Decreased Intracellular Iron Availability Suppresses Epithelial Cell Surface Plasmin Generation: Transcriptional and Post-transcriptional Effects on u-PA and PAI-1 Expression

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.