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J W Berman

Publications and source records attributed to J W Berman.

At least 55 records · Page 3Linked to original sources
PubMed1995

Trypanosoma cruzi induces endothelin release from endothelial cells.

The potential role of endothelin-1 (ET-1) in the pathogenesis of focal microvascular spasm, previously implicated in the etiology of Chagas' cardiomyopathy, was investigated. There was an increase in ET-1 in the supernatants of Trypanosoma cruzi--infected human umbilical vein endothelial cells (HUVEC). Infection of HUVEC and vascular smooth muscle cells had no effect on the synthesis of transforming growth factor-beta, which induces ET-1 synthesis. Bioassay studies of isolated rat aortic rings revealed that the increases in ET-1 production were associated with augmented contractile responses, which were significantly attenuated by preincubation with the ETA receptor antagonist, BQ-123. When big ET was incubated with the parasite, there was no conversion of the precursor to the active hormone (ET-1), demonstrating that the parasite did not possess the necessary converting enzyme. These observations suggest the potential importance of ET-1 in the etiology of the microvascular spasm associated with Chagas' disease.

Animals↗
PubMed1995

Internalization of Staphylococcus aureus by endothelial cells induces cytokine gene expression.

The ability of the vascular endothelium to elaborate cytokines in response to gram-positive sepsis has received limited attention. This study examined cytokine expression by human umbilical vein endothelial cells (EC) following infection with a gram-positive bacterial pathogen, Staphylococcus aureus. S. aureus infection of EC resulted in the production of interleukin-6 (IL-6) and IL-1 beta. For IL-6, message was detected at 3 h after infection, protein was present at 24 h, and both message and protein persisted for 72 h. IL-1 beta message was detected at 12 h, IL-1 beta protein was detected at 24 h, and both persisted for 72 h. Message for colony-stimulating factor 1 remained unaltered. UV-killed S. aureus also elicited IL-1 beta and IL-6 message and protein expression at 24 and 48 h. Twenty-one clinical isolates of S. aureus were tested, and all induced IL-6 release by 48 h. However, the laboratory strain 8325-4 did not induce cytokine expression at any time point and was internalized by EC 1,000-fold less than other strains were. Internalization of latex beads by EC did not induce IL-6 gene expression. Furthermore, cytochalasin D treatment of the EC prevented IL-1 and IL-6 induction by S. aureus but not by tumor necrosis factor alpha or lipopolysaccharide. These results indicate that S. aureus is a potent inducer of IL-1 and IL-6 in EC and that internalization of S. aureus by EC is necessary for their cytokine expression. Thus, our data suggest that the vascular endothelium may play an important role in the pathogenesis of septicemia caused by gram-positive organisms.

Blotting, Northern↗
PubMed1994

Relationship between the structure of taxol and other taxanes on induction of tumor necrosis factor-alpha gene expression and cytotoxicity.

Taxol is an antitumor drug with cytotoxic properties that correlate with its microtubule-stabilizing activities. It has been reported that taxol parallels lipopolysaccharide in its effects on the induction of tumor necrosis factor-alpha (TNF-alpha) gene expression in macrophages (C. Bogdan and A. Ding, J. Leukocyte Biol., 52: 119-121, 1992; C. L. Manthey, M. E. Brandes, P. Y. Perera, and S. Vogel, J. Immunol., 149: 2459-2465, 1992; J. M. Carboni, C. Singh, and M. A. Tepper, Natl. Cancer Inst. Monogr., 15: 95-101, 1993). Structure-activity studies using taxol and related taxanes have been done to determine the relationship between the effects of taxol on TNF-alpha gene expression and its cytotoxic and microtubule-stabilizing activities. Using Northern blot analysis, it was found that changes in the structure of taxol that did not alter cytotoxicity did prevent the induction of TNF-alpha gene expression. The data presented in this paper demonstrate that the effects of taxol on TNF-alpha gene expression are distinct from its known cytotoxic properties.

Animals↗
PubMed1994

TNF-alpha inhibits the further development of committed progenitors while stimulating multipotential progenitors in mouse long-term bone marrow cultures.

We studied simultaneously the effect of TNF on both relatively primitive and more mature hematopoietic progenitors by using a modification of the mouse long-term bone marrow culture system of Dexter. Mycophenolic acid-treated long-term bone marrow cultures were charged with stromally depleted bone marrow cells along with 10 to 500 U/ml recombinant human TNF-alpha, and assayed each week for 5 wk for the presence of primitive (CFU-S and high proliferative potential colony-forming cell) and mature (CFU-C) colony-forming units. The results demonstrate that TNF-alpha has differential effects on hematopoiesis; it virtually eliminates CFU-C, significantly lowers high proliferative potential colony-forming cell (CFC) numbers and increases CFU-S numbers. This effect appears to be independent of CSF production in the cultures as shown by protein assays. Northern blot analyses showed no differences in expression of CSF genes or any expression of those encoding for IL-1, IL-3, or IL-6. These results, obtained in a long-term culture system that closely mimics in vivo bone marrow, demonstrate that many of the apparently contradictory effects of TNF observed in vitro occur concomitantly and are attributable to the presence of cells at various stages of maturity in the cultures. The data suggest a mechanism of this activity in which TNF is able to block the differentiation of primitive progenitors even as they are stimulated to proliferate.

Animals↗
PubMed1994

The role of the blood-brain barrier in HIV infection of the central nervous system.

The blood-brain barrier (BBB) functions to regulate the entry of macromolecules, microbial pathogens, and circulating leukocytes into the central nervous system (CNS). It consists, in part, of the microvascular endothelium and associated astrocyte foot processes, found in close apposition to the abluminal side of the vascular endothelial cells (EC). During the pathogenesis of certain nervous system diseases with inflammatory components, the BBB may function to facilitate the entry of leukocytes into the CNS parenchyma. A common histologic observation in human immunodeficiency virus type-1 (HIV) encephalitis is the localization of HIV proteins to multinucleated giant cells that co-immunolabel with antibodies specific for cells of the monocyte/macrophage lineage, suggesting that HIV can enter the CNS as cell-associated virus. We previously characterized a tissue culture model of the BBB that consists of the co-culture of autologous EC and astrocytes. In this presentation, we used this model to examine the expression of adhesion molecules by both the EC and astrocyte components of this BBB model, and to characterize the interactions between HIV-infected monocytes and EC. The data presented in this review of our work demonstrates that astrocytes upregulate the expression of intercellular adhesion molecule (ICAM-1) by EC. In a parallel study, western blot analysis demonstrated that ICAM-1 is also expressed in the developing human CNS. When exposed to the proinflammatory cytokine tumor necrosis factor alpha (TNF), both EC cocultured with astrocytes and astrocytes cultured alone expressed the adhesion proteins IG9, ICAM-1, vascular cell adhesion molecule 1 (VCAM) and E-selection.(ABSTRACT TRUNCATED AT 250 WORDS)

Astrocytes↗
PubMed1994

Pathophysiological correlates of increased serum tumor necrosis factor in patients with congestive heart failure. Relation to nitric oxide-dependent vasodilation in the forearm circulation.

BACKGROUND: Tumor necrosis factor-alpha (TNF alpha), which we and others have shown to be elevated in patients with severe congestive heart failure (CHF), is involved in the regulation of nitric oxide metabolism. Whether increased concentrations of TNF alpha affect nitric oxide-mediated vasodilation in patients with CHF has not been studied previously. METHODS AND RESULTS: Serum concentrations of TNF alpha, interleukin-1 (IL-1), interleukin-2 (IL-2), and interleukin-6 (IL-6) were determined in venous blood (pg/mL) from 17 patients with stable New York Heart Association classes II and III CHF (mean age, 58 +/- 11 years; mean left ventricular ejection fraction, 19.5 +/- 7.3) and 17 age-matched normal subjects with enzyme-linked immunosorbent assays (detection limit of assays, 20 pg/mL). Forearm blood flows were determined with plethysmography (mL/min per 100 mL) in 17 patients and 7 normal subjects in response to brachial artery administration of graded concentrations of acetylcholine (10(-6) mol/L and 10(-5) mol/L) and nitroglycerin (10(-7) mol/L and 10(-6) mol/L). Serum concentrations of TNF alpha were above the detection limits of the assay in 10 of 17 patients with CHF (mean serum concentration, 39.4 +/- 3.8 pg/mL). Forearm blood flow responses to acetylcholine and nitroglycerin were significantly greater in these 10 patients than in the 7 patients without detectable serum TNF alpha and were closely correlated with TNF alpha serum concentrations (r > or = .81, P < .01 and r > or = .65, P < .05 respectively). In 1 of 17 normal subjects, the serum concentration of TNF alpha was just above the detection limit of the assay. Serum concentrations of IL-2 were above the detection limit of the assay in 14 of 17 patients with CHF (mean serum concentration, 112 +/- 19 pg/mL). IL-2 was not detected in the serum of normal subjects. Serum concentrations of IL-1 and IL-6 were below the detection limit of the assays in all patients and normal subjects assayed. CONCLUSIONS: Increased TNF alpha concentrations are closely correlated with forearm blood flow responses to regional administration of acetylcholine and nitroglycerin. The significant correlation between serum concentrations of TNF alpha and forearm blood flow responses to acetylcholine and nitroglycerin suggests that both the inducible and the constitutive forms of nitric oxide synthase are involved in the regulation of peripheral vasomotor tone in patients with CHF.

Adult↗
PubMed1994

An endothelial cell adhesion protein for monocytes recognized by monoclonal antibody IG9. Expression in vivo in inflamed human vessels and atherosclerotic human and Watanabe rabbit vessels.

BACKGROUND: Monocyte adhesion to the vascular endothelium, an important component of an inflammatory response, is one of the earliest detected events in the pathogenesis of atherosclerosis. We have identified a monocyte adhesion molecule, recognized by monoclonal antibody (mAb) IG9, on the cell surface of human umbilical vein endothelial cells (HUVEC) treated with tumor necrosis factor-alpha (TNF-alpha), interleukin-1, or lipopolysaccharide. Endothelial cell expression in vitro and in vivo of the protein recognized by mAb IG9 (IG9 protein) was further characterized. EXPERIMENTAL DESIGN: The kinetics of cytokine-induced IG9 protein expression on HUVEC were evaluated by enzyme-linked immunosorbent assay. TNF-alpha-treated HUVEC surface proteins, labeled with [125I]Na, were solubilized in NP-40 detergent and immunoprecipitated with mAb IG9 to determine the molecular weight of the IG9 protein. The functional role of the IG9 protein in monocyte binding in vitro to cytokine-activated endothelial cells was established in adhesion assays utilizing U937 cells (human promyelomonocytic cell line) and human peripheral blood monocytes. Minimally oxidized or modified low density lipoproteins (MM-LDL) have previously been shown to induce monocyte adhesion to endothelial cells for up to 48 hours after exposure. In order to characterize the adhesion molecule(s) contributing to this increase in monocyte binding, MM-LDL-treated HUVEC and human aortic endothelial cells were assayed for monocyte adhesion molecule expression by enzyme-linked immunosorbent assay. In addition, mAb IG9-mediated alterations in MM-LDL-induced monocyte binding were studied in endothelial-monocyte adhesion assays. To assess IG9 protein expression in vivo, formalin-fixed, paraffin-embedded sections of inflamed human tissues obtained from lung and healing myocardial infarctions, in addition to sections of human atherosclerotic coronary arteries, were analyzed by immunohistochemistry. Tissue sections from atherosclerotic Watanabe heritable hyperlipidemic rabbit aortas were also included in these studies. RESULTS: The IG9 protein, undetected on untreated HUVEC, was expressed on their cell surface within 3 hours of treatment with TNF-alpha, peaked at 4 to 9 hours, and persisted for up to 48 hours as determined by enzyme-linked immunosorbent assay. A similar kinetic profile was elicited by interleukin-1 and lipopolysaccharide, whereas interferon-gamma (IFN-gamma) had minimal effect on IG9 expression. The IG9 protein has a molecular weight of 105,000 as determined by immunoprecipitation studies with TNF-alpha-treated HUVEC protein lysates. mAb IG9 significantly inhibited the binding of U937 cells and human peripheral blood monocytes to TNF-alpha-treated HUVEC and had no effect on peripheral blood lymphocyte or granulocyte adhesion. Treatment of human aortic endothelial cells or HUVEC with MM-LDL for 24 hours induced IG9 protein expression 3-fold above background with no concomitant increase in binding of antibodies to intercellular adhesion molecule-1 (ICAM-1), E-selectin, or vascular cell adhesion molecule-1 (VCAM-1), endothelial cell adhesion proteins involved in monocyte binding. mAb IG9 F(ab')2 inhibited MM-LDL-induced monocyte adhesion to HAEC by 23%. Immunohistochemical analysis demonstrated that the endothelial cell lining of vessels in human lung and heart with evidence of inflammation characterized by an extensive mononuclear cell infiltration exhibited reactivity with mAb IG9, whereas vessels with no evidence of inflammation in the same sections as well as in sections from normal lung and heart were nonreactive.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Human fetal astrocytes induce the expression of blood-brain barrier specific proteins by autologous endothelial cells.

The blood-brain barrier (BBB) is involved in many normal regulatory mechanisms as well as in pathologic conditions of the central nervous system. Previous studies examining the development and function of the BBB in vitro have primarily utilized cell lines or cultured tissues from non-human sources. In contrast, this study used a coculture system of human fetal astrocytes and autologous endothelial cells. Astrocytes and endothelial cells (EC) were isolated and cultured on the opposite sides of a synthetic permeable membrane. The cocultures were characterized by electron and light microscopy for morphology and by immunocytochemistry for cell-type specific markers. Using these coculture conditions, astrocytes displayed characteristic morphology and expressed glial fibrillary acidic protein. When cocultured with astrocytes, endothelial cells retained factor VIII expression and expressed the BBB-specific proteins, brain-type glucose transporter (GLUT-1) and gamma-glutamyl transpeptidase. This expression was dependent on EC being in close apposition to or in direct contact with astrocytes. The model presented in this study may permit further examination of the role of the BBB in both normal human neurodevelopment and neuropathologic conditions.

Astrocytes↗
PubMed1993

A tumor necrosis factor-responsive long-term-culture-initiating cell is associated with the stromal layer of mouse long-term bone marrow cultures.

Long-term bone marrow cultures provide a model for the study of hematopoiesis. Both an intact, adherent stromal layer and hematopoietic stem cells are necessary components in these cultures. Mycophenolic acid treatment of mouse long-term bone marrow cultures depletes them of all assayable hematopoietic precursors. The residual stromal cells are functional and support hematopoiesis if new progenitor cells are supplied. We now show that these mycophenolic acid-treated stromal cell cultures contain cells capable of hematopoietic differentiation without the addition of new progenitors. When treated with tumor necrosis factor alpha (20-200 units/ml), the apparently pure stromal cultures undergo an intense burst of hematopoietic activity. After 4 days such cultures contain approximately 2 x 10(6) hematopoietic cells and, by 1 week, they are indistinguishable from control long-term cultures that were not treated with mycophenolic acid. These results suggest that the stromal cultures either contain hematopoietic stem cells that are maintained quiescent and mycophenolic acid-resistant, perhaps by intimate contact with the stroma, or contain adherent cells that can be induced to differentiate into hematopoietic stem cells. These stem cells are primitive, in that they are capable of multilineage development in the long-term cultures, but are unable to form spleen colonies or myeloid colonies in semisolid medium. These data demonstrate that the adherent fraction of cultured bone marrow contains very primitive hematopoietic cells and that tumor necrosis factor alpha activates their proliferation and differentiation. They also suggest a strategy for obtaining the earliest progenitors free of other, more mature cell types.

Animals↗
PubMed1993

Cytokine production by human fetal microglia and astrocytes. Differential induction by lipopolysaccharide and IL-1 beta.

As part of a study on the role of cytokines in central nervous system development and dysfunction, we determined the pattern of cytokine production in highly purified cultures of microglia and astrocytes isolated from second-trimester human fetal brains. Levels of TNF-alpha, IL-1 beta, and IL-6 mRNA and protein were determined by Northern blot analysis and ELISA before and after stimulation with LPS, TNF-alpha, or IL-1 beta. In microglia, LPS induced mRNA for all three cytokines. High protein levels of IL-6 and TNF-alpha were also found in the medium, whereas IL-1 beta protein was mostly cell associated. IL-1 beta also induced message for all three cytokines, in the rank order of IL-1 beta > IL-6 > TNF-alpha. TNF-alpha induced mRNA and protein for IL-1 beta but not for TNF-alpha or IL-6. In contrast, LPS failed to stimulate either mRNA or protein expression for any of the three cytokines in astrocytes. On the other hand, IL-1 beta provided a strong stimulus for astrocytes. IL-1 beta induced mRNA and protein for both TNF-alpha and IL-6, but the kinetics of the response differed for the two cytokines. TNF-alpha mRNA and protein levels peaked early (at 4 h and 16 h, respectively) and were undetectable by 72 h, whereas IL-6 mRNA peaked later (at 16 h) and protein levels continued to accumulate in the medium through 72 h. IL-1 beta did not induce IL-1 beta mRNA or protein in astrocytes. TNF-alpha did not induce expression of any of the cytokines in astrocytes. In conclusion, our results demonstrate that cytokine production can be induced in human fetal microglia and astrocytes but that the stimuli for induction differed significantly for the two cell types. Whereas LPS was a potent stimulus for microglia, astrocytes primarily responded to IL-1 beta. The data further suggest that microglia may be key regulators of astrocyte response, working primarily through the expression of cell-associated IL-1 beta.

Astrocytes↗
PubMed1993

Expression of CSF-1, c-fms, and MCP-1 in the central nervous system of rats with experimental allergic encephalomyelitis.

We have examined the expression of factors associated with the growth, differentiation, and chemotaxis of cells of the monocyte/macrophage series in the central nervous system of Lewis rats sensitized to develop experimental allergic encephalomyelitis. CSF-1 mRNA increased significantly over that found in control animals (sensitized with OVA in CFA or CFA alone). The elevation in the levels of this growth factor commenced immediately before the onset of early clinical signs and peaked immediately before maximal clinical incidence of disease. Expression of CSF-1 message declined to base-line values with resolution of the disease process. CSF-1 protein was also detected in the central nervous system at the height of clinical disease. Expression of the receptor for CSF-1, the proto-oncogene c-fms, also paralleled the early disease process. Elevated levels of c-fms mRNA were detected immediately before the onset and peaked at the height of clinical signs of disease. In contrast to CSF-1 levels, elevated c-fms message expression persisted after resolution of the acute phase of experimental allergic encephalomyelitis. Levels of macrophage chemotactic factor-1 message were also elevated immediately before the onset of clinical signs, peaked with the height of clinical disease, and declined with resolution of the disease. Unlike CSF-1 or c-fms, no endogenous macrophage chemotactic factor-1 message was detected in control animals. Macrophage chemotactic factor-1 protein was demonstrated by Western blot in the central nervous system at the height of clinical disease. The results support the conclusion that expression of factors that specifically target cells of the monocyte/macrophage series are an important component of the disease process in experimental allergic encephalomyelitis.

Animals↗
PubMed1993

Macrophage colony-stimulating factor in human fetal astrocytes and microglia. Differential regulation by cytokines and lipopolysaccharide, and modulation of class II MHC on microglia.

CSF-1 is a growth factor that selectively promotes the proliferation, survival, and differentiation of cells of the mononuclear phagocyte series. As part of a study on the role of cytokine and hematopoietic growth factors in central nervous system (CNS) development and inflammation, we examined the expression of CSF-1 in dissociated glial cells cultured from human fetal CNS tissue. CSF-1 mRNA and protein were constitutively expressed by astrocytes. The steady state level of CSF-1 mRNA was markedly up-regulated by both IL-1 beta and TNF-alpha in a time- and dose-dependent manner, whereas only a minimal increase was detected after stimulation with LPS. In unstimulated astrocyte cultures, CSF-1 protein levels gradually increased to 3.5-fold base-line values by 96 h and were significantly increased by all three stimulants in the order of IL-1 > or = TNF > LPS. Low levels of CSF-1 mRNA and protein were also detected in unstimulated microglia cultures. In contrast to astrocyte cultures, CSF-1 mRNA and protein increased significantly after stimulation with LPS, but changed only minimally after exposure to TNF-alpha or IL-1 beta. The effect of CSF-1 on cell proliferation, morphology, and class II MHC Ag expression was determined in highly enriched cultures of microglia and astrocytes. Microglia treated with CSF-1 showed a modest level of proliferation and differentiation into rod-shaped cells, whereas neither cell number nor shape was changed in astrocyte cultures. Interestingly, marked inhibition of both basal and IFN gamma-induced class II MHC Ag expression was observed in microglial cells cultured in the presence of CSF-1, whereas no effect was detected in astrocytes. These results suggest the possibility that in situ production of CSF-1 in the CNS may regulate normal glial cell development and contribute to the immunologic status of the CNS through the down-regulation of class II MHC expression.

Astrocytes↗
PubMed1993

CSF-1 expression is upregulated in astrocyte cultures by IL-1 and TNF and affects microglial proliferation and morphology in organotypic cultures.

Astrocytes produce factors that control the growth and differentiation of many cell types within the CNS as well as play a role in the generation of the immune response. The extent to which these two functions interact has received less attention. We now report that astrocyte cultures established from rat brain endogenously express mRNA and low levels of secreted biologically active protein for the monocyte growth and differentiation factor colony stimulating factor-1 (CSF-1). Exposure of astrocytes to interleukin-1 (IL-1) and/or tumor necrosis factor (TNF) upregulated the expression of CSF-1 mRNA and protein. Following treatment with 100 U/ml of TNF, IL-1, or TNF+IL-1, maximum CSF-1 mRNA expression was observed at 3 hr. In the presence of IL-1 an increase in biologically active CSF-1 was detected in the astrocyte conditioned medium at 6 hr. These data indicate that the expression of CSF-1 by astrocytes can be modulated by exposure to the cytokines IL-1 and TNF. To determine whether CSF-1 provides a mitogenic signal for microglia during development, mouse spinal cord organotypic cultures were exposed to recombinant mouse CSF-1 (rmCSF-1), resulting in proliferation of microglia by 7 days and an increase in the number of ramified microglia over ameboid microglia by 14 days.

Animals↗
PubMed1992

Tumor necrosis factor alpha induces adhesion molecule expression on human fetal astrocytes.

Leukocyte adhesion molecules on endothelial cells of the blood-brain barrier may participate in the entry of leukocytes into the central nervous system. Because astrocytes are also a component of the blood-brain barrier and have been associated with inflammation, we studied the ability of astrocytes to express leukocyte adhesion molecules using Northern blot and immunocytochemical techniques. Astrocytes treated with the proinflammatory cytokine tumor necrosis factor alpha (TNF) expressed messenger RNA for the adhesion molecules E-selectin, vascular cell adhesion molecule 1, and intercellular adhesion molecule 1, as well as their corresponding proteins. In addition, TNF-treated astrocytes expressed a monocyte adhesion protein identified by our laboratory, recognized by the monoclonal antibody IG9. These results indicate that under inflammatory conditions in the central nervous system, such as multiple sclerosis and acquired immune deficiency syndrome, astrocyte expression of adhesion molecules may facilitate the migration of leukocytes and contribute to the disease process.

Astrocytes↗
PubMed1992

Interleukin 6 modulates c-sis gene expression in cultured human endothelial cells.

Human vascular endothelial cells secrete platelet-derived growth factor (PDGF)-like polypeptides which may mediate some of the vascular effects in the inflammatory process. We have demonstrated that IL-6 caused a significant increase in the mRNA level of the c-sis gene (PDGF B chain) in cultured human endothelial cells. IL-1 alpha and IL-1 beta also increased c-sis mRNA transcripts after an extended incubation period and both cytokines acted synergistically with IL-6 in increasing c-sis expression. Tumor necrosis factor enhanced the accumulation of c-sis mRNA and interferon-gamma decreased its level. In the inflammatory process specific cytokines can modulate c-sis expression in human endothelial cells. Their subsequent production of PDGF-like polypeptides could stimulate cell migration and proliferation, and cause the release of vascular inflammatory mediators.

Cells, Cultured↗
PubMed1992

Chronic inflammatory effects of interleukin-1 on the blood-retina barrier.

The chronic effects of human recombinant IL-1 (hrIL-1) on the specialized vasculature of the central nervous system (CNS) and on the CNS itself have been examined over a 35-day period in the rabbit retina. A single intraocular injection of physiological levels of hrIL-1 (300 units) induced a biphasic inflammatory reaction with well-defined acute and chronic phases in the challenged eye. Quantitative histopathological examination of the vascularized portion of the retina in the IL-1-challenged eye documented a persistent mononuclear (MN) cell response that peaked 7-14 days post-challenge. Included in the MN cell count were perivascular plasma cells. Elevated protein levels in the vitreous persisted throughout the time points studied and alterations in vascular permeability of the epiretinal vessels were demonstrated by tracer leakage at 2 weeks post-challenge. The results show that exposure of the CNS-vasculature to IL-1 induces long-lasting inflammatory changes typical of a chronic inflammatory reaction.

Animals↗
PubMed1990

Pathophysiologic effect of interleukin-1b in the rabbit retina.

Interleukin-1 is a potent immunomodulator and has been shown to initiate many aspects of the inflammatory response. To determine the effects of IL-1b in the central nervous system (CNS), the rabbit retina was used, adjacent to which factors can be injected with minimal trauma and both pathologic and physiologic effects can be monitored. Intravitreal injection of 300 units of IL-1b induced an alteration in the visual evoked potentials (VEP) that was associated with marked intravascular red blood cell accumulations, hemorrhage, and cellular inflammation of the epiretinal vessels. Analysis of these events showed slowing and occasional hyper-excitability of the compound action potential of the optic tract and of the cortical VEP that correlate with the maximum inflammatory response. Histologic studies show the following: no apparent response occurs within the first 1.5 hours after intraocular challenge; and between 3 and 6 hours after injection an extensive intravascular red blood cell accumulation and progressive hemorrhage is accompanied by an increase in the number of mononuclear (MN) cells and the appearance of polymorphonuclear (PMN) cells. Polymorphonuclear cells continue to increase with time to give a single wave of inflammation that peaks 24 hours after injection, while the number of MN cells steadily increases. These events are associated with changes in the permeability of the blood-brain barrier and correlate with the electrophysiologic dysfunctions. Forty-one hours after injection, MN inflammation, reactive gliosis, and residual PMN inflammation are evident. Neutralization with specific antibody inhibited the responses through 6 hours after injection. It is concluded that the rabbit retina provides a valuable model for the in vivo analysis of CNS inflammation.

Animals↗