Document Type : Original Article

Authors

1 Department of Pediatrics, North Khorasan University of Medical Sciences, Bojnurd, Iran

2 Department of Obstetrics and Gynecology, School of Medicine, University of Texas Medical Branch, Texas, USA

3 Department of Pathobiology and Laboratory Sciences, North Khorasan University of Medical Sciences, Bojnurd, Iran

Abstract

Background: Neonatal hypoxic-ischemic encephalopathy (HIE) is one of the most common causes of long-term neurological disabilities among children. Various types of cellular stress stimuli, including oxidative stress, inflammation, and hypoxia, induce heme oxygenase-1 (HO-1) enzyme for different kinds of tissues. The purpose of this study was to evaluate the plasma level of HO-1 enzyme in neonatal HIE patients and to determine the relationship between HO-1 enzyme level and clinical severity of HIE.
Methods: In this case-control study, the plasma level of HO-1 enzyme was measured through sandwich ELISA in 28 newborns with a proven diagnosis of HIE and 31 healthy full-term newborns admitted to Bentolhoda Hospital, Bojnourd, Iran. Newborns with HIE were classified according to the Sarnat staging to mild, moderate, and severe HIE. Maternal and neonatal data were recorded in checklists and compared between the two groups.
Results: The mean plasma level of HO-1 enzyme in HIE patients was significantly higher than that in the control group (104.0 ± 4.01 and 91.63± 2.67 pg/ml, respectively, P=0.011). We also found that plasma HO-1 levels were significantly higher in severe neonatal HIE patients compared to mild and moderate neonatal HIE patients (121.0 ± 8.48Vs. 91.23 ± 3.35 and 105.5 ± 5.76,
P ˂ 0.001).
Conclusion: Our findings suggested that HO-1enzyme may be associated with the pathophysiology and clinical severity of neonatal HIE. We suggest further research on the correlation of plasma level of HO-1 enzyme at birth with the multi-organ dysfunction and abnormal neurodevelopmental outcomes in full-term newborns with HIE.

Keywords

  1. Mishra J, Dent C, Tarabishi R, Mitsnefes MM, Ma Q, Kelly C, et al. Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery. Lancet. 2005; 365(9466):1231-8. doi: 10.1016/S0140-6736(05)74811-X.
  2. Sánchez Illana Á, Piñeiro Ramos JD, Kuligowski J. Small molecule biomarkers for neonatal hypoxic ischemic encephalopathy. Semin Fetal Neonatal Med. 2020; 25(2):101084. doi: 10.1016/j.siny.2020.101084.
  3. Babiker MS, Omer AM, Al Oufi AR. Evaluation of neonatal hypoxic-ischemic encephalopathy by MRI and ultrasound. Journal of Diagnostic Medical Sonography. 2013; 29(4):159-64. doi: 10.1177/8756479313484549.
  4. Kurinczuk JJ, White Koning M, Badawi N. Epidemiology of neonatal encephalopathy and hypoxic–ischaemic encephalopathy. Early Hum Dev. 2010; 86(6):329-38. doi: 10.1016/j.earlhumdev.2010.05.010.
  5. Yıldız EP, Ekici B, Tatlı B. Neonatal hypoxic ischemic encephalopathy: An update on disease pathogenesis and treatment. Expert Rev Neurother. 2017; 17(5):449-59. doi: 10.1080/14737175.2017.1259567.
  6. Greco P, Nencini G, Piva I, Scioscia M, Volta CA, Spadaro S, et al. Pathophysiology of hypoxic–ischemic encephalopathy: A review of the past and a view on the future. Acta Neurol Belg. 2020; 120(2):277-88. doi: 10.1007/s13760-020-01308-3.
  7. Allen KA, Brandon DH. Hypoxic ischemic encephalopathy: Pathophysiology and experimental treatments. Newborn Infant Nurs Rev. 2011; 11(3):125-33. doi: 10.1053/j.nainr.2011.07.004.
  8. Millar LJ, Shi L, Hoerder Suabedissen A, Molnár Z. Neonatal hypoxia ischaemia: Mechanisms, models, and therapeutic challenges. Front Cell Neurosci. 2017; 11:78. doi: 10.3389/fncel.2017.00078.
  9. Vreman HJ, Wong RJ, Stevenson DK, Engel RR. Role of carbon monoxide and nitric oxide in newborn infants with postasphyxial hypoxic-ischemic encephalopathy. Pediatrics. 2002; 109(4):715-6; author reply 715-6. doi: 10.1542/peds.109.4.715.
  10. Ryter SW, Choi AM. Heme oxygenase-1/carbon monoxide: From metabolism to molecular therapy. Am J Respir Cell Mol Biol. 2009; 41(3):251-60. doi: 10.1165/rcmb.2009-0170TR.
  11. Soares MP, Bach FH. Heme oxygenase-1: From biology to therapeutic potential. Trends in molecular medicine. 2009; 15(2):50-8. doi: 10.1016/j.molmed.2008.12.004.
  12. Qin X, Cheng J, Zhong Y, Mahgoub OK, Akter F, Fan Y, et al. Mechanism and treatment related to oxidative stress in neonatal hypoxic-ischemic encephalopathy. Front Mol Neurosci. 2019; 12:88. doi: 10.3389/fnmol.2019.00088.
  13. Dani C, Poggi C, Fancelli C, Pratesi S. Changes in bilirubin in infants with hypoxic–ischemic encephalopathy. Eur J Pediatr. 2018; 177(12):1795-1801. doi: 10.1007/s00431-018-3245-4.
  14. Bergeron M, Ferriero DM, Vreman HJ, Stevenson DK, Sharp FR. Hypoxia-ischemia, but not hypoxia alone, induces the expression of heme oxygenase-1 (HSP32) in newborn rat brain. J Cereb Blood Flow Metab. 1997; 17(6):647-58. doi: 10.1097/00004647-199706000-00006.
  15. Martinello K, Hart AR, Yap S, Mitra S, Robertson NJ. Management and investigation of neonatal encephalopathy: 2017 update. Arch Dis Child Fetal Neonatal Ed. 2017; 102(4):F346-F58. doi: 10.1136/archdischild-2015-309639.
  16. Wang Z, Zhang P, Zhou W, Xia S, Zhou W, Zhou X, et al. Neonatal hypoxic-ischemic encephalopathy diagnosis and treatment: A National Survey in China. BMC Pediatr. 2021; 21(1):261. doi: 10.1186/s12887-021-02737-6.
  17. Mia AH, Akter KR, Rouf MA, Islam MN, Hoque MM, Hossain MA, et al. Grading of perinatal asphyxia by clinical parameters and agreement between this grading and Sarnat & Sarnat stages without measures. Mymensingh Med J. 2013; 22(4):807-13. PMID: 24292315.
  18. Mrelashvili A, Russ JB, Ferriero DM, Wusthoff CJ. The Sarnat score for neonatal encephalopathy: Looking back and moving forward. Pediatr Res. 2020; 88(6):824-5. doi: 10.1038/s41390-020-01143-5.
  19. Dong Z, Lavrovsky Y, Venkatachalam MA, Roy AK. Heme oxygenase-1 in tissue pathology: The Yin and Yang. Am J Pathol. 2000; 156(5):1485-8. doi: 10.1016/S0002-9440(10)65019-5.
  20. Pachori AS, Smith A, McDonald P, Zhang L, Dzau VJ, Melo LG. Heme-oxygenase-1-induced protection against hypoxia/reoxygenation is dependent on biliverdin reductase and its interaction with PI3K/Akt pathway. J Mol Cell Cardiol. 2007; 43(5):580-92. doi: 10.1016/j.yjmcc.2007.08.003.
  21. Araujo JA, Zhang M, Yin F. Heme oxygenase-1, oxidation, inflammation, and atherosclerosis. Front Pharmacol. 2012; 3:119. doi: 10.3389/fphar.2012.00119.
  22. Li S, Fujino M, Takahara T, Li XK. Protective role of heme oxygenase-1 in fatty liver ischemia–reperfusion injury. Med Mol Morphol. 2019; 52(2):61-72. doi: 10.1007/s00795-018-0205-z.
  23. Gupta A, Lacoste B, Pistell PJ, Ingram DK, Hamel E, Alaoui Jamali MA, et al. Neurotherapeutic effects of novel HO‐1 inhibitors in vitro and in a transgenic mouse model of Alzheimer's disease. J Neurochem. 2014; 131(6):778-90. doi: 10.1111/jnc.12927.
  24. Ding Y, Chen M, Wang M, Wang M, Zhang T, Park J, et al. Neuroprotection by acetyl-11-keto-β-boswellic acid, in ischemic brain injury involves the Nrf2/HO-1 defense pathway. Sci Rep. 2014; 4:7002. doi: 10.1038/srep07002.
  25. Zhao H, Mitchell S, Koumpa S, Cui YT, Lian Q, Hagberg H, et al. Heme oxygenase-1 mediates neuroprotection conferred by argon in combination with hypothermia in neonatal hypoxia–ischemia brain injury. Anesthesiology. 2016; 125(1):180-92. doi: 10.1097/ALN.0000000000001128.
  26. Lai MC, Yang SN. Perinatal hypoxic-ischemic encephalopathy. J Biomed Biotechnol. 2011; 2011:609813. doi: 10.1155/2011/609813.
  27. Appleton SD, Lash GE, Marks GS, Nakatsu K, Brien JF, Smith GN, et al. Effect of glucose and oxygen deprivation on heme oxygenase expression in human chorionic villi explants and immortalized trophoblast cells. Am J Physiol Regul Integr Comp Physiol. 2003; 285(6):1453-60. doi: 10.1152/ajpregu.00234.2003.
  28. Nitti M, Piras S, Brondolo L, Marinari UM, Pronzato MA, Furfaro AL. Heme oxygenase 1 in the nervous system: Does it favor neuronal cell survival or induce neurodegeneration? Int J Mol Sci. 2018; 19(8):2260. doi: 10.3390/ijms19082260.