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Respiratory Research
Published in: Respiratory Research 1/2023

Open Access 01-12-2023 | Patent Ductus Arteriosus | Research

Vascular and pulmonary effects of ibuprofen on neonatal lung development

Authors: Xueyu Chen, Dongshan Han, Xuan Wang, Xuemei Huang, Zilu Huang, Yijun Liu, Junyan Zhong, Frans J. Walther, Chuanzhong Yang, Gerry T. M. Wagenaar

Published in: Respiratory Research | Issue 1/2023

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Abstract

Background

Ibuprofen is a nonsteroidal anti-inflammatory drug that is commonly used to stimulate closure of a patent ductus arteriosus (PDA) in very premature infants and may lead to aberrant neonatal lung development and bronchopulmonary dysplasia (BPD).

Methods

We investigated the effect of ibuprofen on angiogenesis in human umbilical cord vein endothelial cells (HUVECs) and the therapeutic potential of daily treatment with 50 mg/kg of ibuprofen injected subcutaneously in neonatal Wistar rat pups with severe hyperoxia-induced experimental BPD. Parameters investigated included growth, survival, lung histopathology and mRNA expression.

Results

Ibuprofen inhibited angiogenesis in HUVECs, as shown by reduced tube formation, migration and cell proliferation via inhibition of the cell cycle S-phase and promotion of apoptosis. Treatment of newborn rat pups with ibuprofen reduced pulmonary vessel density in the developing lung, but also attenuated experimental BPD by reducing lung inflammation, alveolar enlargement, alveolar septum thickness and small arteriolar wall thickening.

Conclusions

In conclusion, ibuprofen has dual effects on lung development: adverse effects on angiogenesis and beneficial effects on alveolarization and inflammation. Therefore, extrapolation of the beneficial effects of ibuprofen to premature infants with BPD should be done with extreme caution.
Literature
1.
Morty RE. Recent advances in the pathogenesis of BPD. Semin Perinatol. 2018;42:404–12.CrossRef
2.
Thébaud B, Goss KN, Laughon M, Whitsett JA, Abman SH, Steinhorn RH, Aschner JL, Davis PG, McGrath-Morrow SA, Soll RF, Jobe AH. Bronchopulmonary dysplasia. Nat Rev Dis Prim. 2019;5:78.CrossRef
3.
Principi N, Di Pietro GM, Esposito S. Bronchopulmonary dysplasia: clinical aspects and preventive and therapeutic strategies. J Transl Med. 2018;16:36.CrossRef
4.
Islam JY, Keller RL, Aschner JL, Hartert TV, Moore PE. Understanding the short- and long-term respiratory outcomes of prematurity and bronchopulmonary dysplasia. Am J Respir Crit Care Med. 2015;192:134–56.CrossRef
5.
Baraldi E, Filippone M. Chronic lung disease after premature birth. N Engl J Med. 2007;357:1946–55.CrossRef
6.
McGrath-Morrow SA, Collaco JM. Bronchopulmonary dysplasia: what are its links to COPD? Ther Adv Respir Dis. 2019;13:1753466619892492.CrossRef
7.
O’Reilly M, Thébaud B. Animal models of bronchopulmonary dysplasia. The term rat models. Am J Physiol Lung Cell Mol Physiol. 2014;307:L948–58.CrossRef
8.
Chen X, Walther FJ, Sengers RM, el Laghmani H, Salam A, Folkerts G, Pera T, Wagenaar GT. Metformin attenuates hyperoxia-induced lung injury in neonatal rats by reducing the inflammatory response. Am J Physiol Lung Cell Mol Physiol. 2015;309:L262-270.CrossRef
9.
Visser YP, Walther FJ, el Laghmani H, Laarse A, Wagenaar GT. Apelin attenuates hyperoxic lung and heart injury in neonatal rats. Am J Respir Crit Care Med. 2010;182:1239–50.CrossRef
10.
Wagenaar GT, ter Horst SA, van Gastelen MA, Leijser LM, Mauad T, van der Velden PA, de Heer E, Hiemstra PS, Poorthuis BJ, Walther FJ. Gene expression profile and histopathology of experimental bronchopulmonary dysplasia induced by prolonged oxidative stress. Free Radic Biol Med. 2004;36:782–801.CrossRef
11.
de Visser YP, Walther FJ, el Laghmani H, Steendijk P, Middeldorp M, van der Laarse A, Wagenaar GT. Phosphodiesterase 4 inhibition attenuates persistent heart and lung injury by neonatal hyperoxia in rats. Am J Physiol Lung Cell Mol Physiol. 2012;302:L56-67.CrossRef
12.
Dauletbaev N, Lam J, Eklove D, Iskandar M, Lands LC. Ibuprofen modulates NF-kB activity but not IL-8 production in cystic fibrosis respiratory epithelial cells. Respiration. 2010;79:234–42.CrossRef
13.
Shiff SJ, Rigas B. Nonsteroidal anti-inflammatory drugs and colorectal cancer: evolving concepts of their chemopreventive actions. Gastroenterology. 1997;113:1992–8.CrossRef
14.
Conrad C, Newberry D. Understanding the pathophysiology, implications, and treatment options of patent ductus arteriosus in the neonatal population. Adv Neonatal Care. 2019;19:179–87.CrossRef
15.
Ohlsson A, Walia R, Shah SS. Ibuprofen for the treatment of patent ductus arteriosus in preterm or low birth weight (or both) infants. Cochrane Database Syst Rev. 2018;9:CD003481.
16.
Chen X, Qiu X, Sun P, Lin Y, Huang Z, Yang C, Walther FJ. Neonatal ibuprofen exposure and bronchopulmonary dysplasia in extremely premature infants. J Perinatol. 2020;40:124–9.CrossRef
17.
Mitra S, Florez ID, Tamayo ME, Mbuagbaw L, Vanniyasingam T, Veroniki AA, Zea AM, Zhang Y, Sadeghirad B, Thabane L. Association of placebo, indomethacin, ibuprofen, and acetaminophen with closure of hemodynamically significant patent ductus arteriosus in preterm infants: a systematic review and meta-analysis. JAMA. 2018;319:1221–38.CrossRef
18.
Patel J, Marks KA, Roberts I, Azzopardi D, Edwards AD. Ibuprofen treatment of patent ductus arteriosus. Lancet. 1995;346:255.CrossRef
19.
Kim SY, Shin SH, Kim HS, Jung YH, Kim EK, Choi JH. Pulmonary arterial hypertension after ibuprofen treatment for patent ductus arteriosus in very low birth weight infants. J Pediatr. 2016;179:49-53.e41.CrossRef
20.
Jones LJ, Craven PD, Attia J, Thakkinstian A, Wright I. Network meta-analysis of indomethacin versus ibuprofen versus placebo for PDA in preterm infants. Arch Dis Child Fetal Neonatal Ed. 2011;96:F45-52.CrossRef
21.
Beharry KD, Modanlou HD, Hasan J, Gharraee Z, Abad-Santos P, Sills JH, Jan A, Nageotte S, Aranda JV. Comparative effects of early postnatal ibuprofen and indomethacin on VEGF, IGF-I, and GH during rat ocular development. Invest Ophthalmol Vis Sci. 2006;47:3036–43.CrossRef
22.
Zhang K, Yuan G, Werdich AA, Zhao Y. Ibuprofen and diclofenac impair the cardiovascular development of zebrafish (Danio rerio) at low concentrations. Environ Pollut. 2020;258: 113613.CrossRef
23.
Richards J, Johnson A, Fox G, Campbell M. A second course of ibuprofen is effective in the closure of a clinically significant PDA in ELBW infants. Pediatrics. 2009;124:e287-293.CrossRef
24.
Chen X, Orriols M, Walther FJ, Laghmani EH, Hoogeboom AM, Hogen-Esch ACB, Hiemstra PS, Folkerts G, Goumans MTH, Ten Dijke P, et al. Bone morphogenetic protein 9 protects against neonatal hyperoxia-induced impairment of alveolarization and pulmonary inflammation. Front Physiol. 2017;8:486.CrossRef
25.
Baudin B, Bruneel A, Bosselut N, Vaubourdolle M. A protocol for isolation and culture of human umbilical vein endothelial cells. Nat Protoc. 2007;2:481–5.CrossRef
26.
Koppel R, Han RN, Cox D, Tanswell AK, Rabinovitch M. Alpha 1-antitrypsin protects neonatal rats from pulmonary vascular and parenchymal effects of oxygen toxicity. Pediatr Res. 1994;36:763–70.CrossRef
27.
28.
Chen FZ, You LJ, Yang F, Wang LN, Guo XQ, Gao F, Hua C, Tan C, Fang L, Shan RQ, et al. CNGBdb: China national GeneBank DataBase. Yi Chuan. 2020;42:799–809.
29.
Husain MA, Sarwar T, Rehman SU, Ishqi HM, Tabish M. Ibuprofen causes photocleavage through ROS generation and intercalates with DNA: a combined biophysical and molecular docking approach. Phys Chem Chem Phys. 2015;17:13837–50.CrossRef
30.
Yao M, Zhou W, Sangha S, Albert A, Chang AJ, Liu TC, Wolfe MM. Effects of nonselective cyclooxygenase inhibition with low-dose ibuprofen on tumor growth, angiogenesis, metastasis, and survival in a mouse model of colorectal cancer. Clin Cancer Res. 2005;11:1618–28.CrossRef
31.
Thébaud B, Abman SH. Bronchopulmonary dysplasia: where have all the vessels gone? Roles of angiogenic growth factors in chronic lung disease. Am J Respir Crit Care Med. 2007;175:978–85.CrossRef
32.
Akrami H, Aminzadeh S, Fallahi H. Inhibitory effect of ibuprofen on tumor survival and angiogenesis in gastric cancer cell. Tumour Biol. 2015;36:3237–43.CrossRef
33.
Wiktorowska-Owczarek A, Namiecińska M, Owczarek J. The effect of ibuprofen on bFGF, VEGF secretion and cell proliferation in the presence of LPS in HMEC-1 cells. Acta Pol Pharm. 2015;72:889–94.
34.
Sánchez-Fidalgo S, Martín-Lacave I, Illanes M, Motilva V. Angiogenesis, cell proliferation and apoptosis in gastric ulcer healing. Effect of a selective cox-2 inhibitor. Eur J Pharmacol. 2004;505:187–94.CrossRef
35.
Palayoor ST, Tofilon PJ, Coleman CN. Ibuprofen-mediated reduction of hypoxia-inducible factors HIF-1alpha and HIF-2alpha in prostate cancer cells. Clin Cancer Res. 2003;9:3150–7.
36.
Jones MK, Wang H, Peskar BM, Levin E, Itani RM, Sarfeh IJ, Tarnawski AS. Inhibition of angiogenesis by nonsteroidal anti-inflammatory drugs: insight into mechanisms and implications for cancer growth and ulcer healing. Nat Med. 1999;5:1418–23.CrossRef
37.
Lemmens B, Lindqvist A. DNA replication and mitotic entry: a brake model for cell cycle progression. J Cell Biol. 2019;218:3892–902.CrossRef
38.
Bartek J, Lukas C, Lukas J. Checking on DNA damage in S phase. Nat Rev Mol Cell Biol. 2004;5:792–804.CrossRef
39.
Elsisi NS, Darling-Reed S, Lee EY, Oriaku ET, Soliman KF. Ibuprofen and apigenin induce apoptosis and cell cycle arrest in activated microglia. Neurosci Lett. 2005;375:91–6.CrossRef
40.
Wagenaar GT, Sengers RM, el Laghmani H, Chen X, Lindeboom MP, Roks AJ, Folkerts G, Walther FJ. Angiotensin II type 2 receptor ligand PD123319 attenuates hyperoxia-induced lung and heart injury at a low dose in newborn rats. Am J Physiol Lung Cell Mol Physiol. 2014;307:L261-272.CrossRef
41.
Deng H, Mason SN, Auten RL Jr. Lung inflammation in hyperoxia can be prevented by antichemokine treatment in newborn rats. Am J Respir Crit Care Med. 2000;162:2316–23.CrossRef
42.
Daphtary KM, Heidemann SM, Glibetic M. Ibuprofen attenuates early lung injury in endotoxemic, neutropenic rats. Prostaglandins Leukot Essent Fatty Acids. 2001;65:59–65.CrossRef
43.
Niitsu T, Tsuchida S, Peltekova V, Engelberts D, Copland I, Otulakowski G, Post M, Kavanagh BP. Cyclooxygenase inhibition in ventilator-induced lung injury. Anesth Analg. 2011;112:143–9.CrossRef
44.
Perlman MB, Johnson A, Malik AB. Ibuprofen prevents thrombin-induced lung vascular injury: mechanism of effect. Am J Physiol. 1987;252:H605-614.
45.
Lands LC, Dauletbaev N. High-dose ibuprofen in cystic fibrosis. Pharmaceuticals. 2010;3:2213–24.CrossRef
46.
Ricciotti E, FitzGerald GA. Prostaglandins and inflammation. Arterioscler Thromb Vasc Biol. 2011;31:986–1000.CrossRef
47.
Britt RD Jr, Velten M, Tipple TE, Nelin LD, Rogers LK. Cyclooxygenase-2 in newborn hyperoxic lung injury. Free Radic Biol Med. 2013;61:502–11.CrossRef
48.
Kuniyoshi KM, Brock RS, Gebrekristos BH, Abad-Santos M, Hoang D, Modanlou HD, Willis BC, Beharry KD. Effects of combined hyperoxia and cyclooxygenase inhibition in neonatal rat lungs. Am J Transl Res. 2010;2:332–44.
49.
McCurnin D, Seidner S, Chang LY, Waleh N, Ikegami M, Petershack J, Yoder B, Giavedoni L, Albertine KH, Dahl MJ, et al. Ibuprofen-induced patent ductus arteriosus closure: physiologic, histologic, and biochemical effects on the premature lung. Pediatrics. 2008;121:945–56.CrossRef
50.
de Visser YP, Walther FJ, LaghmaniBoersma HEH, van der Laarse A, Wagenaar GT. Sildenafil attenuates pulmonary inflammation and fibrin deposition, mortality and right ventricular hypertrophy in neonatal hyperoxic lung injury. Respir Res. 2009;10:30.CrossRef
51.
Safdar Z. Treatment of pulmonary arterial hypertension: the role of prostacyclin and prostaglandin analogs. Respir Med. 2011;105:818–27.CrossRef
52.
Siobal M. Aerosolized prostacyclins. Respir Care. 2004;49:640–52.
53.
Rabinovitch M, Guignabert C, Humbert M, Nicolls MR. Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension. Circ Res. 2014;115:165–75.CrossRef
54.
Tasneem S, Saleem M, Saeed SA. Nonsteroidal anti-inflammatory drugs as potential ecto-nucleotide phosphodiesterase inhibitors. Braz J Pharm Sci. 2020;56: e18271.CrossRef
55.
Tinsley HN, Piazza GA. Novel therapeutics: NSAIDs, derivatives, and phosphodiesterases. Curr Colorectal Cancer Rep. 2012;8:325–30.CrossRef
56.
Ladha F, Bonnet S, Eaton F, Hashimoto K, Korbutt G, Thébaud B. Sildenafil improves alveolar growth and pulmonary hypertension in hyperoxia-induced lung injury. Am J Respir Crit Care Med. 2005;172:750–6.CrossRef
57.
ter Horst SA, Walther FJ, Poorthuis BJ, Hiemstra PS, Wagenaar GT. Inhaled nitric oxide attenuates pulmonary inflammation and fibrin deposition and prolongs survival in neonatal hyperoxic lung injury. Am J Physiol Lung Cell Mol Physiol. 2007;293:L35-44.CrossRef
58.
Wagenaar GT, Hiemstra PS, Gosens R. Therapeutic potential of soluble guanylate cyclase modulators in neonatal chronic lung disease. Am J Physiol Lung Cell Mol Physiol. 2015;309:L1037-1040.CrossRef
59.
Huang X, Han D, Wei Y, Lin B, Zeng D, Zhang Y, Wei B, Huang Z, Chen X, Yang C. Decreased plasma levels of PDGF-BB, VEGF-A, and HIF-2α in preterm infants after ibuprofen treatment. Front Pediatr. 2022;10: 919879.CrossRef
60.
Metadata
Title
Vascular and pulmonary effects of ibuprofen on neonatal lung development
Authors
Xueyu Chen
Dongshan Han
Xuan Wang
Xuemei Huang
Zilu Huang
Yijun Liu
Junyan Zhong
Frans J. Walther
Chuanzhong Yang
Gerry T. M. Wagenaar
Publication date
01-12-2023
Publisher
BioMed Central
Published in
Respiratory Research / Issue 1/2023
Electronic ISSN: 1465-993X
DOI
https://doi.org/10.1186/s12931-023-02342-4

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