Neutral proteases and disruption of the blood-brain barrier in rat

Blood-brain barrier disruption is common in many neurological diseases. Matrix metalloproteinases are induced in brain injury and increase capillary permeability by attacking the extracellular matrix around cerebral capillaries. Other neutral proteases are also increased in sites of secondary injury, and may contribute to the proteolysis of the blood-brain barrier. Therefore, we studied capillary permeability and histological tissue damage after intracerebral injection of neutrophil elastase, cathepsin G, heparatinase and plasmin. Adult rats were injected intracerebrally with an enzyme. After 1, 4 or 24 h, measurements were made of brain uptake of a radiolabeled tracer, [14C]sucrose. Enzymes that significantly increased capillary permeability were injected into other rats for histological assessment of tissue damage. Elastase increased capillary permeability significantly when compared with controls; maximal damage was seen at 4 h. Plasmin produced smaller increases in permeability at 4 h, exerting its maximal effect on sucrose uptake at 24 h. Cathepsin G had a small effect at 4 h. Heparitinase had no effect. Histologic examination of elastase-injected brains at 24 h revealed multifocal perivascular and intraparenchymal acute hemorrhages accompanied by a polymorphonuclear cell infiltrate. Elastase-injected brains were microscopically similar to saline-injected brains at 1 and 4 h. Plasmin produced fibrinoid changes in the blood vessels at 24 h, coinciding with the maximal increase in capillary permeability. We conclude that neutrophil elastase attacks the capillary extracellular matrix, causing extensive hemorrhage, while plasmin leads to increased vascular permeability and fibrinoid necrosis of blood vessel walls. Differential effects of neutral proteases released secondary to injury could be important in both the acute changes in blood vessel permeability and long-term alterations in vessel structure.