Abstract
Although treatment with agents that block leukocyte function, including anti-ICAM-1 and doxycycline, reduces experimental central nervous system (CNS) ischemic injury, it is not known how leukocyte subset accumulation is affected by these agents. Using the rat two-vessel occlusion model and immunohistochemistry, we investigated granulocyte (PMN) and monocyte/macrophage (Mφ) accumulation at 1 and 4 d postischemia. A total of 24 animals were randomized to sham surgery, or to ischemia with saline, anti-ICAM-1, or doxycycline treatments. No leukocytes were observed in sham animals. At 24 h postischemia, there was a moderate infiltration of PMN and Mφ in untreated animals that was significantly decreased with either treatment. At 4 d after ischemia no PMN were identified, with extensive Mφ accumulation occurring in untreated animals that was only partially reduced with doxycycline treatment. These results confirm that both anti-ICAM-1 and doxycycline treatments reduce PMN and Mφ infiltration at 24 h. Delayed Mφ accumulation occurs despite treatment, suggesting that some of these cells represent transformed resident microglia.
Similar content being viewed by others
References
Argenbright L., Letts L., and Rothlein R. (1991) Monoclonal antibodies to the leukocyte membrane CD-18 glycoprotein complex and to intercellular adhesion molecule-1 inhibit leukocyte-endothelial adhesion in rabbits.J. Leukocyte Bio. 49, 253–257.
Barone F., Schmidt D., Hillegass L., Price W., White R., Feuerstein G., Clark R., Lee E., Griswold D., and Sarau H. (1992) Reperfusion increases neutrophils and leukotriene B4 receptor binding in rat focal ischemia.Stroke 23, 1337–1348.
Chauhan N., Spencer P., and Sabri M. (1993) Effect of acrylamide on the distribution of microtubule associated proteins in selected regions of rat brain.Mol. Chem. Neuropath. 18, 225–245.
Chopp M., Zhang R., Chen H., Li Y., Jiang N., and Rusche J. (1991) Postischemic administration of an anti-mac-1 antibody reduces ischemic cell damage after transient middle cerebral artery occlusion in rats.Stroke 25, 869–875.
Clark W., Calcagno F., Gabler W., Smith J., and Coull B. (1994) Reduction of central nervous system reperfusion injury in rabbits using doxycycline treatment.Stroke 25, 1411–1416.
Clark W., Coull B., Corliss L., Beamer N., Austin T., de Garmo P., and Briley D. (1992) Role of leukocyte adhesion in clinical stroke.J. Stroke Cerebrovasc. Dis. 2, 80–84.
Clark W., Madden K., Rothlein R., and Zivin J. (1991a) Reduction of CNS ischemic injury using leukocyte adhesion antibody treatment.Stroke 22, 877–883.
Clark W., Madden K., Rothlein R., and Zivin J. (1991b) Reduction of central nervous system ischemic injury by monoclonal antibody to intercellular adhesion molecule.J. Neurosurg. 75, 623–627.
Clark W., Walsh C., Briley D., and Coull B. (1993) Neutrophil adhesion in central nervous system ischemia in rabbits.Brain Behav. Immun. 7, 63–69.
del Zoppo G., Schmid-Schonbein G., Mori E., Copeland B., and Chang C. (1991) Polymorphonuclear leukocytes occlude capillaries following middle cerebral artery occlusion and reperfusion in baboons.Stroke 22, 1276–1283.
Dereski M. O., Chopp M., Knight R. A., Chen H., and Garcia J. H. (1992) Focal cerebral ischemia in the rat: temporal profile of neutrophil responses.Neurosci. Res. Commun. 11, 179–185.
Dijkstra C. D., Döpp E. A., Joling P., and Kraal G. (1985) The heterogeneity of mononuclear phagocytes in lymphoid organs: distinct macrophage subpopulations in the rat recognized by monoclonal antibodies ED1, ED2, and ED3.Immunology 54, 589–599.
Engler R., Dahlgren M., Morris D., and Schmid-Schonbein G. (1986) Role of leukocytes in response to acute myocardial ischemia and reflow in dogs.Am. J. Physiol. 251, 314–322.
Gabler W. and Creamer H. (1991) Suppression of human neutrophil function by tetracyclines.J. Periodont. Res. 26, 52–58.
Garcia J. H. and Kamijyo Y. (1974) Cerebral infarction: evolution of histopathological changes after occlusion of a middle cerebral artery in primates.J. Neuropathol. Exp. Neurol. 33, 409–421.
Garcia J., Liu K., Yoshida Y., Lian J., Chen S., and del Zoppo G. (1994) Influx of leukocytes and platelets in an evolving brain infarct.Am. J. Physiol. 144, 188,189.
Gehrmann J., Bonnekoh P., Miyazawa T., Hossmann K., and Kreutzberg G. W. (1992) Immunocytochemical study of an early microglial activation in ischemia.J. Cereb. Blood Flow Metab. 12, 257–269.
Giulian D. and Robertson C. (1990) Inhibition of mononuclear phagocytes reduces ischemic injury in the spinal cord.Ann. Neurol. 27, 33–42.
Graeber M., Streit W., and Kreutzberg G. (1989) Identity of ED2-positive perivascular cells in rat brain.J. Neurosci. Res. 22, 103–106.
Hallenbeck J., Dutka A., Tanishima T., Kochanek P., Kumaroo K., Thompson C., Obreovitch T., and Contreras T. (1986) Polymorphonuclear leukocyte accumulation in brain regions with low blood flow during the early postischemic period.Stroke 17, 246–253.
Jander S., Kraemer M., Schroeter M., Witte O., and Stoll G. (1995) Lymphocytic infiltration and expression of intercellular adhesion molecule-1 in photochemically induced ischemia of the rat cortex.J. Cereb. Blood Flow Metab. 15, 42–51.
Kochanek P. M. and Hallenbeck J. M. (1992) Polymorphonuclear leukocytes and monocytes/macrophages in the pathogenesis of cerebral ischemia and stroke.Stroke 23, 1367–1379.
Liu X., Kato H., Natata N., Kogure K., and Kata K. (1993) An immunohistochemical study of copper/zinc superoxide dismutase and manganese superoxide dismutase in rat hippocampus after transient cerebral ischemia.Brain Res. 625, 29–37.
McCormick W. F. (1983) The clinical neurosciences, inNeuropathology (Rosenburg R. N., ed.), Churchill Livingstone, New York, p. 66.
Mori E., del Zoppo G., Chambers D., Copeland B., and Arfors K. (1992) Inhibition of polymorphonuclear leukocyte adherence suppresses no-reflow after focal cerebral ischemia in baboon.Stroke 23, 712–718.
Morioka T., Kalehua A., and Streit W. (1993) Characterization of microglial reaction after middle cerebral artery occlusion in rat brain.J. Comp. Neuro. 327, 123–132.
Polman C. H., Dijkstra C. D., Sminia T., and Koetsier J. C. (1986) Immunohistological analysis of macrophages in the central nervous system of lewis rats with acute experimental allergic encephalomyelitis.J. Neuroimmunol. 11, 215–222.
Pozzilli C., Lenzi G., and Argentino C. (1985) Imaging of leukocyte infiltration in human cerebral infarcts.Stroke 16, 251–256.
Schmid-Schonbein G. (1987) Capillary plugging by granulocytes and the no-reflow phenomenon in the microcirculation.FASEB J. 46, 2397–2401.
Schmid-Schonbein G. and Engler R. (1986) Granulocytes as active participants in acute myocardial ischemia and infarction.Am. J. Cardiovasc. Path. 1, 15–29.
Smith C., Rothlein R., Hughes B., Mariscalco M., Rudloff H., Schmaistieg F., and Anderson D. (1988) Recognition of an endothelial determinant for CD-18-dependent human neutrophil adherence and transendothelial migration.J. Clin. Invest. 82, 1746–1756.
Smith J. and Gabler W. (1994) Doxycycline suppression of ischemia/reperfusion induced hepatic injury.Inflammation 18, 193–201.
Smith M. L., Auer R. N., and Siesjo B. K. (1984a) The density and distribution of ischemic brain injury in the rat following 2–10 min. of forebrain ischemia.Acta. Neuropathol. (Berl.) 64, 319–332.
Smith M. L., Bendek G., Dahlgren N., Rosen I., Wieloch T., and Siesjo B. K. (1984b) Models for studying long-term recovery following forebrain ischemia in the rat. 2. A 2-vessel occlusion model.Acta. Neurol. Scand. 69, 385–401.
Wang P., Kao M., and Wand S. (1993) Leukocyte infiltration in acute hemispheric stroke.Stroke 24, 236–240.
Wieloch T. (1985) Neurochemical correlates to selective neuronal vulnerability.Prog. Brain Res. 63, 69–85.
Zhang R., Chopp M., Li Y., Zaloga M., Jiang N., Jones M., Miyasaka M., and Ward P. (1994) Anti-ICAM-1 antibody reduces ischemic cell damage after transient middle cerebral artery occlusion in the rat.Neurology 44, 1747.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Clark, W.M., Lauten, J.D., Lessov, N. et al. The influence of antiadhesion therapies on leukocyte subset accumulation in central nervous system ischemia in rats. J Mol Neurosci 6, 43–50 (1995). https://doi.org/10.1007/BF02736758
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF02736758