title: Decreased intracellular iron availability suppresses epithelial cell surface plasmin generation. Transcriptional and post-transcriptional effects on u-PA and PAI-1 expression.
abstract: Iron and iron metabolism are critical in a variety of physiologic and pathophysiologic processes, including lung injury and repair. The plasmin/plasminogen activator (PA) system is involved in the extensive remodeling process that follows acute lung injury, and alveolar epithelial cells play a key role in this repair process. Herein we report that decreased intracellular iron availability markedly suppresses cell-surface plasmin generation by A549 human carcinoma-derived pulmonary epithelial cells. This effect is mediated by concomitant downregulation of urokinase-type PA and upregulation of PA inhibitor-type 1 expression. Northern analyses, runoff transcription assays, and messenger RNA half-life experiments using actinomycin demonstrate that transcriptional and post-transcriptional mechanisms are operative. Given these potent in vitro effects on the plasmin/PA system, we speculate that adequate intracellular iron stores are important for successful repair of acute lung injury.
authors.affiliation: Division of Respiratory, Critical Care and Occupational Medicine, Department of Internal Medicine, Salt Lake City, Utah, USA.
authors.forename: T
authors.initials: T
authors.lastname: Hasegawa
authors.forename: L
authors.initials: L
authors.lastname: Sorensen
authors.forename: H
authors.initials: H
authors.lastname: Ooi
authors.forename: B C
authors.initials: BC
authors.lastname: Marshall
mesh_terms: D001682:Biological Availability; D002614:Chelating Agents / Q000494:pharmacology; D016895:Culture Media, Serum-Free / Q000378:metabolism; D003676:Deferoxamine / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism*; D005341:Fibrinolysin / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D017395:Plasminogen Activator Inhibitor 1 / Q000276:immunology / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000276:immunology / Q000378:metabolism
chemical_list: D002614:Chelating Agents; D016895:Culture Media, Serum-Free; D007375:Interleukin-1; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D007501:Iron; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator; D003676:Deferoxamine