ULTRASTRUCTURAL STUDIES OF THE BLOOD-RETINA BARRIER AFTER EXPOSURE TOINTERLEUKIN-1-BETA OR TUMOR-NECROSIS-FACTOR-ALPHA

BACKGROUND: During inflammatory conditions of the central nervous syst em (CNS), the protective function of the blood-brain barrier (BBB) may be compromised, resulting in CNS edema. However, it is not well under stood how inflammatory cells may increase BBB permeability, since incr eased 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 circulati ng cytokines produce detectable increases in BBB permeability. EXPERIM ENTAL DESIGN: To investigate the role of inflammatory cytokines in ind uction of endothelial cell changes and inflammation in the CNS, we uti lized the rabbit retinal system as a model. This system shows vascular ization similar to the BBB, and is termed the blood-retina barrier (BR B). The rabbit visual system allows injection of cytokines, causing mi nimal trauma, and the contralateral eye serves as an intra-animal cont rol. RESULTS: Ultrastructural morphometric analysis of vesicular conte nt in BRB endothelium showed significant increase at 3 hours postintra vitreal injection of interleukin-1 beta (IL-1 beta) or tumor necrosis factor-alpha (TNF-alpha). Increased transport did not correlate with i ncreased vitreal protein. However, intravascular tracer (horseradish p eroxidase) revealed that pericytes, Muller cells, and perivascular mic roglia accumulate serum proteins, thus acting as sinks for extravasate d proteins after BRB disruption. The IL-1 beta-induced inflammatory re sponse was characterized by polymorphonuclear and mononuclear cells, w hereas the TNF-alpha-induced response was less intense and comprised m onocytes 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 nec rotic changes on endothelial cells, being most severe at 3 hours posti ntravitreal injection, revascularization was noted at 24 hours postint ravitreal injection. CONCLUSIONS: These results demonstrate that proin flammatory effects of IL-1 beta and TNF-alpha in the BRB initiate many of the changes associated with inflammation of the CNS vasculature, s uch as those induced during experimental autoimmune encephalitis and m ultiple sclerosis. Once the permeability of the BRB endothelium is inc reased, perivascular phagocytic cells such as perivascular, microglia and Muller cells may act as secondary barriers to extravasated protein s.