In vivo pathophysiologic effects of interleukin-1b on the blood-retina barrier
Martiney, James A.
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Interleukin-1 (IL-1) is a potent immunomodulator responsible for the initiation and/or augmentation of several aspects of the inflammatory response. Most of the vascular effects of IL-1 have been determined either in vitro or on the systemic vasculature. To determine the in vivo effects of IL-1b on the central nervous system (CNS) vasculature, the rabbit retina model was developed. The epiretinal vessels of the retina constitute the blood-retina barrier (BRB), essentially identical to the blood-brain barrier (BBB). We have shown that a single intraocular injection of 300U hrIL-1b induces a biphasic inflammatory response with well defined acute and chronic phases. Acute phase changes include hemorrhage, cellular inflammation and increased vascular permeability, associated with electrophysiologic deficits in retinal conduction. Histopathologic analysis of inflamed retinas during the acute phase showed the following: no response within the first hour post-intraocular challenge (PIC); progressive mononuclear (MN) and polymorphonuclear (PMN) cell accumulations between 3 and 6h PIC; a peak in PMN inflammation, hemorrhage and increased vascular permeability at 24h PIC, correlating with slowing of the visual evoked potential; continual MN infiltration, residual PMN inflammation, and reactive gliosis at 41h PIC. The chronic phase was examined over a 35 day(d) period and was characterized by a persistent MN infiltration which peaked at 7d-14d PIC and increased vascular permeability, still an active process at 14d PIC. Reactive gliosis was documented by pathology and GFAP mRNA levels. The control contralateral eyes showed signs of reactive gliosis that lagged behind temporally the observations made in the experimental eyes. These results support the hypothesis that exposure of CNS endothelial cells to IL-1b induces long-lasting inflammatory changes that affect the CNS vasculature in both the immediate vicinity and at some distance from the lesion site. We hypothesize that this complex inflammatory reaction with its changing profile, is driven, in part, by the induction of local endogenous cytokines and upregulation of adhesion molecules in the surface of endothelial and inflammatory cells. Attempts to detect endogenous rabbit (rb) IL-1b production by the involved and control tissues by RIA, RNA PCR, and immunocytochemistry were inconclusive. However, there is some suggestion of endogenous production of rbIL-1b by the retina at the height of the inflammatory response (24h PIC). More experiments need to be performed to prove this conclusively. Use of a suppressor cytokine (TGFb) and of monoclonal antibodies (MAbs) directed against adhesion molecules on the surface of endothelial and inflammatory cells (IG9 and CD18) inhibited the IL-1-induced hemorrhage, inflammation and vascular permeability. However, all three blockers demonstrate different inhibition patterns. The rabbit retina provides a valuable model for the in vivo analysis of CNS-inflammation. Using our model and reagents, specific components of the inflammatory response can be dissected out.
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