THE EXPRESSION OF TISSUE-TYPE PLASMINOGEN-ACTIVATOR, MATRIX METALLOPROTEASES AND ENDOGENOUS INHIBITORS IN THE CENTRAL-NERVOUS-SYSTEM IN MULTIPLE-SCLEROSIS - COMPARISON OF STAGES IN LESION EVOLUTION

The expression of tissue-type plasminogen activator (t-PA) and a numbe r of metalloproteases as well as plasminogen activator inhibitor-1 (PA I-1) and tissue inhibitor of metalloproteases-1 (TIMP-1) was analyzed in the central nervous system (CNS) of normal control and multiple scl erosis (MS) cases by immunohistopathology. The expression of t-PA was detectable only in the blood vessel matrix in control white matter, bu t positive infiltrating mononuclear cells were also observed in MS whi te matter and primary lesions. In active plaques this pattern converte d to strong positivity of foamy macrophages in areas of demyelination, declining in chronic lesions. In general PAI-1 expression paralleled that of t-PA. Gelatinase A and B were detected predominantly in astroc ytes and microglia throughout normal control white matter, with additi onal positive mononuclear cells in perivascular cuffs in MS white matt er. In the demyelinating lesion there is widespread prominent expressi on of gelatinase B in reactive astrocytes and macrophages, which persi sts in astrocytes in the chronic lesion. TIMP-1 was also present in th e vessel matrix and in lesional macrophages. These observations on the coexpression of enzymes and inhibitors of the matrix degrading cascad e in CNS tissue pinpoint t-PA, a rate-limiting enzyme, and gelatinase B as therapeutic targets in MS.