Background: During inflammatory conditions of the central nervous system (CNS), the protective function of the blood-brain barrier (BBB) may be compromised, resulting in CNS edema. However, it is not well understood how inflammatory cells may increase BBB permeability, since increased transendothelial transport of serum proteins is observed in CNS capillaries that are not directly in contact with inflammatory cells. One possible explanation may be that soluble inflammatory factors may cause BBB changes, since pathologic conditions that increase circulating cytokines produce detectable increases in BBB permeability.
Experimental design: To investigate the role of inflammatory cytokines in induction of endothelial cell changes and inflammation in the CNS, we utilized the rabbit retinal system as a model. This system shows vascularization similar to the BBB, and is termed the blood-retina barrier (BRB). The rabbit visual system allows injection of cytokines, causing minimal trauma, and the contralateral eye serves as an intra-animal control.
Results: Ultrastructural morphometric analysis of vesicular content in BRB endothelium showed significant increase at 3 hours postintravitreal injection of interleukin-1 beta (IL-1 beta) or tumor necrosis factor-alpha (TNF-alpha). Increased transport did not correlate with increased vitreal protein. However, intravascular tracer (horseradish peroxidase) revealed that pericytes, Müller cells, and perivascular microglia accumulate serum proteins, thus acting as sinks for extravasated proteins after BRB disruption. The IL-1 beta-induced inflammatory response was characterized by polymorphonuclear and mononuclear cells, whereas the TNF-alpha-induced response was less intense and comprised monocytes and occasional eosinophils. At the height of inflammation, IL-1 beta produced large gaps between endothelial cells that allowed for extensive cellular inflammation and hemorrhage. TNF-alpha induced necrotic changes on endothelial cells, being most severe at 3 hours postintravitreal injection, revascularization was noted at 24 hours postintravitreal injection.
Conclusions: These results demonstrate that proinflammatory effects of IL-1 beta and TNF-alpha in the BRB initiate many of the changes associated with inflammation of the CNS vasculature, such as those induced during experimental autoimmune encephalitis and multiple sclerosis. Once the permeability of the BRB endothelium is increased, perivascular phagocytic cells such as perivascular, microglia and Müller cells may act as secondary barriers to extravasated proteins.