Vascular and pulmonary effects of ibuprofen on neonatal lung development

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.

Repurposing Inhaled Ibuprofenate, a Non Steroidal Anti‐Inflammatory Drug, as a Potential Adjuvant Treatment for Pneumonia, CARDS and its Aetiological Agent SARS‐CoV‐2

“…40 This therapeutic effect of ibuprofen was studied in endothelial cells of the human umbilical cord veins in vitro and in neonatal rats with induced bronchopulmonary dysplasia in vivo, demonstrating in the first group the antiangiogenic effect by a significant reduction of neovascularization through inhibition of wound closure, tube formation, cell migration, cell proliferation and also by the induction of endothelial apoptosis; and in the second group, has also demonstrated the mentioned antiangiogenic effect by a significant reduction in the density of developing pulmonary vessels. 40 In addition, ibuprofen has been shown to inhibit the vascular development of the rat eye, 40 the cardiovascular development of zebrafish, 40 the growth of certain tumours and their metastases. 40 The possible underlying mechanisms of action of ibuprofen proposed in this study are the negative modulation of vascular endothelial growth factor (VEGF), 40 basic fibroblast growth factor (bFGF), 40 HIF, 40 extracellular signal-regulated kinase 2 (ERK2), 40 MAPK, 40 cyclin-dependent kinase 1/2 (CDK 1/2), 40 checkpoint kinase 1 (CHK1), 40 cyclin A, 40 via Apelin/G protein-coupled receptor (APJ).…”

“…40 In addition, ibuprofen has been shown to inhibit the vascular development of the rat eye, 40 the cardiovascular development of zebrafish, 40 the growth of certain tumours and their metastases. 40 The possible underlying mechanisms of action of ibuprofen proposed in this study are the negative modulation of vascular endothelial growth factor (VEGF), 40 basic fibroblast growth factor (bFGF), 40 HIF, 40 extracellular signal-regulated kinase 2 (ERK2), 40 MAPK, 40 cyclin-dependent kinase 1/2 (CDK 1/2), 40 checkpoint kinase 1 (CHK1), 40 cyclin A, 40 via Apelin/G protein-coupled receptor (APJ). 40 One study in particular is worth highlighting, due to its importance since the onset of the SARS-CoV-2 pandemic, and the reasons for such relevance will be developed and analysed later.…”

“…This way, NaIHS through direct inhibition of COX-2, would negatively modulate VEGF, 40,42 bFGF, 40,42 HGF, 27 CCL2, 27 ERK2, 40 MAPK, 40 CDK 1/2, 40 CHK1, 40 cyclin A 40 and via Apelin/APJ 40 and, by COX-independent effects, NaIHS would inhibit HIF-1 alpha (HIF-1α) 37 and HIF-2α, 43 thereby it may inhibit pulmonary angiogenesis, 27,37,40,42,43 fibrosis 27,37,41,42,43 and fibrotic sequelae. 27,37,41,42,43 Furthermore, it is important to mention that for other authors, some of the mentioned antiangiogenic effects of ibuprofen may be COX-independent effects 11,43,44 such as VEGF, 11 ERK2, 44 MAPK, 44 CDK 1/2, 44 CHK1, 44 cyclin A 44 and others.…”

“…40 The possible underlying mechanisms of action of ibuprofen proposed in this study are the negative modulation of vascular endothelial growth factor (VEGF), 40 basic fibroblast growth factor (bFGF), 40 HIF, 40 extracellular signal-regulated kinase 2 (ERK2), 40 MAPK, 40 cyclin-dependent kinase 1/2 (CDK 1/2), 40 checkpoint kinase 1 (CHK1), 40 cyclin A, 40 via Apelin/G protein-coupled receptor (APJ). 40 One study in particular is worth highlighting, due to its importance since the onset of the SARS-CoV-2 pandemic, and the reasons for such relevance will be developed and analysed later. 41 This study has demonstrated the beneficial therapeutic effect of ibuprofen on the reduction and improvement of cardiac fibrosis in streptozotocininduced diabetic rats.…”

“…IL‐8, 27 IL‐10, 27 IL‐18, 24 tumor necrosis factor‐alpha (TNF‐α), 13 interferon‐gamma (IFN‐γ), 13 transforming growth factor‐beta 1 (TGF‐β1), 13 intercellular adhesion molecule‐1 (ICAM‐1), 13 vascular adhesion molecule‐1 (VCAM‐1), 28 E‐selectin, 12 monocyte chemoattractant protein 1 (MCP‐1), 27 chemokine (C‐C motif) ligand 2 (CCL2), 27 growth factors granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) 29 and hepatocyte growth factor (HGF) 27 ; (3) Down‐regulation of nitric oxide (NO) hyperproduction : see Table 3; (4) Inhibition of the main local inflammatory mediators : by COX2 inhibition effect, it may inhibit prostaglandins, 12 prostacyclins, 12 histamine, 38 bradykinins 6,33,39 and NO 31 and (5) Antiangiogenic effect : by COX‐2 inhibition effect, it would negatively modulate vascular endothelial growth factor (VEGF), 40,42 basic fibroblast growth factor (bFGF), 40,42 CCL2, 27 HGF, 27 extracellular signal‐regulated kinase 2 (ERK2), 40 mitogen‐activated protein kinase (MAPK), 40 cyclin‐dependent kinase 1/2 (CDK 1/2), 40 checkpoint kinase 1 (CHK1), 40 cyclin A, 40 via Apelin/G protein‐coupled receptor (APJ) 40 and, by COX‐independent effect, NaIHS would inhibit hypoxia inducible factor‐1 alpha (HIF‐1α) 37 and HIF‐2α 43 . .…”