Production of plasminogen activator inhibitor-1 by human mast cells and its possible role in asthma

The plasminogen activator inhibitor type 1 (PAI-1) has an essential role in tissue remodeling. The PAI-1 gene was induced by a combination of phorbol ester and calcium ionophore at the highest level among the inducible human mast cell genes that we have analyzed on a DNA microarray. PAI-1 was secret ed by both a human mast cell line (HMC)-1 and primary cultured human mast c ells upon stimulation, whereas PAI-1 was undetectable in either group of un stimulated cells. The secretion of PAI-1 was due to de novo synthesis of PA I-1 rather than secretion of preformed PAI-1, The functional significance o f PAI-1 secretion was demonstrated by complete inhibition of tissue-type pl asminogen activator activity with supernatants of stimulated HMC-1 cells. F urthermore, we were able to regulate PAI-I gene expression in HMC-1 cells b y known therapeutic agents, High-dose (1 muM) dexamethasone induced PAI-1 m RNA expression, Cyclosporin down-regulated the expression of the PAI-1 gene , Cycloheximide abrogated PAI-I mRNA expression, suggesting that transcript ion of the PAI-1 gene requires de novo synthesis of early gene products, in cluding transcription factors, Finally, we demonstrated PAI-I in lung mast cells from a patient with asthmatic attack by double-immunofluorescence stu dy. This is the first report demonstrating that activated human mast cells release a striking amount of functionally active PAI-1, These results sugge st that PAI-1 could play an important role in airway remodeling of asthma, and inhibition of PAI-1 activity could represent a novel therapeutic approa ch in the management of airway remodeling.