American Journal of Perinatology, Table of Contents

Am J Perinatol 2024; 41(08): 1039-1049
DOI: 10.1055/a-1787-3396

Original Article

Resveratrol Attenuates Hyperoxia Lung Injury in Neonatal Rats by Activating SIRT1/PGC-1α Signaling Pathway

Kun Yang

¹Division of Neonatology, Department of Pediatrics, The Affiliated Hospital of Southwest Medical University, Luzhou, China

²Department of Perinatology, The Affiliated Hospital of Southwest Medical University, Luzhou, China

³Sichuan Clinical Research Center for Birth Defects, Luzhou, China

,

¹Division of Neonatology, Department of Pediatrics, The Affiliated Hospital of Southwest Medical University, Luzhou, China

²Department of Perinatology, The Affiliated Hospital of Southwest Medical University, Luzhou, China

³Sichuan Clinical Research Center for Birth Defects, Luzhou, China

,

¹Division of Neonatology, Department of Pediatrics, The Affiliated Hospital of Southwest Medical University, Luzhou, China

²Department of Perinatology, The Affiliated Hospital of Southwest Medical University, Luzhou, China

³Sichuan Clinical Research Center for Birth Defects, Luzhou, China

,

Lan Kang

¹Division of Neonatology, Department of Pediatrics, The Affiliated Hospital of Southwest Medical University, Luzhou, China

²Department of Perinatology, The Affiliated Hospital of Southwest Medical University, Luzhou, China

³Sichuan Clinical Research Center for Birth Defects, Luzhou, China

,

Xiaodan Zhu

¹Division of Neonatology, Department of Pediatrics, The Affiliated Hospital of Southwest Medical University, Luzhou, China

²Department of Perinatology, The Affiliated Hospital of Southwest Medical University, Luzhou, China

³Sichuan Clinical Research Center for Birth Defects, Luzhou, China

,

Wenbin Dong

¹Division of Neonatology, Department of Pediatrics, The Affiliated Hospital of Southwest Medical University, Luzhou, China

²Department of Perinatology, The Affiliated Hospital of Southwest Medical University, Luzhou, China

³Sichuan Clinical Research Center for Birth Defects, Luzhou, China

,

Xiaoping Lei

¹Division of Neonatology, Department of Pediatrics, The Affiliated Hospital of Southwest Medical University, Luzhou, China

²Department of Perinatology, The Affiliated Hospital of Southwest Medical University, Luzhou, China

³Sichuan Clinical Research Center for Birth Defects, Luzhou, China

› Author Affiliations

Abstract

Objectives Our previous study showed that resveratrol (Res) attenuates apoptosis and mitochondrial dysfunction in alveolar epithelial cell injury induced by hyperoxia by activating the SIRT1/PGC-1α signaling pathway. In the present study, we investigated whether Res protects against hyperoxia-induced lung injury in neonatal rats by activating SIRT1/PGC-1α signaling pathway.

Methods Naturally delivered neonatal rats were randomly divided into six groups: normoxia + normal saline, normoxia + dimethyl sulfoxide (DMSO), normoxia + Res, hyperoxia + normal saline, hyperoxia + DMSO, and hyperoxia + Res. Lung tissue samples were collected on postnatal days 1, 7, and 14. Hematoxylin and eosin staining was used to evaluate lung development. Dual-immunofluorescence staining, real-time polymerase chain reaction, and western blotting were used to evaluate the levels of silencing information regulator 2-related enzyme 1 (SIRT1), peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α), nuclear respiratory factor 1 (Nrf1), Nrf2, transcription factor A (TFAM) and citrate synthase, the number of mitochondrial DNA (mtDNA) and mitochondria, the integrity of mtDNA, and the expression of TFAM in mitochondria.

Results We found that hyperoxia insulted lung development, whereas Res attenuated the hyperoxia lung injury. Res significantly upregulated the levels of SIRT1, PGC-1α, Nrf1, Nrf2, TFAM, and citrate synthase; promoted TFAM expression in the mitochondria; and increased the copy number of ND1 and the ratio of ND4/ND1.

Conclusion Our data suggest that Res attenuates hyperoxia-induced lung injury in neonatal rats, and this was achieved, in part, by activating the SIRT1/PGC-1α signaling pathway to promote mitochondrial biogenesis.

Key Points

Hyperoxia insulted lung development in neonatal rats.
Resveratrol promoted mitochondrial biogenesis to attenuate hyperoxia lung injury in neonatal rats.
Resveratrol, at least in part, promoted mitochondrial biogenesis by activating the SIRT1/PGC-1α signaling pathway.

Keywords

Keywords

bronchopulmonary dysplasia - resveratrol - SIRT1 - PGC-1α - mitochondrial biogenesis

References
1 Yang K, Dong W. SIRT1-related signaling pathways and their association with bronchopulmonary dysplasia. Front Med (Lausanne) 2021; 8: 595634
2 Wang J, Dong W. Oxidative stress and bronchopulmonary dysplasia. Gene 2018; 678: 177-183
3 Perez M, Robbins ME, Revhaug C, Saugstad OD. Oxygen radical disease in the newborn, revisited: oxidative stress and disease in the newborn period. Free Radic Biol Med 2019; 142: 61-72
4 Garcia D, Carr JF, Chan F. et al. Short exposure to hyperoxia causes cultured lung epithelial cell mitochondrial dysregulation and alveolar simplification in mice. Pediatr Res 2021; 90 (01) 58-65
5 Kandasamy J, Rezonzew G, Jilling T, Ballinger S, Ambalavanan N. Mitochondrial DNA variation modulates alveolar development in newborn mice exposed to hyperoxia. Am J Physiol Lung Cell Mol Physiol 2019; 317 (06) L740-L747
6 Kandasamy J, Olave N, Ballinger SW, Ambalavanan N. Vascular endothelial mitochondrial function predicts death or pulmonary outcomes in preterm infants. Am J Respir Crit Care Med 2017; 196 (08) 1040-1049
7 Popov L-D. Mitochondrial biogenesis: an update. J Cell Mol Med 2020; 24 (09) 4892-4899
8 Halling JF, Pilegaard H. PGC-1α-mediated regulation of mitochondrial function and physiological implications. Appl Physiol Nutr Metab 2020; 45 (09) 927-936
9 Fontecha-Barriuso M, Martin-Sanchez D, Martinez-Moreno JM. et al. The role of PGC-1α and mitochondrial biogenesis in kidney diseases. Biomolecules 2020; 10 (02) 347
10 Wang T, Wang Y, Liu L. et al. Research progress on sirtuins family members and cell senescence. Eur J Med Chem 2020; 193: 112207
11 Chen C, Zhou M, Ge Y, Wang X. SIRT1 and aging related signaling pathways. Mech Ageing Dev 2020; 187: 111215
12 Yang X, Dong W-B, Lei X-P, Li QP, Zhang LY, Zhang LP. Resveratrol suppresses hyperoxia-induced nucleocytoplasmic shuttling of SIRT1 and ROS production in PBMC from preterm infants in vitro. J Matern Fetal Neonatal Med 2018; 31 (09) 1142-1150
13 Mody K, Saslow JG, Kathiravan S. et al. Sirtuin1 in tracheal aspirate leukocytes: possible role in the development of bronchopulmonary dysplasia in premature infants. J Matern Fetal Neonatal Med 2012; 25 (08) 1483-1487
14 Tian B, Liu J. Resveratrol: a review of plant sources, synthesis, stability, modification and food application. J Sci Food Agric 2020; 100 (04) 1392-1404
15 de Oliveira MTP, de Sá Coutinho D, Tenório de Souza É. et al. Orally delivered resveratrol-loaded lipid-core nanocapsules ameliorate LPS-induced acute lung injury via the ERK and PI3K/Akt pathways. Int J Nanomedicine 2019; 14: 5215-5228
16 Wang K, Zhao J, Zhang W. et al. Resveratrol attenuates aortic dissection by increasing endothelial barrier function through the SIRT1 pathway. J Cardiovasc Pharmacol 2020; 76 (01) 86-93
17 Wu Q, Hu Y, Jiang M, Wang F, Gong G. Effect of autophagy regulated by SIRT1/FoxO1 pathway on the release of factors promoting thrombosis from vascular endothelial cells. Int J Mol Sci 2019; 20 (17) 4132
18 Li Y, Xi Y, Tao G. et al. Sirtuin 1 activation alleviates primary biliary cholangitis via the blocking of the NF-κB signaling pathway. Int Immunopharmacol 2020; 83: 106386
19 Zhu X, Lei X, Wang J, Dong W. Protective effects of resveratrol on hyperoxia-induced lung injury in neonatal rats by alleviating apoptosis and ROS production. J Matern Fetal Neonatal Med 2020; 33 (24) 4150-4158
20 Lagouge M, Argmann C, Gerhart-Hines Z. et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell 2006; 127 (06) 1109-1122
21 Fang W-J, Wang C-J, He Y, Zhou YL, Peng XD, Liu SK. Resveratrol alleviates diabetic cardiomyopathy in rats by improving mitochondrial function through PGC-1α deacetylation. Acta Pharmacol Sin 2018; 39 (01) 59-73
22 Zhu X, Wang F, Lei X, Dong W. Resveratrol alleviates alveolar epithelial cell injury induced by hyperoxia by reducing apoptosis and mitochondrial dysfunction. Exp Biol Med (Maywood) 2021; 246 (05) 596-606
23 Ruan Y, Dong W, Kang L. et al. The changes of Twist1 pathway in pulmonary microvascular permeability in a newborn rat model of hyperoxia-induced acute lung injury. Front Pediatr 2020; 8: 190
24 Xu W, Zhao Y, Zhang B. et al. Resveratrol attenuates hyperoxia-induced oxidative stress, inflammation and fibrosis and suppresses Wnt/β-catenin signalling in lungs of neonatal rats. Clin Exp Pharmacol Physiol 2015; 42 (10) 1075-1083
25 Wei P, Liu Q, Xue W, Wang J. A colorimetric assay of citrate synthase activity in drosophila melanogaster. J Vis Exp 2020; (155) e59454
26 Jiang Z, Bahr T, Zhou C. et al. Diagnostic value of circulating cell-free mtDNA in patients with suspected thyroid cancer: ND4/ND1 ratio as a new potential plasma marker. Mitochondrion 2020; 55: 145-153
27 Goss KN, Kumari S, Tetri LH. et al. Postnatal hyperoxia exposure durably impairs right ventricular function and mitochondrial biogenesis. Am J Respir Cell Mol Biol 2017; 56 (05) 609-619
28 O'Reilly M, Thébaud B. Animal models of bronchopulmonary dysplasia. The term rat models. Am J Physiol Lung Cell Mol Physiol 2014; 307 (12) L948-L958
29 Lian N, Zhang S, Huang J, Lin T, Lin Q. Resveratrol attenuates intermittent hypoxia-induced lung injury by activating the Nrf2/ARE pathway. Lung 2020; 198 (02) 323-331
30 Wang X, Liu M, Zhu M-J. et al. Resveratrol protects the integrity of alveolar epithelial barrier via SIRT1/PTEN/p-Akt pathway in methamphetamine-induced chronic lung injury. Cell Prolif 2020; 53 (03) e12773
31 Wang X-L, Li T, Li J-H, Miao S-Y, Xiao X-Z. The effects of resveratrol on inflammation and oxidative stress in a rat model of chronic obstructive pulmonary disease. Molecules 2017; 22 (09) 1529
32 Zhang T, Chi Y, Kang Y. et al. Resveratrol ameliorates podocyte damage in diabetic mice via SIRT1/PGC-1α mediated attenuation of mitochondrial oxidative stress. J Cell Physiol 2019; 234 (04) 5033-5043
33 Chuang YC, Chen SD, Hsu CY, Chen SF, Chen NC, Jou SB. Resveratrol promotes mitochondrial biogenesis and protects against seizure-induced neuronal cell damage in the hippocampus following status epilepticus by activation of the PGC-1α signaling pathway. Int J Mol Sci 2019; 20 (04) 998
34 Li Z, Wang F, Zha S, Cao Q, Sheng J, Chen S. SIRT1 inhibits TGF-β-induced endothelial-mesenchymal transition in human endothelial cells with Smad4 deacetylation. J Cell Physiol 2018; 233 (11) 9007-9014
35 Zhang L, Zhang Y, Chang X, Zhang X. Imbalance in mitochondrial dynamics induced by low PGC-1α expression contributes to hepatocyte EMT and liver fibrosis. Cell Death Dis 2020; 11 (04) 226
36 Shah D, Torres C, Bhandari V. Adiponectin deficiency induces mitochondrial dysfunction and promotes endothelial activation and pulmonary vascular injury. FASEB J 2019; 33 (12) 13617-13631
37 García-Quintans N, Sánchez-Ramos C, Prieto I. et al. Oxidative stress induces loss of pericyte coverage and vascular instability in PGC-1α-deficient mice. Angiogenesis 2016; 19 (02) 217-228
38 Jia L, Wang J, Cao H, Zhang X, Rong W, Xu Z. Activation of PGC-1α and mitochondrial biogenesis protects against prenatal hypoxic-ischemic brain injury. Neuroscience 2020; 432: 63-72
39 Porter C, Herndon DN, Bhattarai N. et al. Severe burn injury induces thermogenically functional mitochondria in murine white adipose tissue. Shock 2015; 44 (03) 258-264
40 Lim SC, Hroudová J, Van Bergen NJ, Lopez Sanchez MI, Trounce IA, McKenzie M. Loss of mitochondrial DNA-encoded protein ND1 results in disruption of complex I biogenesis during early stages of assembly. FASEB J 2016; 30 (06) 2236-2248
41 Wang S, Moustaid-Moussa N, Chen L. et al. Novel insights of dietary polyphenols and obesity. J Nutr Biochem 2014; 25 (01) 1-18
42 Tabrizi R, Tamtaji OR, Lankarani KB. et al. The effects of resveratrol intake on weight loss: a systematic review and meta-analysis of randomized controlled trials. Crit Rev Food Sci Nutr 2020; 60 (03) 375-390