Nuclear localization of leukotriene [A.sub.4] hydrolase in type II alveolar epithelial cells in normal and fibrotic lung

Leukotriene [A.sub.4] (LT[A.sub.4]) hydrolase catalyzes the final step in leukotriene [B.sub.4] (LT[B.sub.4]) synthesis. In addition to its role in LT[B.sub.4] synthesis, the enzyme possesses aminopeptidase activity. In this study, we sought to define the subcellular distribution of LT[A.sub.4] hydrolase in alveolar epithelial cells, which lack 5-lipoxygenase and do not synthesize LT[A.sub.4]. Immunohistochemical staining localized LT[A.sub.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 LT[A.sub.4] hydrolase was also demonstrated in proliferating type II-like A549 cells. The apparent redistribution of LT[A.sub.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 LT[A.sub.4] hydrolase did not affect the capacity of isolated cells to convert LT[A.sub.4] to LT[B.sub.4]. However, proliferation of A549 cells was inhibited by the aminopeptidase inhibitor bestatin. Nuclear accumulation of LT[A.sub.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 LT[A.sub.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 LT[A.sub.4] hydrolase within the nucleus may play a role in promoting epithelial cell growth. aminopeptidase; bleomycin; fibrosis; leukotriene [B.sub.4]