Physiological and Biochemical Consequences of Exposure of Neonatal Rats to Chronic Hypoxia PAF and neonatal pulmonary hypertension
Main Article Content
Abstract
We studied effect of chronic hypoxia (CH) on expression of platelet activating factor receptor (PAFR) by neonatal rats (pups). We hypothesized that PAFR antagonist will prevent pulmonary hypertension (PH) in pups exposed to CH. Pups were placed in an air-tight chamber ventilated with 13% oxygen, hypoxia (Hpx) or room air normoxia (Nmx) from 1d to 22d of age. Three groups of pups were studied (each group, n=10-14 pups): Group1, pups in Nmx; Group2, pups in Hpx given 5mg/kg PAFR receptor antagonist, WEB 2170, IP, every other day for 22d, (Hpx+WEB); Group3, pups in Hpx control. Hemotocrit, RV/LV+S, PAF binding, PAF synthesis, and PAFR expression were determined. Hyx control group had 2-fold higher RV/LV+S than Nmx group and PAFR antagonist decreased RV/LV+S to the Nmx control value. Lungs of pups in Hpx expressed more PAFR protein than Hpx+WEB and Nmx groups. Additionally, Hpx increased PAF synthesis and PAFR binding whereas WEB treatment decreased PAFR binding, but produced no difference in PAF synthesis compared to Nmx group. Hpx increased NF-kB p65 and TLR4 expression. WEB treatment abrogated expression or NF-kB p65 and TLR4 proteins. Our findings show that chronic hypoxia induces expression of PAFR, NF-kB p65 and TLR4 by pups’ lungs and suggest that increased PAFR expression may be responsible for the right ventricular hypertrophy and PH. Thus a PAFR antagonist may offer a therapeutic intervention for CH-induced PH in human neonates.
Keywords:
chronic hypoxia, hypertrophy, PAF receptor, , NF-kB, TLR4
Article Details
How to Cite
IBE, Basil O.; ABDALLAH, May F.; RAJ, J. Usha.
Physiological and Biochemical Consequences of Exposure of Neonatal Rats to Chronic Hypoxia.
Medical Research Archives, [S.l.], v. 8, n. 10, oct. 2020.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/2249>. Date accessed: 21 dec. 2024.
doi: https://doi.org/10.18103/mra.v8i10.2249.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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doi: 10.1590/1414-431X20198092.
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21. Gao Y, Zhou H, Ibe BO, Raj JU. Prostaglandins E2 and I2 cause greater relaxations in pulmonary veins than in arteries of newborn lambs. J Appl Physiol. 1996;81(6):2534-2539.
Doi: 10. 1152/jappl.1996.81.6.2534.
22. Ibe BO, Abdallah MF, Portugal AM, Raj JU. Platelet-activating factor stimulates ovine foetal pulmonary vascular smooth muscle cell proliferation: role of nuclear factor-kappa B and cyclin-dependent kinases. Cell Prolif. 2008;41(2):208-229. doi: 10.1111/j.1365-2184.2008.00517.x.
23. Renteria LS, Cruz E, Ibe BO. Platelet-activating factor synthesis and receptor-mediated signaling are downregulated in ovine newborn lungs: relevance in postnatal pulmonary adaptation and persistent pulmonary hypertension of the newborn. J Dev Orig Health Dis. 2013;4(6): 458-469. doi: 10.1017/S2040174413000366.
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26. Welsh DJ and Peacock AJ. Cellular responses to hypoxia in the pulmonary circulation. High Alt Med Biol. 2013;14(2):111-116. doi: 10.1089/ham.2013.1016
27. Papamatheakis DG, Chandu M, Blood AB, Wilson SM. Prenatal programming of pulmonary hypertension induced by chronic hypoxia or ductal ligation in sheep. Pulm Circ. 2013;3(4):757-780. Doi: 10.1086/674767.
28. Hansmann G. Pulmonary hypertension in infants, children, and young adults. J Am Coll Cardiol. 2017;69(20):2551-2569. Doi.org/10.1016/j.acc.2017.03.575
29. Yang Q, Sun M, Ramchandran R, Raj JU. IGF-1 signaling in neonatal hypoxia-induced pulmonary hypertension: Role of epigenetic regulation. Vascul Pharmacol. 2015;73:20-31.
doi: 10.1016/j.vph.2015.04.005.
30. Ninio E, Joly F. (1991) Transmembrane signalling and paf-acether biosynthesis. Lipids. 1991;26(12):1034-7.
doi: 10.1007/BF02536497.
31. Ibe BO, Pham HH, Kääpä P, Raj JU. Maturational changes in ovine pulmonary metabolism of platelet-activating factor: implications for postnatal adaptation. Mol Genet Metab. 2001;74(3):385-395. doi: 10.1006/mgme.2001.3253.
32. Ibe BO, Portugal AM, Charturvedi S, Raj JU. Oxygen-dependent PAF receptor binding and intracellular signaling in ovine fetal pulmonary vascular smooth muscle. Am J Physiol Lung Cell Mol Physiol. 2005;288(5):L879-L886.
doi: 10.1152/ajplung.00341.2004.
33. Xu CL, Sun R, Qiao XJ, Xu CC, Shang XY, Niu WN. (2014) Protective effect of glutamine on intestinal injury and bacterial community in rats exposed to hypobaric hypoxia environment. World J Gastroenterol. 2014;20(16): 4662-4674. doi: 10.3748/wjg.v20.i16.4662
2. Dakshinamurti S. Pathophysiologic mechanisms of persistent pulmonary hypertension of the newborn. Pediatr Pulmonol. 2005;39(6): 492-503. doi: 10.1002/ppul.20201.
3. Geggel RL, Reid LM. The structural basis of PPHN. Clin perinatal. 1984;11(3): 525-549.
4. Adnot S, Raffestin B, Eddahibi S, Braquet P, Chabrier PE. Loss of endothelium-dependent relaxant activity in pulmonary circulation of rats exposed to chronic hypoxia. J Clin Invest. 1991;87(1):155-162. doi: 10. 1172/JCI114965.
5. Kennaugh JM JM, Kinsella JP, Abman SH, Hernandez JA, Moreland SG, Rosenberg AA. Impact of new treatments for neonatal pulmonary hypertension on extracorporeal membrane oxygenation use and outcome. J Perinatol. 1997;17(5):366-369.
6. Davis JM, Spitzer AR, Cox C, Fox WW. Predicting survival in infants with persistent pulmonary hypertension of the newborn. Pediatr Pulmonol. 1988;5(1):6-9. doi: 10. 1002/ppul.1950050103
7. Travadi JN, Patole SK. Phosphodiesterase inhibitors for persistent pulmonary hypertension of the newborn: a review. Pediatr Pulmonol. 2003;36(6): 529-535. doi: 10. 1002/ppul.10389.
8. Fukunaga K, Ishii S, Asano K, Yokomizo T, Shiomi T, Shimizu T, Yamaguchi K. Single nucleotide polymorphism of human platelet-activating factor (PAF) receptor impairs G-protein activation J Biol Chem. 2001;276(46):43025-43030. doi: 10.1074/jbc.M108288200.
9. Caplan MS, Hsueh W, Sun X-M, Gidding SS, Hageman JR. Circulating plasma platelet activating factor in persistent pulmonary hypertension of the newborn. Am Rev Respir Dis. 1990;142(6 Pt 1):1258-1262.
doi: 10. 1164/ajrccm/142.6_Pt_1.1258.
10. Ono S, Westcott JY, Voelkel NF. PAF antagonists inhibit pulmonary vascular remodeling induced by hypobaric hypoxia in rats. J Appl Physiol. 1992;73(3):1084-1092. doi: 10. 1152/jappl.1992.73.3.1084.
11. Chen D, Chen W. Changes of distribution of platelet activating factor in the lung of rats with hypoxic pulmonary hypertension. Chin Med J (Eng). 1996;109(10):776-779.
12. Ibe BO, Hibler S, Raj JU. Platelet-activating factor modulates vasomotor tone in the perinatal lamb. J Appl Physiol. 1998;85(3):1079-1085. doi. 1152/jappl.1998-85-3-1079.
13. Bixby CE, Ibe BO, Abdallah MF, Zhou W, Hislop AA, Longo LD, Raj JU. Role of platelet activating factor in pulmonary vascular remodeling associated with chronic high-altitude hypoxia in ovine fetal lambs. Am J Physiol Lung Cell Mol Physiol. 2007;293(6):L1475-L1482. doi: 10.1152/ajplung.00089.2007.
14. DiDonato JA, Mercurio F, Karin M. NF-kB and the link between inflammation and cancer. Immunol Rev. 2012;246(1):379-400. doi: 10.1111/j.1600-065X.2012.01099.x.
15. Ogbozor UD, Opene M, Renteria LS, McBride S, Ibe BO. Mechanism by which nuclear factor-kappa beta (NF-kB) regulates ovine fetal pulmonary vascular smooth muscle cell proliferation. Mol Genet Metab Rep. 2015;4:11-18. doi: 10.1016/j.ymgmr.2015.05.003.
16. Li Y, Yang L, Dong L, Yang Z-w, Zhang J, Zhang S-l, et t al. Crosstalk between the Akt/mTORC1 and NF-κB signaling pathways promotes hypoxia-induced pulmonary hypertension by increasing DPP4 expression in PASMCs. Acta Pharmacol Sinica. 2019;40(10):1322-1333. doi: 10.1038/s41401-019-0272-2.
17. Patel H, Zaghloul N, Lin K, Liu SF, Miller EJ, Ahmed M. Hypoxia-induced activation of specific members of the NF-kB family and its relevance to pulmonary vascular remodeling. Int J Biochem Cell Biol. 2017;92:141-147. doi: 10.1016/j.biocel.2017.09.022
18. Ibe BO, Portugal AM, Raj JU. Metabolism of platelet activating factor by intrapulmonary vascular smooth muscle cells. Effect of oxygen on phospholipase A2 protein expression and activities of acetyl-CoA acetyltransferase and cholinephosphotransferase. Mol Genet Metab. 2002;77(3):237-248. doi: 10.1016/s1096-7192(02)00147-6.
19. Wang J, Fan SH, Zhang J. Epigallocatechin-3-gallate ameliorates lipopolysaccharide-induced acute lung injury by suppression of TLR4/NF-κB signaling activation. Braz J Med Biol Res. 2019;52(7):1414-1431,e8092.
doi: 10.1590/1414-431X20198092.
20. Wang P, Han X, Mo B, Huang G, Wang C. LPS enhances TLR4 expression and IFN γ production via the TLR4/IRAK/NF κB signaling pathway in rat pulmonary arterial smooth muscle cells. Mol Med Rep. 2017;16(3):3111-3116. doi: 10.3892/mmr.2017.6983.
21. Gao Y, Zhou H, Ibe BO, Raj JU. Prostaglandins E2 and I2 cause greater relaxations in pulmonary veins than in arteries of newborn lambs. J Appl Physiol. 1996;81(6):2534-2539.
Doi: 10. 1152/jappl.1996.81.6.2534.
22. Ibe BO, Abdallah MF, Portugal AM, Raj JU. Platelet-activating factor stimulates ovine foetal pulmonary vascular smooth muscle cell proliferation: role of nuclear factor-kappa B and cyclin-dependent kinases. Cell Prolif. 2008;41(2):208-229. doi: 10.1111/j.1365-2184.2008.00517.x.
23. Renteria LS, Cruz E, Ibe BO. Platelet-activating factor synthesis and receptor-mediated signaling are downregulated in ovine newborn lungs: relevance in postnatal pulmonary adaptation and persistent pulmonary hypertension of the newborn. J Dev Orig Health Dis. 2013;4(6): 458-469. doi: 10.1017/S2040174413000366.
24. Birchard GF. Optimal hematocrit: Theory, Regulation and Implications. Integrative and comparative Biology. 1997;37(1) 67-92. Doi:10.1093/icb/37.1.65.
25. Zubieta-Calleja GR, Paulev PE, Zubieta-Castllo G. Altitude adaptation through hematocrit changes. J Physiol Pharmacol. 2007;58 (Suppl 5); 811-818.
26. Welsh DJ and Peacock AJ. Cellular responses to hypoxia in the pulmonary circulation. High Alt Med Biol. 2013;14(2):111-116. doi: 10.1089/ham.2013.1016
27. Papamatheakis DG, Chandu M, Blood AB, Wilson SM. Prenatal programming of pulmonary hypertension induced by chronic hypoxia or ductal ligation in sheep. Pulm Circ. 2013;3(4):757-780. Doi: 10.1086/674767.
28. Hansmann G. Pulmonary hypertension in infants, children, and young adults. J Am Coll Cardiol. 2017;69(20):2551-2569. Doi.org/10.1016/j.acc.2017.03.575
29. Yang Q, Sun M, Ramchandran R, Raj JU. IGF-1 signaling in neonatal hypoxia-induced pulmonary hypertension: Role of epigenetic regulation. Vascul Pharmacol. 2015;73:20-31.
doi: 10.1016/j.vph.2015.04.005.
30. Ninio E, Joly F. (1991) Transmembrane signalling and paf-acether biosynthesis. Lipids. 1991;26(12):1034-7.
doi: 10.1007/BF02536497.
31. Ibe BO, Pham HH, Kääpä P, Raj JU. Maturational changes in ovine pulmonary metabolism of platelet-activating factor: implications for postnatal adaptation. Mol Genet Metab. 2001;74(3):385-395. doi: 10.1006/mgme.2001.3253.
32. Ibe BO, Portugal AM, Charturvedi S, Raj JU. Oxygen-dependent PAF receptor binding and intracellular signaling in ovine fetal pulmonary vascular smooth muscle. Am J Physiol Lung Cell Mol Physiol. 2005;288(5):L879-L886.
doi: 10.1152/ajplung.00341.2004.
33. Xu CL, Sun R, Qiao XJ, Xu CC, Shang XY, Niu WN. (2014) Protective effect of glutamine on intestinal injury and bacterial community in rats exposed to hypobaric hypoxia environment. World J Gastroenterol. 2014;20(16): 4662-4674. doi: 10.3748/wjg.v20.i16.4662