normal mouse, human, and rat lungs. Nuclear localization of LTA 4 hydrolase was also demonstrated in proliferating type II-like A549 cells. The apparent redistribution of LTA 4 hydrolase from the nucleus to the cytoplasm during type II-to-type I cell differentiation in vivo was recapitulated in vitro. Surprisingly, this change in localization of LTA 4 hydrolase did not affect the capacity of isolated cells to convert LTA 4 to LTB 4 . However, proliferation of A549 cells was inhibited by the aminopeptidase inhibitor bestatin. Nuclear accumulation of LTA 4 hydrolase was also conspicuous in epithelial cells during alveolar repair following bleomycin-induced acute lung injury in mice, as well as in hyperplastic type II cells associated with fibrotic lung tissues from patients with idiopathic pulmonary fibrosis. These results show for the first time that LTA 4 hydrolase can be accumulated in the nucleus of type II alveolar epithelial cells and that redistribution of the enzyme to the cytoplasm occurs with differentiation to the type I phenotype. Furthermore, the aminopeptidase activity of LTA 4 hydrolase within the nucleus may play a role in promoting epithelial cell growth. aminopeptidase; bleomycin; fibrosis; leukotriene B 4 Address for reprint requests and other correspondence: T. G. Brock, Dept. of Internal Medicine, Univ. of Michigan, 6301 MSRB III, Ann Arbor, MI 48109-0642 (e-mail: brocko{at}umich.edu )