Genetic Ablation of Pyruvate Dehydrogenase Kinase Isoform 4 Gene Enhances Recovery from Hyperoxic Lung Injury: Insights into Antioxidant and Inflammatory Mechanisms

Overview

Journal Biomedicines

Specialty Biomedical Engineering

Date 2024 Apr 27

PMID 38672101

Authors

Keisuke Watanabe

Akie Kato

Hiroyuki Adachi

Atsuko Noguchi

Hirokazu Arai

Masato Ito

Fumihiko Namba

Tsutomu Takahashi

Affiliations

Soon will be listed here.

Abstract

Background: Pyruvate dehydrogenase kinase isoform 4 (PDK4) plays a pivotal role in the regulation of cellular proliferation and apoptosis. The objective of this study was to examine whether the genetic depletion of the PDK4 gene attenuates hyperoxia-induced lung injury in neonatal mice.

Methods: Neonatal PDK4-/- mice and wild-type (WT) mice were exposed to oxygen concentrations of 21% (normoxia) and 95% (hyperoxia) for the first 4 days of life. Pulmonary histological assessments were performed, and the mRNA levels of lung PDK4, monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-6 were assessed. The levels of inflammatory cytokines in lung tissue were quantified.

Results: Following convalescence from neonatal hyperoxia, PDK4-/- mice exhibited improved lung alveolarization. Notably, PDK4-/- mice displayed significantly elevated MCP-1 protein levels in pulmonary tissues following 4 days of hyperoxic exposure, whereas WT mice showed increased IL-6 protein levels under similar conditions. Furthermore, neonatal PDK4-/- mice subjected to hyperoxia demonstrated markedly higher MCP-1 mRNA expression at 4 days of age compared to WT mice, while IL-6 mRNA expression remained unaffected in PDK4-/- mice.

Conclusions: Newborn PDK4-/- mice exhibited notable recovery from hyperoxia-induced lung injury, suggesting the potential protective role of PDK4 depletion in mitigating lung damage.

References

Huang J, Zhang J, Sun C, Yang R, Sheng M, Hu J . Adjuvant role of Salvia miltiorrhiza bunge in cancer chemotherapy: A review of its bioactive components, health-promotion effect and mechanisms. J Ethnopharmacol. 2023; 318(Pt B):117022. DOI: 10.1016/j.jep.2023.117022. View

Durlak W, Thebaud B . The vascular phenotype of BPD: new basic science insights-new precision medicine approaches. Pediatr Res. 2022; 96(5):1162-1171. DOI: 10.1038/s41390-022-02428-7. View

Voynow J . "New" bronchopulmonary dysplasia and chronic lung disease. Paediatr Respir Rev. 2017; 24:17-18. DOI: 10.1016/j.prrv.2017.06.006. View

Wei P, Lin D, Luo C, Zhang M, Deng B, Cui K . High glucose promotes benign prostatic hyperplasia by downregulating PDK4 expression. Sci Rep. 2023; 13(1):17910. PMC: 10589318. DOI: 10.1038/s41598-023-44954-2. View

Chetty A, Cao G, Manzo N, Nielsen H, Waxman A . The role of IL-6 and IL-11 in hyperoxic injury in developing lung. Pediatr Pulmonol. 2008; 43(3):297-304. DOI: 10.1002/ppul.20777. View

Shen M, Zheng C, Chen L, Li M, Huang X, He M . LCZ696 (sacubitril/valsartan) inhibits pulmonary hypertension induced right ventricular remodeling by targeting pyruvate dehydrogenase kinase 4. Biomed Pharmacother. 2023; 162:114569. DOI: 10.1016/j.biopha.2023.114569. View

Yang G, Hinson M, Bordner J, Lin Q, Fernando A, La P . Silencing hyperoxia-induced C/EBPα in neonatal mice improves lung architecture via enhanced proliferation of alveolar epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2011; 301(2):L187-96. PMC: 3154632. DOI: 10.1152/ajplung.00082.2011. View

Jeon J, Thoudam T, Choi E, Kim M, Harris R, Lee I . Loss of metabolic flexibility as a result of overexpression of pyruvate dehydrogenase kinases in muscle, liver and the immune system: Therapeutic targets in metabolic diseases. J Diabetes Investig. 2020; 12(1):21-31. PMC: 7779278. DOI: 10.1111/jdi.13345. View

Choo-Wing R, Nedrelow J, Homer R, Elias J, Bhandari V . Developmental differences in the responses of IL-6 and IL-13 transgenic mice exposed to hyperoxia. Am J Physiol Lung Cell Mol Physiol. 2007; 293(1):L142-50. DOI: 10.1152/ajplung.00434.2006. View

10.

Zoulikha M, Xiao Q, Boafo G, Sallam M, Chen Z, He W . Pulmonary delivery of siRNA against acute lung injury/acute respiratory distress syndrome. Acta Pharm Sin B. 2021; 12(2):600-620. PMC: 8359643. DOI: 10.1016/j.apsb.2021.08.009. View

11.

McFate T, Mohyeldin A, Lu H, Thakar J, Henriques J, Halim N . Pyruvate dehydrogenase complex activity controls metabolic and malignant phenotype in cancer cells. J Biol Chem. 2008; 283(33):22700-8. PMC: 2504897. DOI: 10.1074/jbc.M801765200. View

12.

Okuma T, Terasaki Y, Sakashita N, Kaikita K, Kobayashi H, Hayasaki T . MCP-1/CCR2 signalling pathway regulates hyperoxia-induced acute lung injury via nitric oxide production. Int J Exp Pathol. 2007; 87(6):475-83. PMC: 2517387. DOI: 10.1111/j.1365-2613.2006.00502.x. View

13.

Terado T, Kim C, Ushio A, Minami K, Tambe Y, Kageyama S . Cryptotanshinone suppresses tumorigenesis by inhibiting lipogenesis and promoting reactive oxygen species production in KRAS‑activated pancreatic cancer cells. Int J Oncol. 2022; 61(3). PMC: 9339489. DOI: 10.3892/ijo.2022.5398. View

14.

Kimura R, Thulin G, Wender D, WARSHAW J . Decreased oxidative metabolism in neonatal rat lung exposed to hyperoxia. J Appl Physiol Respir Environ Exerc Physiol. 1983; 55(5):1501-5. DOI: 10.1152/jappl.1983.55.5.1501. View

15.

Zhu Q, Wang J, Li Y, Bai Z, Guo X, Pan T . PRKCA Promotes Mitophagy through the miR-15a-5p/PDK4 Axis to Relieve Sepsis-Induced Acute Lung Injury. Infect Immun. 2022; 91(1):e0046522. PMC: 9872609. DOI: 10.1128/iai.00465-22. View

16.

Tanaka K, Watanabe T, Ozawa J, Ito M, Nagano N, Arai Y . Difference in pyruvic acid metabolism between neonatal and adult mouse lungs exposed to hyperoxia. PLoS One. 2020; 15(9):e0238604. PMC: 7470327. DOI: 10.1371/journal.pone.0238604. View

17.

Ward N, Waxman A, Homer R, Mantell L, Einarsson O, Du Y . Interleukin-6-induced protection in hyperoxic acute lung injury. Am J Respir Cell Mol Biol. 2000; 22(5):535-42. DOI: 10.1165/ajrcmb.22.5.3808. View

18.

Hirani D, Alvira C, Danopoulos S, Milla C, Donato M, Tian L . Macrophage-derived IL-6 trans-signalling as a novel target in the pathogenesis of bronchopulmonary dysplasia. Eur Respir J. 2021; 59(2). PMC: 8850688. DOI: 10.1183/13993003.02248-2020. View

19.

Yang M, Wu Z, Liao X, Zhang B, Chen X, Wu Y . Remifentanil reduces multiple organ and energy metabolism disturbances in a rat sepsis model. J Physiol Pharmacol. 2022; 73(1). DOI: 10.26402/jpp.2022.1.08. View

20.

Wang X, Wan W, Zhang J, Lu J, Liu P . Efficient pulmonary fibrosis therapy via regulating macrophage polarization using respirable cryptotanshinone-loaded liposomal microparticles. J Control Release. 2023; 366:1-17. DOI: 10.1016/j.jconrel.2023.12.042. View