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Acute and chronic immunomodulatory changes in rat liver after fetal and perinatal asphyxia

Published online by Cambridge University Press:  22 January 2014

E. Vlassaks ,
M. Nikiforou ,
E. Strackx ,
M. Hütten ,
O. Bekers ,
D. Gazzolo ,
G. Li Volti ,
P. Martinez-Martinez ,
B. W. Kramer  and
A. W. D. Gavilanes
E. Vlassaks
Affiliation:
Department of Neuropsychology, Division Neuroscience, Maastricht University, School of Mental Health and Neuroscience (MHeNS), Maastricht, the Netherlands Department of Pediatrics, Division of Neonatology, Maastricht University Medical Center, Maastricht, the Netherlands School for Oncology and Developmental Biology Maastricht (GROW), Maastricht University, Maastricht, the Netherlands
M. Nikiforou
Affiliation:
Department of Neuropsychology, Division Neuroscience, Maastricht University, School of Mental Health and Neuroscience (MHeNS), Maastricht, the Netherlands Department of Pediatrics, Division of Neonatology, Maastricht University Medical Center, Maastricht, the Netherlands
E. Strackx
Affiliation:
Department of Neuropsychology, Division Neuroscience, Maastricht University, School of Mental Health and Neuroscience (MHeNS), Maastricht, the Netherlands Department of Pediatrics, Division of Neonatology, Maastricht University Medical Center, Maastricht, the Netherlands
M. Hütten
Affiliation:
Department of Pediatrics, Division of Neonatology, Maastricht University Medical Center, Maastricht, the Netherlands Department of Childhood and Adolescent Medicine, Division of Neonatology, Medical Faculty RWTH Aaachen, University Hospital, Germany
O. Bekers
Affiliation:
Department of Clinical Chemistry, Maastricht University Medical Center, Maastricht, the Netherlands
D. Gazzolo
Affiliation:
Department of Pediatrics, Obstetrics and Reproductive Medicine, Siena, Italy
G. Li Volti
Affiliation:
Department of Drug Sciences, University of Catania, Catania, Italy
P. Martinez-Martinez
Affiliation:
Department of Neuropsychology, Division Neuroscience, Maastricht University, School of Mental Health and Neuroscience (MHeNS), Maastricht, the Netherlands
B. W. Kramer
Affiliation:
Department of Neuropsychology, Division Neuroscience, Maastricht University, School of Mental Health and Neuroscience (MHeNS), Maastricht, the Netherlands Department of Pediatrics, Division of Neonatology, Maastricht University Medical Center, Maastricht, the Netherlands School for Oncology and Developmental Biology Maastricht (GROW), Maastricht University, Maastricht, the Netherlands
A. W. D. Gavilanes*
Affiliation:
Department of Neuropsychology, Division Neuroscience, Maastricht University, School of Mental Health and Neuroscience (MHeNS), Maastricht, the Netherlands Department of Pediatrics, Division of Neonatology, Maastricht University Medical Center, Maastricht, the Netherlands
*
*Address for correspondence: A. W. D. Gavilanes, MD, PhD, Associate Professor, Department of Pediatrics, Division of Neonatology, Maastricht University Medical Centre, Postbus 5800, 6202AZ Maastricht, the Netherlands. (Email [email protected])
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Abstract

Hypoxic-ischemic encephalopathy (HIE) caused by fetal and perinatal asphyxia is an important cause of mortality in the neonatal period. Not only will asphyxia affect the brain but also other organs such as the liver and kidneys. Interestingly, it has been shown that liver damage is proportional to the severity of the asphyctic insult, implying an association between liver impairment and HIE. Accordingly, we investigated in an established rat model the acute and chronic hepatic response to both fetal (FA) and perinatal asphyxia (PA). In addition, we assessed whether fetal asphyctic preconditioning (PC) would have any beneficial effect on the liver. Inflammation, ceramide signaling and hepatocellular damage were analyzed in the livers of newborn and adult rats at several short- and long-term time points after both FA and PA. We found that although FA induced an acute inflammatory response, apoptotic mRNA levels and oxidative DNA damage were decreased at 96 h post FA. Whereas increased IL-6 and IL-10 mRNA levels were observed after PA, the combination of FA and PA (PC) attenuated the inflammatory response. Moreover, 6 h after PA anti-apoptotic genes were downregulated and associated with less lipid peroxidation, while preconditioned animals were comparable to controls. In summary, asphyctic PC seems to have an acute protective effect on the liver by modulating the inflammatory, apoptotic and anti-oxidative response. More insight into the hepatic response to asphyxia is necessary, as disturbed hepatic function is associated with metabolic diseases in later life.

Keywords

asphyxiainflammationliverpreconditioningrat
Type
Original Article
Information
Journal of Developmental Origins of Health and Disease , Volume 5 , Issue 2 , April 2014 , pp. 98 - 108
Copyright
© Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2014 

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Footnotes

†

Equal contribution.

References

1. Lawn, JE, Cousens, S, Darmstadt, GL, Paul, V, Martines, J. Why are 4 million newborn babies dying every year? Lancet. 2004; 364, 2020.CrossRefGoogle ScholarPubMed
2. Alonso-Spilsbury, M, Mota-Rojas, D, Villanueva-Garcia, D, et al. Perinatal asphyxia pathophysiology in pig and human: a review. Anim Reprod Sci. 2005; 90, 1–30.CrossRefGoogle ScholarPubMed
3. Hankins, GD, Koen, S, Gei, AF, et al. Neonatal organ system injury in acute birth asphyxia sufficient to result in neonatal encephalopathy. Obstet Gynecol. 2002; 99(Pt 1), 688–691.Google ScholarPubMed
4. Shah, P, Riphagen, S, Beyene, J, Perlman, M. Multiorgan dysfunction in infants with post-asphyxial hypoxic-ischaemic encephalopathy. Arch Dis Child Fetal Neonatal Ed. 2004; 89, F152–F155.CrossRefGoogle ScholarPubMed
5. Karlsson, M, Blennow, M, Nemeth, A, Winbladh, B. Dynamics of hepatic enzyme activity following birth asphyxia. Acta Paediatr. 2006; 95, 1405–1411.CrossRefGoogle ScholarPubMed
6. Islam, MT, Islam, MN, Mollah, AH, et al. Status of liver enzymes in babies with perinatal asphyxia. Mymensingh Med J. 2011; 20, 446–449.Google ScholarPubMed
7. Okazaki, K, Nishida, A, Kato, M, et al. Elevation of cytokine concentrations in asphyxiated neonates. Biol Neonate. 2006; 89, 183–189.CrossRefGoogle ScholarPubMed
8. Ashdown, H, Joita, S, Luheshi, GN, Boksa, P. Acute brain cytokine responses after global birth hypoxia in the rat. J Neurosci Res. 2008; 86, 3401–3409.CrossRefGoogle ScholarPubMed
9. Mari, M, Fernandez-Checa, JC. Sphingolipid signalling and liver diseases. Liver Int. 2007; 27, 440–450.CrossRefGoogle ScholarPubMed
10. Ding, WX, Yin, XM. Dissection of the multiple mechanisms of TNF-alpha-induced apoptosis in liver injury. J Cell Mol Med. 2004; 8, 445–454.CrossRefGoogle ScholarPubMed
11. Vlassaks, E, Mencarelli, C, Nikiforou, M, et al. Fetal asphyxia induces acute and persisting changes in the ceramide metabolism in rat brain. J Lipid Res. 2013; 54, 1825–1833.CrossRefGoogle ScholarPubMed
12. Zhai, ST, Liu, GY, Xue, F, et al. Changes of sphingolipids profiles after ischemia-reperfusion injury in the rat liver. Chin Med J. 2009; 122, 3025–3031.Google ScholarPubMed
13. Llacuna, L, Mari, M, Garcia-Ruiz, C, Fernandez-Checa, JC, Morales, A. Critical role of acidic sphingomyelinase in murine hepatic ischemia-reperfusion injury. Hepatology. 2006; 44, 561–572.CrossRefGoogle ScholarPubMed
14. Vlassaks, E, Strackx, E, Vles, J, et al. Fetal asphyctic preconditioning modulates the acute cytokine response thereby protecting against perinatal asphyxia in neonatal rats. J Neuroinflammation. 2013; 10, 14.CrossRefGoogle ScholarPubMed
15. Cai, Z, Sigrest, T, Hersey, K, Rhodes, PG. Intrauterine hypoxia-ischemia increases N-methyl-D-aspartate-induced cGMP formation and glutamate accumulation in cultured rat cerebellar granule cells. Pediatr Res. 1995; 38, 107–112.CrossRefGoogle ScholarPubMed
16. Strackx, E, Van den Hove, DL, Prickaerts, J, et al. Fetal asphyctic preconditioning protects against perinatal asphyxia-induced behavioral consequences in adulthood. Behav Brain Res. 2010; 208, 343–351.CrossRefGoogle ScholarPubMed
17. Strackx, E, Zoer, B, Van den Hove, D, et al. Brain apoptosis and carotid artery reactivity in fetal asphyctic preconditioning. Front Biosci (Schol Ed). 2010; 2, 781–790.CrossRefGoogle ScholarPubMed
18. Kramer, BW, Moss, TJ, Willet, KE, et al. Dose and time response after intraamniotic endotoxin in preterm lambs. Am J Respir Crit Care Med. 2001; 164, 982–988.CrossRefGoogle ScholarPubMed
19. Bieghs, V, Vlassaks, E, Custers, A, et al. Chorioamnionitis induced hepatic inflammation and disturbed lipid metabolism in fetal sheep. Pediatr Res. 2010; 68, 466–472.CrossRefGoogle ScholarPubMed
20. Adibhatla, RM, Dempsy, R, Hatcher, JF. Integration of cytokine biology and lipid metabolism in stroke. Front Biosci. 2008; 13, 1250–1270.CrossRefGoogle ScholarPubMed
21. Alessenko, AV, Galperin, EI, Dudnik, LB, et al. Role of tumor necrosis factor alpha and sphingomyelin cycle activation in the induction of apoptosis by ischemia/reperfusion of the liver. Biochemistry (Mosc). 2002; 67, 1347–1355.CrossRefGoogle ScholarPubMed
22. Mencarelli, C, Martinez-Martinez, P. Ceramide function in the brain: when a slight tilt is enough. Cell Mol Life Sci. 2013; 70, 181–203.CrossRefGoogle Scholar
23. Mencarelli, C, Bode, GH, Losen, M, et al. Goodpasture antigen-binding protein/ceramide transporter binds to human serum amyloid P-component and is present in brain amyloid plaques. J Biol Chem. 2012; 287, 14897–14911.CrossRefGoogle ScholarPubMed
24. Mencarelli, C, Losen, M, Hammels, C, et al. The ceramide transporter and the goodpasture antigen binding protein: one protein – one function? J Neurochem. 2010; 113, 1369–1386.CrossRefGoogle ScholarPubMed
25. Al-Aubaidy, HA, Jelinek, HF. 8-Hydroxy-2-deoxy-guanosine identifies oxidative DNA damage in a rural prediabetes cohort. Redox Rep. 2010; 15, 155–160.CrossRefGoogle Scholar
26. Marrazzo, G, Bosco, P, La Delia, F, et al. Neuroprotective effect of silibinin in diabetic mice. Neurosci Lett. 2011; 504, 252–256.CrossRefGoogle ScholarPubMed
27. Maddaiah, VT. Glutathione correlates with lipid peroxidation in liver mitochondria of triiodothyronine-injected hypophysectomized rats. FASEB J. 1990; 4, 1513–1518.CrossRefGoogle ScholarPubMed
28. Li Volti, G, Musumeci, T, Pignatello, R, et al. Antioxidant potential of different melatonin-loaded nanomedicines in an experimental model of sepsis. Exp Biol Med (Maywood). 2012; 237, 670–677.CrossRefGoogle Scholar
29. Anthony, DC, Couch, Y, Losey, P, Evans, MC. The systemic response to brain injury and disease. Brain Behav Immun. 2012; 26, 534–540.CrossRefGoogle ScholarPubMed
30. Martin-Ancel, A, Garcia-Alix, A, Pascual-Salcedo, D, et al. Interleukin-6 in the cerebrospinal fluid after perinatal asphyxia is related to early and late neurological manifestations. Pediatrics. 1997; 100, 789–794.CrossRefGoogle ScholarPubMed
31. Silveira, RC, Procianoy, RS. Interleukin-6 and tumor necrosis factor-alpha levels in plasma and cerebrospinal fluid of term newborn infants with hypoxic-ischemic encephalopathy. J Pediatr. 2003; 143, 625–629.CrossRefGoogle ScholarPubMed
32. Novgorodov, SA, Gudz, TI. Ceramide and mitochondria in ischemia/reperfusion. J Cardiovasc Pharmacol. 2009; 53, 198–208.CrossRefGoogle ScholarPubMed
33. Jin, J, Hou, Q, Mullen, TD, et al. Ceramide generated by sphingomyelin hydrolysis and the salvage pathway is involved in hypoxia/reoxygenation-induced BAX redistribution to mitochondria in NT-2 cells. J Biol Chem. 2008; 283, 26509–26517.CrossRefGoogle ScholarPubMed
34. Zhu, Q, Lin, L, Cheng, Q, et al. The role of acid sphingomyelinase and caspase 5 in hypoxia-induced HuR cleavage and subsequent apoptosis in hepatocytes. Biochim Biophys Acta. 2012; 1821, 1453–1461.CrossRefGoogle ScholarPubMed
35. Dobrowsky, RT, Kolesnick, RN. Analysis of sphingomyelin and ceramide levels and the enzymes regulating their metabolism in response to cell stress. Methods Cell Biol. 2001; 66, 135–165.CrossRefGoogle ScholarPubMed
36. Aly, H, Khashaba, MT, El-Ayouty, M, El-Sayed, O, Hasanein, BM. IL-1beta, IL-6 and TNF-alpha and outcomes of neonatal hypoxic ischemic encephalopathy. Brain Dev. 2006; 28, 178–182.CrossRefGoogle ScholarPubMed
37. Gadient, RA, Otten, UH. Interleukin-6 (IL-6) – a molecule with both beneficial and destructive potentials. Prog Neurobiol. 1997; 52, 379–390.CrossRefGoogle ScholarPubMed
38. Sharma, S, Yang, B, Xi, X, et al. IL-10 directly protects cortical neurons by activating PI-3 kinase and STAT-3 pathways. Brain Res. 2011; 1373, 189–194.CrossRefGoogle ScholarPubMed
39. Park, KW, Lee, HG, Jin, BK, Lee, YB. Interleukin-10 endogenously expressed in microglia prevents lipopolysaccharide-induced neurodegeneration in the rat cerebral cortex in vivo. Exp Mol Med. 2007; 39, 812–819.CrossRefGoogle ScholarPubMed
40. Suzuki, S, Tanaka, K, Suzuki, N. Ambivalent aspects of interleukin-6 in cerebral ischemia: inflammatory versus neurotrophic aspects. J Cereb Blood Flow Metab. 2009; 29, 464–479.CrossRefGoogle ScholarPubMed
41. Sabat, R, Grutz, G, Warszawska, K, et al. Biology of interleukin-10. Cytokine Growth Factor Rev. 2010; 21, 331–344.CrossRefGoogle ScholarPubMed
42. Maulik, N, Engelman, RM, Rousou, JA, et al. Ischemic preconditioning reduces apoptosis by upregulating anti-death gene Bcl-2. Circulation. 1999; 100(Suppl. 19), II369–II375.CrossRefGoogle ScholarPubMed
43. Parsadanian, AS, Cheng, Y, Keller-Peck, CR, Holtzman, DM, Snider, WD. Bcl-XL is an antiapoptotic regulator for postnatal CNS neurons. J Neurosci. 1998; 18, 1009–1019.CrossRefGoogle ScholarPubMed
44. Wiessner, C, Allegrini, PR, Rupalla, K, et al. Neuron-specific transgene expression of Bcl-XL but not Bcl-2 genes reduced lesion size after permanent middle cerebral artery occlusion in mice. Neurosci Lett. 1999; 268, 119–122.CrossRefGoogle Scholar
45. Bonestroo, HJ, Nijboer, CH, van Velthoven, CT, et al. Cerebral and hepatic inflammatory response after neonatal hypoxia-ischemia in newborn rats. Dev Neurosci. 2013; 35, 197–211.CrossRefGoogle ScholarPubMed
46. Chamorro, A, Urra, X, Planas, AM. Infection after acute ischemic stroke: a manifestation of brain-induced immunodepression. Stroke. 2007; 38, 1097–1103.CrossRefGoogle ScholarPubMed
47. Grenz, A, Clambey, E, Eltzschig, HK. Hypoxia signaling during intestinal ischemia and inflammation. Curr Opin Crit Care. 2012; 18, 178–185.CrossRefGoogle ScholarPubMed
48. Barker, DJ. The origins of the developmental origins theory. J Intern Med. 2007; 261, 412–417.CrossRefGoogle ScholarPubMed
49. Vlassaks, E, Gavilanes, AWD, Bieghs, V, et al. Antenatal exposure to chorioamnionitis affects lipid metabolism in 7-week-old sheep. J Dev Orig Health Dis. 2012; 3, 103–110.CrossRefGoogle ScholarPubMed
50. Rueda-Clausen, CF, Dolinsky, VW, Morton, JS, et al. Hypoxia-induced intrauterine growth restriction increases the susceptibility of rats to high-fat diet-induced metabolic syndrome. Diabetes. 2011; 60, 507–516.CrossRefGoogle ScholarPubMed