A pathological role of increased expression of plasminogen activator inhibitor-1 in human or animal disorders.

Plasminogen activator inhibitor-1 (PAI-1) is a specific inhibitor of plasminogen activators and may be the principal regulator of plasminogen activation in vivo. Abnormal expression of PAI-1 has been reported in various types of human disorders and in animal models for the diseases in relation to thrombosis. For example, plasma PAI-1 activity was elevated in patients with endotoxemia, and a dramatic induction of PAI-1 mRNA was observed in tissues of endotoxin-treated animals, resulting in tissue microthrombosis. It has also been demonstrated that PAI-1 expression levels are increased in the kidneys of mice with glomerulonephritis, in the adipose tissue of obese subjects or mice, and in human atherosclerotic arteries. This PAI-1 induction may be relevant to pathological processes in these diseases because PAI-1 not only regulated fibrin dissolution in vivo but also inhibited degradation of extracellular matrix by reducing plasmin generation. The responsible cells for abnormal expression of PAI-1 have been identified in each tissue under pathological conditions and PAI-1 synthesis appears to be regulated in a tissue-specific manner. These observations suggest that PAI-1 could play an important role in the progression of tissue pathologies in a variety of human diseases by controlling the rate of plasmin formation.