DOI 10.1515/jpem-2013-0418 J Pediatr Endocr Met 2014; 27(7-8): 799–800
Letter to the Editor Raffaella Mormile*
Vitamin D intake and premature infants with intraventricular hemorrhage: how advisable is it? Keywords: intraventricular hemorrhage; preterm infant; Vitamin D. *Corresponding author: Raffaella Mormile, MD, Division of Pediatrics and Neonatology, Moscati Hospital, Via A. Gramsci, 3-81031 Aversa, Italy, Phone: +390815001503, Mobile: +393392045468, E-mail: [email protected]
Preterm neonates are at high risk for rickets (1, 2). This condition in them is almost always linked to the reduced total absorbed calcium and phosphorus (1, 2). A decrease in the absorption of these minerals may be correlated with either low intake or low absorption efficiency (1). Although special attention is focused on calcium ingestion, the very high urinary calcium concentrations demonstrated in preterm infants fed unfortified human milk advises that phosphorus deficiency is at least as important, if not more important, than calcium paucity in the etiology of rickets (1). The most important measure to prevent rickets in the preterm neonates is incorporating high mineral content to their diet even if optimal or safest forms and doses of calcium and phosphorus remain unclear (1). Vitamin D increases the absorption efficiency of both calcium and phosphorus (1). Low serum concentrations of vitamin D are common in preterm neonates during the birth and at the time of discharge from the neonatal intensive care unit due to the lack of sunlight exposure and difficulty in ensuring sufficient enteral nutrition (2). The European Society for Paediatrics Gastroenterology, Hepatology and Nutrition have recommended vitamin D intake in the range of 800–1000 UI/day for preterm neonates (2). However, the exact timing and the proportion of vitamin D-dependent absorption of calcium and phosphorus in preterm neonates are unknown (1). The preterm neonates show calcium absorption as being relatively constant across a wide range of intakes (1). Moreover, most calcium absorption may not depend on the vitamin D in the 1st month after birth but rather takes place primarly via a passive, paracellular absorption (1). Although previous research done in this area
proposed an effect of high dose of vitamin D on calcium absorption, to date no such unequivocal data have been reported (1). Intraventricular hemorrhage (IVH) is one of the most severe complications of prematurity and a common cause of death in this category of neonates (3, 4). IVH frequently results in severe long-term neurologic disability that constitutes a worldwide public health problem (1, 2). The high prevalence of permanent neurological sequelae in preterm neonates has emphasized the need for better neuroprotective strategies (3, 4). Despite significant efforts made to clarify the pathophysiology of IVH, prevention of brain damage represents an unsolved problem (1). The pathogenesis of IVH in preterm neonates involves a number of mechanisms leading to neuronal damage including apoptosis (3, 4). Apoptosis in lesions of the central nervous system (CNS) represents a major type of cell death (4). Apoptotic features have been associated with the evolution of neurodevelopmental deficits and cerebral palsy of the preterm neonates (4). Although apoptosis plays a critical role during the development of the brain, it can also be induced by hypoxic/ischemic insult such as injury occurring in most of the preterm neonates (4, 5). Anti-apoptosis genes such as survivin are also present in the human fetal tissues as the regulators of tissue differentiations including brain and contribute to tissue homeostasis during the fetal life (5, 6). Survivin is a member of the inhibitor of apoptosis gene family of proteins that is widely expressed in cancer cells where it can suppress both caspase-dependent- and -independent apoptotic cell death (6). Survivin has been described as a biomarker predictive of an aggressive cancer because of its promoting effects on tumor progression and drug resistance with short-term survival of the patients (6, 7). Even if it is barely detectable in normal tissues, survivin expression can be reactivated by a number of prosurvival stimuli (6). Although survivin level is considered as an unfavorable prognostic factor in cancer, it seems to have a crucial anti-apoptosis role in vascular cell responses to injuries including ischemia (7, 8). A growing body of evidence indicates that survivin may limit brain tissue damage improving functional outcome (6–8). An
Brought to you by | University of California - San Francisco Authenticated Download Date | 2/17/15 10:32 AM
800 Mormile: Vitamin D intake and premature infants with intraventricular hemorrhage: how advisable is it? apoptotic cell death during the phase of reperfusion is an important contributor to lethal reperfusion-induced injury (9). The enhancement of re-endothelialization represents an important therapeutic option for repairing injured blood vessels (8, 9). A brain injury may induce survivin expression (6). Survivin seems to be a key determinant in enhancing neural cell survival after a traumatic brain injury and in response to hypoxia/ischemia (7, 8). Hypoxic preconditioning has been shown to protect human brain endothelium from ischemic apoptosis by PI3-kinase/Akt-dependent survivin activation (7). Endothelial progenitor cells (EPC) are the major source of cells connected with endothelium repair and re-endothelialization (9). Id1/PI3K/Akt/NFkB/survivin signaling pathway plays an essential role in the EPC proliferation (9). According to the findings, vitamin D is linked to the inhibition of cell proliferation and induction of apoptosis in a variety of cancer cell models through the suppression of the expression of survivin (10, 11). Conversely, it has been proved that survivin expression could be significantly upregulated by calcium (12). Intriguingly, the less calcemic vitamin D analogue TX 527 has been demo nstrated to inhibit the proliferation of endothelial cells by negative modulation on NF-κB pathway (13). Thus, we advance the hypothesis that vitamin D may be not
advisable in preterm neonates with IVH-inhibiting survivin that is involved in re-endothelialization after vascular injury by PI3K/AKT/NFkB/survivin signaling pathway. On the contrary, calcium intake may be recommended in these infants for increasing survivin levels. The identification of signal interactions associated with survivin regulation and function at cellular level may provide novel therapeutic strategies to prevent rickets and ameliorate the prognosis after IVH in preterm neonates. The research studies are needed to implement direct supplementation with added calcium and phosphorous via ideal oral form delaying administration of vitamin D at the time of discharge from the hospital. The minimum effective and maximum safe doses of minerals and vitamin D for the preterm neonates with IVH should more appropriately be defined in order to verify the levels of vitamin D above which supplementations may not be safe for recovering from the brain injury downregulating survivin expression. The upregulation of survivin may be considered a future potential approach for brain injury therapy in the preterm neonates with IVH.
Received October 23, 2013; accepted February 18, 2014; previously published online March 26, 2014
References 1. Abrams SA and the Committee on Nutrition Pediatrics. 2013;131:e1676–83. 2. Monangi N, Slaughter JL, Dawodu A, Smith C, Akinbi HT. Vitamin D status of early preterm infants and the effects of vitamin D intake during hospital stay. Arch Dis Child Fetal Neonatal 2014;99:F166–68 3. Ballabh P. Intraventricular hemorrhage in premature infants: mechanism of disease. Ped Res 2010;67:1–8. 4. Hargital B, Szabo V, Hajdu J, Harmath A, Pataki M, Farid P, et al. Apoptosis in various organs of preterm infants: histopathologic study of lung, kidney, liver, and brain of ventilated infants. Ped Res 2001;50:110–4. 5. Falkowski A, Hammond R, Han V, Richardson B. Apoptosis in the preterm and near term ovine fetal brain and the effect of intermittent umbelical cord occlusion. Dev Brain Res 2002;136:165–73. 6. Li F, Brattain MG. Role of the survivin gene in pathophysiology. Am J Pathol 2006;169:1–11. 7. Zhang Y, Park TS, Gidday JM. Hypoxic preconditioning protects human brain endothelium from ischemic apoptotis by Akt-dependent survivin activation. Am J Physiol Heart Circ Physiol 2007;292:H2573–81. 8. Conway EM, Zwerts F, Van Eygen V, De Vriese A, Nagai N, Luo W, et al. Survivin-dependent angiogenesis in ischemic brain: molecular mechanism of hypoxia-induced up-regulation. Am J Pathol 2003;163:935–46.
9. Wei L, Wang H, Kuang CY, Zhu JK, Yu Y, Qui ZX. An essential role for the Id1/PI3K/Akt/NFkB/survivin signalling pathway in promoting the proliferation of endothelial progenitor cells in vitro. Mol Cell Biochem 2012;363:135–45. 10. Li F, Ling X, Huang H, Brattain L, Apontes P, Wu J, et al. Differential regulation of survivin expression and apoptosis by vitamin D3 compounds in two isogenic MCF-7 breast cancer cell sublines. Oncogene 2005;24:1385. 11. Koike H, Morikawa Y, Sekine Y, Matsui H, Shibata Y, Suzuki K. Survivin is associated with cell proliferation and has a role in 1α,25-dihydroxyvitamin D3 induced cell growth inhibition in prostate cancer. J Urol 2011;185:1497–503. 12. González-Pardo V, Verstuyf A, Boland R, Russo de Boland A. Vitamin D analogue TX 527 down-regulates the NF-κB pathway and controls the proliferation of endothelial cells transformed by Kaposi sarcoma herpesvirus. Br J Pharmacol 2013;169:1635–45. 13. Ortiz J, Chou LL. Calcium upregulated survivin expression and asociated osteogenesis of normal human osteoblasts. J Biomed Marer Res A 2012;100:1770–6.
Article note: In memory of Professor Luciano Tatò.
Brought to you by | University of California - San Francisco Authenticated Download Date | 2/17/15 10:32 AM
Letter to the Editor Raffaella Mormile*
Vitamin D intake and premature infants with intraventricular hemorrhage: how advisable is it? Keywords: intraventricular hemorrhage; preterm infant; Vitamin D. *Corresponding author: Raffaella Mormile, MD, Division of Pediatrics and Neonatology, Moscati Hospital, Via A. Gramsci, 3-81031 Aversa, Italy, Phone: +390815001503, Mobile: +393392045468, E-mail: [email protected]
Preterm neonates are at high risk for rickets (1, 2). This condition in them is almost always linked to the reduced total absorbed calcium and phosphorus (1, 2). A decrease in the absorption of these minerals may be correlated with either low intake or low absorption efficiency (1). Although special attention is focused on calcium ingestion, the very high urinary calcium concentrations demonstrated in preterm infants fed unfortified human milk advises that phosphorus deficiency is at least as important, if not more important, than calcium paucity in the etiology of rickets (1). The most important measure to prevent rickets in the preterm neonates is incorporating high mineral content to their diet even if optimal or safest forms and doses of calcium and phosphorus remain unclear (1). Vitamin D increases the absorption efficiency of both calcium and phosphorus (1). Low serum concentrations of vitamin D are common in preterm neonates during the birth and at the time of discharge from the neonatal intensive care unit due to the lack of sunlight exposure and difficulty in ensuring sufficient enteral nutrition (2). The European Society for Paediatrics Gastroenterology, Hepatology and Nutrition have recommended vitamin D intake in the range of 800–1000 UI/day for preterm neonates (2). However, the exact timing and the proportion of vitamin D-dependent absorption of calcium and phosphorus in preterm neonates are unknown (1). The preterm neonates show calcium absorption as being relatively constant across a wide range of intakes (1). Moreover, most calcium absorption may not depend on the vitamin D in the 1st month after birth but rather takes place primarly via a passive, paracellular absorption (1). Although previous research done in this area
proposed an effect of high dose of vitamin D on calcium absorption, to date no such unequivocal data have been reported (1). Intraventricular hemorrhage (IVH) is one of the most severe complications of prematurity and a common cause of death in this category of neonates (3, 4). IVH frequently results in severe long-term neurologic disability that constitutes a worldwide public health problem (1, 2). The high prevalence of permanent neurological sequelae in preterm neonates has emphasized the need for better neuroprotective strategies (3, 4). Despite significant efforts made to clarify the pathophysiology of IVH, prevention of brain damage represents an unsolved problem (1). The pathogenesis of IVH in preterm neonates involves a number of mechanisms leading to neuronal damage including apoptosis (3, 4). Apoptosis in lesions of the central nervous system (CNS) represents a major type of cell death (4). Apoptotic features have been associated with the evolution of neurodevelopmental deficits and cerebral palsy of the preterm neonates (4). Although apoptosis plays a critical role during the development of the brain, it can also be induced by hypoxic/ischemic insult such as injury occurring in most of the preterm neonates (4, 5). Anti-apoptosis genes such as survivin are also present in the human fetal tissues as the regulators of tissue differentiations including brain and contribute to tissue homeostasis during the fetal life (5, 6). Survivin is a member of the inhibitor of apoptosis gene family of proteins that is widely expressed in cancer cells where it can suppress both caspase-dependent- and -independent apoptotic cell death (6). Survivin has been described as a biomarker predictive of an aggressive cancer because of its promoting effects on tumor progression and drug resistance with short-term survival of the patients (6, 7). Even if it is barely detectable in normal tissues, survivin expression can be reactivated by a number of prosurvival stimuli (6). Although survivin level is considered as an unfavorable prognostic factor in cancer, it seems to have a crucial anti-apoptosis role in vascular cell responses to injuries including ischemia (7, 8). A growing body of evidence indicates that survivin may limit brain tissue damage improving functional outcome (6–8). An
Brought to you by | University of California - San Francisco Authenticated Download Date | 2/17/15 10:32 AM
800 Mormile: Vitamin D intake and premature infants with intraventricular hemorrhage: how advisable is it? apoptotic cell death during the phase of reperfusion is an important contributor to lethal reperfusion-induced injury (9). The enhancement of re-endothelialization represents an important therapeutic option for repairing injured blood vessels (8, 9). A brain injury may induce survivin expression (6). Survivin seems to be a key determinant in enhancing neural cell survival after a traumatic brain injury and in response to hypoxia/ischemia (7, 8). Hypoxic preconditioning has been shown to protect human brain endothelium from ischemic apoptosis by PI3-kinase/Akt-dependent survivin activation (7). Endothelial progenitor cells (EPC) are the major source of cells connected with endothelium repair and re-endothelialization (9). Id1/PI3K/Akt/NFkB/survivin signaling pathway plays an essential role in the EPC proliferation (9). According to the findings, vitamin D is linked to the inhibition of cell proliferation and induction of apoptosis in a variety of cancer cell models through the suppression of the expression of survivin (10, 11). Conversely, it has been proved that survivin expression could be significantly upregulated by calcium (12). Intriguingly, the less calcemic vitamin D analogue TX 527 has been demo nstrated to inhibit the proliferation of endothelial cells by negative modulation on NF-κB pathway (13). Thus, we advance the hypothesis that vitamin D may be not
advisable in preterm neonates with IVH-inhibiting survivin that is involved in re-endothelialization after vascular injury by PI3K/AKT/NFkB/survivin signaling pathway. On the contrary, calcium intake may be recommended in these infants for increasing survivin levels. The identification of signal interactions associated with survivin regulation and function at cellular level may provide novel therapeutic strategies to prevent rickets and ameliorate the prognosis after IVH in preterm neonates. The research studies are needed to implement direct supplementation with added calcium and phosphorous via ideal oral form delaying administration of vitamin D at the time of discharge from the hospital. The minimum effective and maximum safe doses of minerals and vitamin D for the preterm neonates with IVH should more appropriately be defined in order to verify the levels of vitamin D above which supplementations may not be safe for recovering from the brain injury downregulating survivin expression. The upregulation of survivin may be considered a future potential approach for brain injury therapy in the preterm neonates with IVH.
Received October 23, 2013; accepted February 18, 2014; previously published online March 26, 2014
References 1. Abrams SA and the Committee on Nutrition Pediatrics. 2013;131:e1676–83. 2. Monangi N, Slaughter JL, Dawodu A, Smith C, Akinbi HT. Vitamin D status of early preterm infants and the effects of vitamin D intake during hospital stay. Arch Dis Child Fetal Neonatal 2014;99:F166–68 3. Ballabh P. Intraventricular hemorrhage in premature infants: mechanism of disease. Ped Res 2010;67:1–8. 4. Hargital B, Szabo V, Hajdu J, Harmath A, Pataki M, Farid P, et al. Apoptosis in various organs of preterm infants: histopathologic study of lung, kidney, liver, and brain of ventilated infants. Ped Res 2001;50:110–4. 5. Falkowski A, Hammond R, Han V, Richardson B. Apoptosis in the preterm and near term ovine fetal brain and the effect of intermittent umbelical cord occlusion. Dev Brain Res 2002;136:165–73. 6. Li F, Brattain MG. Role of the survivin gene in pathophysiology. Am J Pathol 2006;169:1–11. 7. Zhang Y, Park TS, Gidday JM. Hypoxic preconditioning protects human brain endothelium from ischemic apoptotis by Akt-dependent survivin activation. Am J Physiol Heart Circ Physiol 2007;292:H2573–81. 8. Conway EM, Zwerts F, Van Eygen V, De Vriese A, Nagai N, Luo W, et al. Survivin-dependent angiogenesis in ischemic brain: molecular mechanism of hypoxia-induced up-regulation. Am J Pathol 2003;163:935–46.
9. Wei L, Wang H, Kuang CY, Zhu JK, Yu Y, Qui ZX. An essential role for the Id1/PI3K/Akt/NFkB/survivin signalling pathway in promoting the proliferation of endothelial progenitor cells in vitro. Mol Cell Biochem 2012;363:135–45. 10. Li F, Ling X, Huang H, Brattain L, Apontes P, Wu J, et al. Differential regulation of survivin expression and apoptosis by vitamin D3 compounds in two isogenic MCF-7 breast cancer cell sublines. Oncogene 2005;24:1385. 11. Koike H, Morikawa Y, Sekine Y, Matsui H, Shibata Y, Suzuki K. Survivin is associated with cell proliferation and has a role in 1α,25-dihydroxyvitamin D3 induced cell growth inhibition in prostate cancer. J Urol 2011;185:1497–503. 12. González-Pardo V, Verstuyf A, Boland R, Russo de Boland A. Vitamin D analogue TX 527 down-regulates the NF-κB pathway and controls the proliferation of endothelial cells transformed by Kaposi sarcoma herpesvirus. Br J Pharmacol 2013;169:1635–45. 13. Ortiz J, Chou LL. Calcium upregulated survivin expression and asociated osteogenesis of normal human osteoblasts. J Biomed Marer Res A 2012;100:1770–6.
Article note: In memory of Professor Luciano Tatò.
Brought to you by | University of California - San Francisco Authenticated Download Date | 2/17/15 10:32 AM
