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M. Iribarne, V. Torbidoni, A.M. Suburo; Endothelin and Endothelin Receptors in Retinal Neuroinflammation . Invest. Ophthalmol. Vis. Sci. 2006;47(13):2065.
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© ARVO (1962-2015); The Authors (2016-present)
Damage of central nervous system induced by sepsis is a consequence of endothelial dysfunction leading to neural damage. Endothelin–1 (ET–1), a small peptide released during shock and sepsis, has been involved in the control of blood–brain barrier. Therefore, we investigated the role of ET–1 and its receptors, ET–A and ET–B, in retinal neuroinflammatory responses induced by endotoxin injection.
Endotoxemia was induced by ip injection of LPS (5 mg/kg) to male BALB–c mice. Samples were obtained after 24 h of LPS injection. Endothelinergic receptors were blocked with 2 doses of tezosentan (T, 10 mg/kg, sc), 1 hour before LPS and 1 hour before euthanasia, respectively. Since saline solution (S) replaced LPS and/or T in control animals, 4 experimental groups: S–S, S–T, LPS–S and LPS–T were compared. Vascular permeability was examined with Evans Blue. Glial fibrillary acidic protein (GFAP), ET–1, ET–A and ET–B were examined immunohistochemically in retinal wholemounts and cryosections. GFAP was also evaluated in Western blots.
After LPS, retinas exhibited Evans Blue leakage around the optic nerve head, and contained obvious sites of focal dye leakage and cell extravasation along the inner retinal vascular plexus. Astrocytes showed large increases in GFAP and ET–B immunoreactivities. LPS also induced a large increase of neuronal ET–A immunoreactivity in the outer plexiform layer, amacrine cells and cells of the ganglion cell layer. Vascular permeability and cell extravasation were significantly reduced in LPS–T mice, together with ET–1 and ET–B astrocytic expression. GFAP, however, remained elevated, both in wholemounts and Western blots. ET–A immunoreactivity was also reduced.
In S–T mice, astrocytes presented a decrease in ET–1 immunoreactivity accompanied by a slight increase of ET–B immunoreactivity. Neuronal ET–A was decreased.
Our observations demonstrate that endotoxemia affects both glial and neuronal cells of the retina and that inhibition of endothelinergic receptors can reduce both glial and neuronal effects. Endothelinergic mechanisms in astrocytes would be primarily involved in the response to sepsis, as supported by the increase of astrocytic ET–B and GFAP induced by LPS and the reduction of astrocytic ET–B in LPS–T mice. These observations, together with the large decrease of astrocytic ET–1 in S–T mice, suggest that perivascular astrocytes might control endothelial permeability by accumulation ET–1 and regulation of the extracellular levels of this peptide.
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