Granulocyte-colony stimulating factor suppresses early inflammatory response of striatum in a cardiopulmonary bypass-circulatory arrest model of ischemic brain injury in newborn piglets

DOI: 10.4236/wjcd.2013.32028   PDF   HTML   XML   3,345 Downloads   4,830 Views   Citations


We investigated the effect of Granulocyte-Colony Stimulating Factor (G-CSF) on expression of pro- and anti-inflammatory proteins in the striatum of new- born piglet brain following cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA). Piglets were placed on CPB, cooled to 18?C, subjected to 30 min of DHCA and 1 h of low-flow (20 ml/kg/min), rewarmed to 37?C, separated from CPB circuit and monitored for 2 h. Striatum was then isolated for protein analysis. The levels of proteins are presented relative to the mean in the control group (mean ± SEM, n = 6). DHCA increased the levels of pro-inflammatory proteins: IL-1alpha (158% ± 23%, P = 0.05), IL-6 (152% ± 16%, P = 0.03), TNF-alpha (144% ± 2%, P = 0.003), MIP-3 alpha (148% ± 12.6%, P = 0.03), NAP-3 (216% ± 16%, P = 0.05), GRO (165% ± 19%, P = 0.03) and BLC (140.4 ± 15%, P = 0.05). Compared to DHCA, the G-CSF-treated group had significantly decreased levels of IL-6 (110.8% ± 11% vs. 152% ± 16%, P = 0.05), TNF-alpha (120.6% ± 5.4% vs. 144% ± 2%, P = 0.001), MIP-3 alpha (148% ± 12.6% vs. 104.8% ± 13%, P = 0.02) and NAP-2 (216% ± 16% vs. 122% ± 23%, P = 0.002). The levels of anti-inflammatory proteins did not change in DHCA group compared to control, except for VEGF which decreased to 37.5% ± 9%, P = 0.003. The levels of all protective proteins in the G-CSF group increased versus the DHCA group, but the increases did not attain a P value of 0.05. Conclusions: In an immature brain subjected to circulatory arrest, the early inflammatory response in the striatum is diminished by pretreatment with G-CSF.

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Pastuszko, P. , Schears, G. , Kubin, J. , Greeley, W. , Nadkarni, V. , Wilson, D. and Pastuszko, A. (2013) Granulocyte-colony stimulating factor suppresses early inflammatory response of striatum in a cardiopulmonary bypass-circulatory arrest model of ischemic brain injury in newborn piglets. World Journal of Cardiovascular Diseases, 3, 197-205. doi: 10.4236/wjcd.2013.32028.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Ballweg, J.A., Wernovsky, G. and Gaynor, J.W. (2007) Neurodevelopmental outcomes following congenital heart surgery. Pediatric Cardiology, 28,126-133. doi:10.1007/s00246-006-1450-9
[2] Bellinger, D.C., Wypij, D. and duPlessis, A.J., et al. (2003) Neurodevelopmental status at eight years in children with dextro-transposition of the great arteries: The Boston circulatory arrest trial. Journal of Thoracic Cardiovascular Surgery, 126, 1385-1396. doi:10.1016/S0022-5223(03)00711-6
[3] Limperopoulos, C., Majnemer, A., Shevell, M.I., et al. (2002) Predictors of developmental disabilities after open- heart surgery in young children with congenital heart defects. Journal of Pediatrics, 141, 51-58. doi:10.1067/mpd.2002.125227
[4] Paparella, D., Yau, T.M. and Young, E. (2002) Cardiopulmonary bypass induced inflammation: Pathophysiology and treatment. An update. European Journal Cardio- Thoracic Surgery, 21, 232-244. doi:10.1016/S1010-7940(01)01099-5
[5] Ben-Abraham, R., Weinbroum, A.A., Dekel, B. and Paret, G. (2003) Chemokines and the inflammatory response following cardiopulmonary bypass—A new target for therapeutic intervention? Paediatric Anaesthesiology, 13, 655-661. doi:10.1046/j.1460-9592.2003.01069.x
[6] Butler, J., Rocker, G.M. and Westaby, S. (1993) Inflammatory response to cardiopulmonary bypass. Annals of Thoracic Surgery, 55, 552-559. doi:10.1016/0003-4975(93)91048-R
[7] Levy, J.H. and Tanaka, K.A. (2003) Inflammatory response to cardiopulmonary bypass. The Annals of Thoracic Surgery, 75, S715-S720. doi:10.1016/S0003-4975(02)04701-X
[8] Hüvels-Gürich, H.H., Schumacher, K., Vazquez-Jimenez, J.F., et al. (2002) Cytokine balance in infants undergoing cardiac operation. The Annals of Thoracic Surgery, 73, 601-608. doi:10.1016/S0003-4975(01)03391-4
[9] Arkader, R., Troster, E.J., Abellan, D.M., et al. (2004) Procalcitonin and C-reactive protein kinetics in postoperative pediatric cardiac surgical patients. Journal of Cardiothoracic Vascular Anesthesiology, 18, 160-165. doi:10.1053/j.jvca.2004.01.021
[10] Beghetti, M., Rimensberger, P.C., Kalangos, A., et al. (2003) Kinetics of procalcitonin, interleukin 6 and C-reactive protein after cardiopulmonary-bypass in children. Cardiology in the Young, 13, 161-167. doi:10.1017/S1047951103000301
[11] Butler, J., Pathi, V.L., Paton, R.D., et al. (1996) Acute- phase responses to cardiopulmonary bypass in children weighing less than 10 kilograms. Annals of Thoracic Surgery, 62, 538-542. doi:10.1016/0003-4975(96)00325-6
[12] Harris, T.B., Ferrucci, L., Tracy, R.P., et al. (1999) Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly. American Journal of Medicine, 106, 506-512. doi:10.1016/S0002-9343(99)00066-2
[13] Weaver, J.D., Huang, M.H., Albert, M., et al. (2002) Interleukin-6 and risk of cognitive decline: MacArthur studies of successful aging. Neurology, 59, 371-378. doi:10.1212/WNL.59.3.371
[14] Gessler, P., Schmitt, B., Prètre, R. and Latal, B. (2009) Inflammatory response and neurodevelopmental outcome after open-heart surgery in children. Pediatrics Cardiology, 30, 301-305. doi:10.1007/s00246-008-9354-5
[15] Pastuszko, A. (2007) Dopamine, its role in regulation newborn brain metabolism and neuronal injury during hypoxia and posthypoxic reoxygenation. In: Mishra, Om P., Ed., Mechanisms of Hypoxic Brain Injury and Potential Strategies for Neuroprotection, Transworld Research Network, Trivandrum, 113-155.
[16] Schneider, A., Kruger, C., Steigleder, T., et al. (2005) The hematopoietic factor G-CSF is a neuronal ligand that counteracts programmed cell death and drives neurogenesis. Journal of Clinical Investigation, 115, 2083- 2098. doi:10.1172/JCI23559
[17] Schabitz, W.R., Kollmar, R., Schwaninger, M., et al. (2003) Neuroprotective effect of granulocyte colony-stimulating factor after focal cerebral ischemia. Stroke, 34, 745-751. doi:10.1161/01.STR.0000057814.70180.17
[18] Gibson, C.L., Bath, P.M. and Murphy, S.P. (2005) G-CSF reduces infarct volume and improves functional outcome after transient focal cerebral ischemia in mice. Journal of Cerebral Blood Flow and Metabolism, 25, 431-439. doi:10.1038/sj.jcbfm.9600033
[19] Hartung, T., Von Aulock, S., Schneider, C. and Faist, E. (2003) How to leverage an endogenous immune defense mechanism: The example of granulocyte colony-stimulating factor. Critical Care Medicine, 31, 65-75. doi:10.1097/00003246-200301001-00010
[20] Solaroglu, I., Tsubokawa, T., Cahill, J. and Zhang, J.H. (2006) Anti-apoptotic effect of granulocyte-colony stimulating factor after focal cerebral ischemia in the rat. Neuroscience, 143, 965-974. doi:10.1016/j.neuroscience.2006.09.014
[21] Xiao, B.G., Lu, C.Z. and Link, H. (2007) Cell biology and clinical promise of G-CSF: Immunomodulation and neuroprotection. Journal of Cellular Molecular Medicine, 11, 1272-1290. doi:10.1111/j.1582-4934.2007.00101.x
[22] Pastuszko, P., Schears, G.J., Pirzadeh, A., et al. (2012) Effect of granulocyte colony stimulating factor (G-CSF) on expression of select proteins involved in apoptosis in a neonatal piglet brain following cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA). Journal of Thoracic Cardiovascular Surgery, 143, 1436- 1442. doi:10.1016/j.jtcvs.2012.01.018
[23] Lee, S.T., Chu, K., Jung, K.H., et al. (2005) Granulocyte colony-stimulating factor enhances angiogenesis after focal cerebral ischemia. Brain Research, 1058, 120-128. doi:10.1016/j.brainres.2005.07.076
[24] Shyu, W.C., Lin, S.Z., Yang, H.I., et al. (2004) Functional recovery of stroke rats induced by granulocyte colony-stimulating factor-stimulated stem cells. Circulation, 110, 1847-1854. doi:10.1161/01.CIR.0000142616.07367.66
[25] Kawada, H., Takizawa, S., Takanashi, T., et al. (2006) Administration of hematopoietic cytokines in the sub- acute phase after cerebral infarction is effective for functional recovery facilitating proliferation of intrinsic neural stem/progenitor cells and transition of bone marrow-derived neuronal cells. Circulation, 113, 701-710. doi:10.1161/CIRCULATIONAHA.105.563668
[26] Boneberg, E.M., Hareng, L., Gantner, F., et al. (2000) Human monocytes express functional receptors for granulocyte colony stimulating factor that mediate suppression of monokines and interferon-gamma. Blood, 95, 270-276.
[27] Saito, M., Kiyokawa, N., Taguchi, T., et al. (2002) Granulocyte colony-stimulating factor directly affects human monocytes and modulates cytokine secretion. Experimental Hematology, 30, 1115-1123. doi:10.1016/S0301-472X(02)00889-5
[28] Pastuszko, P., Liu, H., Mendoza, A., et al. (2007) Regulatory pathways to neuronal injury or survival are dependent on the rate of low flow cardiopulmonary bypass following circulatory arrest in newborn piglets. European Journal of Cardio-Thoracic Surgery, 31, 899-905. doi:10.1016/j.ejcts.2007.01.049
[29] Newman, M.F., Kirchner, J.L., Phillips-Bute. B., et al. (2001) Longitudinal assessment of neurocognitive function after coronary artery bypass surgery. New England Journal of Medicine, 344, 395-402. doi:10.1056/NEJM200102083440601
[30] Hindman, B.J. and Todd, M.M. (1999) Improving neurologic outcome after cardiac surgery. Anesthesiology, 90, 1243-1247. doi:10.1097/00000542-199905000-00002
[31] Homi, H.M., Jones, W.L., de Lange, F., et al. (2010) Exacerbation of systemic inflammation and increased cerebral infarct volume with cardiopulmonary bypass after focal cerebral ischemia in the rat. The Journal of Thoracic and Cardiovascular Surgery, 410, 660-666. doi:10.1016/j.jtcvs.2009.10.063
[32] Rothenburger, M., Soeparwata, R., Deng, M.C., et al. (2001) Prediction of clinical outcome after cardiac surgery: The role of cytokines, endotoxin, and anti-endotoxin core antibodies. Shock, 16, 44-50. doi:10.1097/00024382-200116001-00009
[33] Cremer, J., Marti, M., Redl, H., et al. (1996) Systemic inflammatory response syndrome after cardiac operations. Annals of Thoracic Surgery, 61, 1714-1720. doi:10.1016/0003-4975(96)00055-0
[34] Deng, M.C., Dasch, B., Erren, M., et al. (1996) Impact of left ventricular dysfunction on cytokines, hemodynamics, and outcome in bypass grafting. Annals of Thoracic Surgery, 62, 184-190. doi:10.1016/0003-4975(96)00230-5
[35] Hennein, H.A., Ebba, H., Rodriguez, J.L., et al. (1994) Relationship of the proinflammatory cytokines to myocardial ischemia and dysfunction after uncomplicated coronary revascularization. Journal of Thoracic Cardiovascular Surgery, 108, 626-635.
[36] Dantzer, R. and Kelley, K.W. (2007) Twenty years of research on cytokine induced sickness behavior. Brain Behavior and Immunity, 21,153-160. doi:10.1016/j.bbi.2006.09.006
[37] Allan, C.K., Newburger, J.W., McGrath, E., et al. (2010) The relationship between inflammatory activation and clinical outcome after infant cardiopulmonary bypass. Anesthesia Analgesia, 111, 1244-1251. doi:10.1213/ANE.0b013e3181f333aa
[38] Denes, A., Thornton, P., Rothwell, N.J. and Allan, S.M. (2010) Inflammation and brain injury: Acute cerebral ischaemia, peripheral and central inflammation. Brain, Behavior and Immunity, 24, 708-723. doi:10.1016/j.bbi.2009.09.010
[39] Basic, K.V., Simundic, A.M., Nikolac, N., et al. (2008) Pro-inflammatory and anti-inflammatory cytokines in acute ischemic stroke and their relation to early neurological deficit and stroke outcome. Clinical Biochemistry, 41, 1330-1334. doi:10.1016/j.clinbiochem.2008.08.080
[40] Emsley, H.C., Smith, C.J., Gavin, C.M., et al. (2003) An early and sustained peripheral inflammatory response in acute ischaemic stroke: Relationships with infection and atherosclerosis. Journal of Neuroimmunology, 139, 93- 101. doi:10.1016/S0165-5728(03)00134-6
[41] Smith, C.J., Emsley, H.C., Gavin, C.M., et al. (2004) Peak plasma interleukin-6 and other peripheral markers of inflammation in the first week of ischaemic stroke correlate with brain infarct volume, stroke severity and long-term outcome. BMC Neurology, 4, 2.
[42] Waje-Andreassen, U., Krakenes, J., Ulvestad, E., et al. (2005) IL-6: An early marker for outcome in acute ischemic stroke. Acta Neurologica Scandinavica, 111, 360-365. doi:10.1111/j.1600-0404.2005.00416.x
[43] Yang, G.Y., Gong. C., Qin. Z., et al. (1998) Inhibition of TNF alpha attenuates infarct volume and ICAM-1 expression in ischemic mouse brain. NeuroReport, 9, 2131- 2134. doi:10.1097/00001756-199806220-00041
[44] Hagberg, H., Gilland, E., Bona, E., et al. (1996) Enhanced expression of interleukin (IL)-1 and IL-6 mRNA and bioactive protein after hypoxia-ischemia in neonatal rats. Pediatrics Research, 40, 603-609. doi:10.1203/00006450-199610000-00015
[45] Martin, D., Chinookoswong, N. and Miller, G. (1994) The interleukin-1 receptor antagonist (rhIL-1ra) protects against cerebral infarction in a rat model of hypoxiaischemia. Experimental Neurology, 130, 362-367. doi:10.1006/exnr.1994.1215
[46] Liu, X.H., Kwon, D., Yang, G.Y., et al. (1998) Neonatal mice deficient in interleukin-1 converting enzyme are resistant to cerebral hypoxic-ischemic injury. Pediatric Research, 43, 320A. doi:10.1203/00006450-199804001-01903
[47] Relton, J.K. and Rothwell, N.J. (1992) Interleukin-1 receptor antagonist inhibits ischaemic and excitotoxic neuronal damage in the rat. Brain Research Bulletin, 29, 243-246. doi:10.1016/0361-9230(92)90033-T
[48] Friedlander, R.M., Gagliardini, V., Hara, H., et al. (1997) Expression of a dominant negative mutant of interleukin-1 beta converting enzyme in transgenic mice prevents neuronal cell death induced by trophic factor withdrawal and ischemic brain injury. Journal of Experimental Medicine, 185, 933-940. doi:10.1084/jem.185.5.933
[49] Hara, H., Friedlander, R.M., Gagliardini, V., et al. (1997) Inhibition of interleukin 1β converting enzyme family proteases reduces ischemic and excitotoxic neuronal damage. Proceedings of the National Academy of Sciences of the United States of America, 94, 2007-2012. doi:10.1073/pnas.94.5.2007
[50] Boutin, H., LeFeuvre, R.A., Horai, R., et al. (2001) Role of IL-1alpha and IL-1beta in ischemic brain damage. Journal of Neuroscience, 21, 5528-5534.
[51] Minami, M. and Satoh, M. (2003) Chemokines and their receptors in the brain: Pathophysiological roles in ischemic brain injury. Life Science, 74, 321-327. doi:10.1016/j.lfs.2003.09.019
[52] Croll, S.D., Goodman, J.H. and Scharfman, H.E. (2004) Vascular endothelial growth factor (VEGF) in seizures: A double-edged sword. Advance Experimental Medicine and Biology, 548, 57-68. doi:10.1007/978-1-4757-6376-8_4
[53] Lee, C.Z., Xue, Z., Zhu, Y., et al. (2007) Matrix metalloproteinase-9 inhibition attenuates vascular endothelial growth factor-induced intracerebral hemorrhage. Stroke, 38, 2563-2568. doi:10.1161/STROKEAHA.106.481515
[54] Gluzman-Poltorak, Z., Cohen, T., Herzog, Y., et al. (2000) Nuropilin-2 is a receptor for the Vascular Endothelial Growth Factor (VEGF) forms VEGF-145 and VEGF-165. Journal of Biological Chemistry, 275, 18040-18045. doi:10.1074/jbc.M909259199
[55] Saito, Y., Uppal, A., Byfield, G., et al. (2008) Activated NAD(P)H oxidase from supplemental oxygen induces neovascularization independent of VEGF in retinopathy of prematurity model. Investigative Ophthalmology & Visual Science, 49, 1591-1598. doi:10.1167/iovs.07-1356
[56] Temburni, M.K. and Jacob, M.H. (2001) New functions for glia in the brain. Proceedings of the National Academy of Sciences of the United States of America, 98, 3631-3632. doi:10.1073/pnas.081073198
[57] O’Connor, D.S., Schechner, J.S., Adida, C., et al. (2000) Control of apoptosis during angiogenesis by survivin expression in endothelial cells. American Journal of Pathology, 156, 393-398. doi:10.1016/S0002-9440(10)64742-6
[58] Dvorak, H.F. (2002) Vascular permeability factor/vascular endothelial growth factor: A critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. Journal of Clinical Oncology, 20, 4368- 4380. doi:10.1200/JCO.2002.10.088
[59] Tran, J., Rak, J., Sheehan, C., et al. (1999) Marked induction of the IAP family antiapoptotic proteins survivin and XIAP by VEGF in vascular endothelial cells. Biochemical Biophysical Research Communication, 264, 781-788. doi:10.1006/bbrc.1999.1589
[60] Zhu, W.H., MacIntyre, A. and Nicosia, R.F. (2002) Regulation of angiogenesis by vascular endothelial growth factor and angiopoietin-1 in the rat aorta model: Distinct temporal patterns of intracellular signaling correlate with induction of angiogenic sprouting. American Journal of Pathology, 161, 823-830. doi:10.1016/S0002-9440(10)64242-3
[61] McBride, W.T., Armstrong, M.A., Crockard, A.D., et al. (1995) Cytokine balance and immunosuppressive changes at cardiac surgery: Contrasting response between patients and isolated CPB circuits. British Journal of Anaesthesiology, 75, 724-733. doi:10.1093/bja/75.6.724
[62] Hedtj?rn, M., Mallard, C. and Hagberg, H. (2004) Inflammatory gene profiling in the developing mouse brain after hypoxia-ischemia. Journal of Cerebral Blood Flow and Metabolism, 24, 1333-1351. doi:10.1097/01.WCB.0000141559.17620.36
[63] Pollari, E., Savchenko, E., Jaronen, M., et al. (2011) Granulocyte colony stimulating factor attenuates inflamemation in a mouse model of amyotrophic lateral sclerosis. Journal of Neuroinflammation, 8, 74-87. doi:10.1186/1742-2094-8-74
[64] Diederich, K., Schabitz, W.R. and Minnerup, J. (2012) Seeing old friends from a different angle: Novel properties of hematopoietic growth factors in the healthy and diseased brain. Hippocampus, 22, 1051-1057. doi:10.1002/hipo.20904
[65] Nishio,Y., Koda, M., Kamada, T., et al. (2007) Granulocyte colony-stimulating factor attenuates neuronal death and promotes functional recovery after spinal cord injury in mice. Journal of Neuropathology and Experimental Neurology, 66, 724-731. doi:10.1097/nen.0b013e3181257176
[66] Pitzer, C., Klussmann, S., Kruger, C., et al. (2010) The hematopoietic factor granulocyte-colony stimulating factor improves outcome in experimental spinal cord injury. Journal of Neurochemistry, 113, 930-942. doi:10.1111/j.1471-4159.2010.06659.x
[67] Sanli, A.M., Serbes, G., Caliskan, M., et al. (2010) Effect of granulocyte-colony stimulating factor on spinal cord tissue after experimental contusion injury. Journal of Clinical Neuroscience, 17, 1548-1552. doi:10.1016/j.jocn.2010.03.043

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