Is caffeine a predisposing risk factor for developing intestinal injury in newborn rats?

Abstract

Purpose: To investigate of histopathologic and biochemical effects of caffeine citrate in newborn rats with hypoxia/reoxygenation (H/R)-induced intestinal injury.
Materials and methods: One-day-old, 32 Wistar albino newborn rats (n=8) were randomly divided into four groups: control group (group1, n=8), caffeine group (group2, caffeine citrate administered subcutaneously, n=8), H/R group (group3, exposed to H/R, n=8), and caffeine + H/R group (group4, caffeine citrate administered and exposed to H/R, n=8). Caffeine citrate was initiated at a loading dose of 20 mg/kg, followed by a maintenance dose of 5 mg/kg/day, subcutaneously. On day 4th, all animals except for groups 1 and 2 were exposed to H/R and sacrificed 6 hours after H/R procedure. Histopathological injury scores (HISs), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and oxidative stress index (OSI: total oxidant status “TOS”/total antioxidant status “TAS”) levels were measured in intestinal samples.
Results: As histopathological, the most severe damage was observed in H/R-induced groups (p<0.01). Although not statistically significant, the mean HISs of caffeine group was higher than the control group and lower than the H/R group. The levels of TNF-α, IL-6 and OSI in the groups 2, 3 and 4 were significantly higher than the control group (p<0.05). However, these biochemical parameters in the caffeine group were significantly lower than those of the H/R-induced groups (p<0.01).
Conclusion: This study showed that caffeine citrate significantly increased the intestinal tissue levels of TNF-α, IL-6, and OSI. As a result, caffeine may be a predisposing risk factor for developing intestinal injury.   

Keywords

• Caffeine
• intestinal injury
• newborn

Kafein sıçan yavrularında bağırsak hasarı gelişiminde predispozan bir risk faktörü mü?

Öz

Amaç: Hipoksi/reoksijenizasyon (H/R) ile intestinal hasarlanma oluşturulan sıçan yavrularında kafein sitratın histopatolojik ve biyokimyasal etkilerini araştırmak. Gereç ve yöntem: Bir günlük 32 Wistar albino sıçan yavrusu rastgele dört gruba ayrıldı: kontrol grubu (grup1, n=8), kafein grubu (grup2, subkutan kafein sitrat uygulanan, n=8), H/R grubu (grup3, H/R uygulanan, n=8) ve kafein+H/R grubu (grup4, kafein sitrat verilen ve H/R uygulanan, n=8). Kafein sitrat, 20 mg/kg'lık bir yükleme dozunda başlatıldı, ardından subkutan 5 mg/kg/günlük idame dozu takip edildi. Dördüncü günde, grup 1 ve 2 dışındaki tüm hayvanlar H/R'ye maruz bırakıldı ve H/R prosedüründen 6 saat sonra öldürüldü. Histopatolojik hasarlanma skorları (HIS), interlökin-6 (IL-6), tümör nekroz faktörü-alfa (TNF-α) ve oksidatif stres indeksi (OSI: toplam oksidan durum “TOS”/toplam antioksidan durum “TAS”) seviyeleri bağırsak örnekleri üzerinden değerlendirildi. Bulgular: Histopatolojik olarak en ciddi hasar H/R uygulanan gruplarda görüldü (p <0.01). Kafein grubunun ortalama HIS'leri kontrol grubundan daha yüksek iken, H/R grubundan daha düşüktü, ancak bu istatistiksel olarak anlamlı değildi. Grup 2, 3 ve 4'teki TNF-α, IL-6 ve OSI düzeyleri kontrol grubundan anlamlı olarak yüksekti (p <0.05). Bununla birlikte, kafein grubundaki bu biyokimyasal parametreler, H/R uygulanan gruplardan anlamlı olarak daha düşüktü (p <0.01). Sonuç: Bu çalışma, kafein sitratın TNF-α, IL-6 ve OSI'nin bağırsak doku düzeylerini önemli ölçüde arttırdığını gösterdi. Bu nedenle, kafeinin bağırsak hasarı geliştirmek için predispozan bir risk faktörü olabileceğini düşünüyoruz.

Anahtar Kelimeler

• Kafein
• intestinal hasarlanma
• yenidoğan

References

1. 1. Patrinos ME. Neonatal apnea and the foundation of respiratory control. In: Martin RJ, Fanaroff AA, Walsh MC, eds. Fanaroff and Martin’s neonatal-perinatal medicine: diseases of the fetus and infant. 10th ed. Philadelphia: Elsevier Saunders 2015;1137-1146.
2. 2. Schmidt B, Roberts RS, Davis P, et al. Caffeine therapy for apnea of prematurity. N Engl J Med 2006;18;354:2112-2121. https://doi.org/10.1056/NEJMoa054065
3. 3. Park HW, Lim G, Chung SH, Chung S, Kim KS, Kim SN. Early caffeine use in very low birth weight infants and neonatal outcomes: a systematic review and meta-analysis. J Korean Med Sci 2015;30:1828-1835. https://doi.org/10.3346/jkms.2015.30.12.1828
4. 4. Sweet DG1, Carnielli V, Greisen G, et al. European Consensus Guidelines on the management of respiratory distress syndrome - 2016 update. Neonatology 2017;111:107-125.doi: 10.1159/000448985
5. 5. Cox C, Hashem NG, Tebbs J, Bookstaver PB, Iskersky V. Evaluation of caffeine and the development of necrotizing enterecolitis. J Neonatal Perinatal Med 2015;8:339-347. https://doi.org/10.3233/NPM-15814059
6. 6. Abdel Wahed MA, Issa HM, Khafagy SM, Abdel Raouf SM. Effect of caffeine on superior mesenteric artery blood flow velocities in preterm neonates. J Matern Fetal Neonatal Med 2019;32:357-361. https://doi.org/10.1080/14767058.2017.1378337
7. 7. Welsh C, Pan J, Belik J. Caffeine impairs gastrointestinal function in newborn rats. Pediatr Res 2015;78:24-28. https://doi.org/10.1038/pr.2015.65
8. 8. Okur HM. Kücükaydın M, Köse K, Kontas O, Dogam P, Kazez A. Hypoxia-induced necrotizing enterocolitis in the immature rat: the role of lipid peroxidation and management by vitamin E. J Pediatr Surg 1995;30:1416-1419. https://doi.org/10.1016/0022-3468(95)90395-x

9. 9. Kabaroglu C, Akisu M, Habif S, et al. Effects of L-arginine and L-carnitine in hypoxia/reoxygenation-induced intestinal injury. Pediatr Int 2005;47:10-14. https://doi.org/10.1111/j.1442-200x.2005.01999.x
10. 10. Özkan KU, Özokutan BH, İnanç F, Boran C, Kilinc M. Does maternal nicotine exposure during gestation increase the injury severity of small intestine in the newborn rats subjected to experimental necrotizing enterocolitis. J Pediatr Surg 2005;40:484-488. https://doi.org/10.1016/j.jpedsurg.2004.11.040
11. 11. Erel O. A novel automated direct measurement method for total antioxidant capacity using a new generation, more stable ABTS radical cation. Clin Biochem 2004;37:277-285. https://doi.org/10.1016/j.clinbiochem.2003.11.015
12. 12. Erel O. A new automated colorimetric method for measuring total oxidant status. Clin Biochem 2005;38:1103-1111. https://doi.org/10.1016/j.clinbiochem.2005.08.008
13. 13. Caplan M. Neonatal necrotizing enterocolitis. In: Martin RJ, Fanaroff AA, Walsh MC, eds. Fanaroff and Martin’s neonatal-perinatal medicine: diseases of the fetus and infant.10th ed. Philadelphia: Elsevier Saunders 2015;1423-1432.
14. 14. Hagberg H, Bona E, Gilland E, Puka Sundvall M. Hypoxia-ischemia model in the 7-day old rat: possibilities and shortcomings. Acta Paediatr Suppl 1997;422:85-88. https://doi.org/10.1111/j.1651-2227.1997.tb18353.x
15. 15. Yossuck P, Kraszpulski M, Salm AK. Perinatal corticosteroid effect on amygdala and hippocampus volume during brain development in the rat model. Early Hum Dev 2006;82;267-272. https://doi.org/10.1016/j.earlhumdev.2005.09.017
16. 16. Özdemir ÖMA, Ergin H, Yenisey Ç, Şen Türk N. Protective effects of Ginkgo biloba extract in rats with hypoxia/reoxygenation-induced intestinal injury. J Pediatr Surg 2011;46:685-690. https://doi.org/10.1016/j.jpedsurg.2010.09.053
17. 17. Kumral A, Yesilirmak DC, Tugyan K, et al. Activated protein C reduces intestinal injury in an experimental model of necrotizing enterocolitis. J Pediatr Surg 2010;45:483-489. https://doi.org/10.1016/j.jpedsurg.2009.07.077
18. 18. Caplan MS, Sun XM, Hseuh W, Hageman JR. Role of platelet-activating factor and tumor necrosis factor-alpha in neonatal necrotizing enterocolitis. J Pediatr 1990;116:960-964. https://doi.org/10.1016/s0022-3476(05)80661-4
19. 19. Cakir U, Tayman C, Serkant UE, et al. Ginger (Zingiber officinale Roscoe) for the treatment and prevention of necrotizing enterocolitis. J Ethnopharmacol 2018;225:297-308. https://doi.org/10.1016/j.jep.2018.07.009
20. 20. Papparella A, DeLuca FG, Oyer CE, Pinar H, Stonestreet BS. Ischemia-reperfusion injury in the intestines of newborn pigs. Pediatr Res 1997;42:180-188. https://doi.org/10.1203/00006450-199708000-00009
21. 21. Miller MJ, McNeill H, Mullane KM, Caravella SJ, Clark DA. SOD prevents damage and attenuates eicosanoid release in a rabbit model of necrotizing enterocolitis. Am J Physiol 1988;255:556-565. https://doi.org/10.1152/ajpgi.1988.255.5.G556
22. 22. Granger DN, Höllwarth ME, Parks DA. Ischemia-reperfusion injury: role of oxygen-derived free radicals. Acta Physiol Scand Suppl 1986;548:47-63. PMID: 3529822
23. 23. Lodha A, Seshia M, McMillan DD, et al. Association of early caffeine administration and neonatal outcomes in very preterm neonates. JAMA Pediatr 2015;169:33-38. https://doi.org/10.1001/jamapediatrics.2014.2223
24. 24. Hoecker C, Nelle M, Poeschl J, Beedgen B, Linderkamp O. Caffeine impairs cerebral and intestinal blood flow velocity in preterm infants. Pediatrics 2002;109:784-787. https://doi.org/10.1542/peds.109.5.784
25. 25. Hoecker C, Nelle M, Beedgen B, Rengelshausen J, Linderkamp O. Effects of a divided high loading dose of caffeine on circulatory variables in preterm infants. Arch Dis Child Fetal Neonatal Ed 2006;91:61-64. https://doi.org/10.1136/adc.2005.073866
26. 26. Soraisham AS, Elliott D, Amin H. Effect of single loading dose of intravenous caffeine infusion on superior mesenteric artery blood flow velocities in preterm infants. J Paediatr Child Health 2008;44:119-121. https://doi.org/10.1111/j.1440-1754.2007.01211.x