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Glutamine inhibits inflammation, oxidative stress, and apoptosis and ameliorates hyperoxic lung injury

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Abstract

Glutamine (Gln) is the most widely acting and abundant amino acid in the body and has anti-inflammatory properties, regulates body metabolism, and improves immune function. However, the mechanism of Gln’s effect on hyperoxic lung injury in neonatal rats is unclear. Therefore, this work focused on examining Gln’s function in lung injury of newborn rats mediated by hyperoxia and the underlying mechanism. We examined body mass and ratio of wet-to-dry lung tissue weights of neonatal rats. Hematoxylin and eosin (HE) staining was performed to examine histopathological alterations of lung tissues. In addition, enzyme-linked immunoassay (ELISA) was conducted to measure pro-inflammatory cytokine levels within bronchoalveolar lavage fluid (BALF). Apoptosis of lung tissues was observed using TUNEL assay. Western blotting was performed for detecting endoplasmic reticulum stress (ERS)-associated protein levels. The results showed that Gln promoted body weight gain, significantly reduced pathological damage and oxidative stress in lung tissue, and improved lung function in neonatal rats. Gln reduced pro-inflammatory cytokine release as well as inflammatory cell production in BALF and inhibited apoptosis in lung tissue cells. Furthermore, we found that Gln could downregulate ERS-associated protein levels (GRP78, Caspase-12, CHOP) and inhibit c-Jun N-terminal kinase (JNK) and inositol-requiring enzyme 1 alpha (IRE1α) phosphorylation. These results in an animal model of bronchopulmonary dysplasia (BPD) suggest that Gln may have a therapeutic effect on BPD by reducing lung inflammation, oxidative stress, and apoptosis and improving lung function; its mechanism of action may be related to the inhibition of the IRE1α/JNK pathway.

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References

  1. Bonadies L, Zaramella P, Porzionato A, Perilongo G, Muraca M, Baraldi E (2020) Present and future of bronchopulmonary dysplasia. J Clin Med 9:1539

    Article  PubMed  PubMed Central  Google Scholar 

  2. Bührer C, Fischer HS, Wellmann S (2020) Nutritional interventions to reduce rates of infection, necrotizing enterocolitis and mortality in very preterm infants. Pediatr Res 87:371–377

    Article  PubMed  Google Scholar 

  3. Cruzat V, Macedo Rogero M, Noel Keane K, Curi R, Newsholme P (2018) Glutamine: metabolism and immune function, supplementation and clinical translation. Nutrients 10:1564

    Article  PubMed  PubMed Central  Google Scholar 

  4. Cui ZH, Zhang XJ, Shang HQ, Wang X, Rong D (2020) Glutamine protects myocardial ischemia-reperfusion injury in rats through the PI3K/Akt signaling pathway. Eur Rev Med Pharmacol Sci 24:444–451

    PubMed  Google Scholar 

  5. Cuna A, Quiqley A, Varghese K, Ciccolari-Micaldi G, Oliveros C, Cheng AL et al (2021) Effectiveness and safety of repeat dexamethasone for bronchopulmonary dysplasia. J Perinatol 41:1956–1962

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. D'Angio CT, Ambalavanan N, Carlo WA, McDonald SA, Skogstrand K, Hougaard DM et al (2016) Blood cytokine profiles associated with distinct patterns of bronchopulmonary dysplasia among extremely low birth weight infants. J Pediatr 174:45–51.e5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Dou H, Yang S, Hu Y, Xu D, Liu L, Li X (2018) Sesamin induces ER stress-mediated apoptosis and activates autophagy in cervical cancer cells. Life Sci 200:87–93

    Article  CAS  PubMed  Google Scholar 

  8. Eugene SP, Reddy VS, Trinath J (2020) Endoplasmic reticulum stress and intestinal inflammation: a perilous union. Front Immunol 11:543022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Greco F, Wiegert S, Baumann P, Wellmann S, Pellegrini G, Cannizzaro V (2019) Hyperoxia-induced lung structure-function relation, vessel rarefaction, and cardiac hypertrophy in an infant rat model. J Transl Med 17:91

    Article  PubMed  PubMed Central  Google Scholar 

  10. Huang J, Liu J, Chang G, Wang Y, Ma N, Roy AC et al (2021) Glutamine supplementation attenuates the inflammation caused by LPS-induced acute lung injury in mice by regulating the TLR4/MAPK signaling pathway. Inflammation 44:2180–2192

    Article  CAS  PubMed  Google Scholar 

  11. Jensen EA, Dysart K, Gantz MG, McDonald S, Bamat NA, Keszler M et al (2019) The diagnosis of bronchopulmonary dysplasia in very preterm infants. An evidence-based approach. Am J Respir Crit Care Med 200:751–759

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Jiménez J, Richter J, Nagatomo T, Salaets T, Quarck R, Wagennar A et al (2016) Progressive vascular functional and structural damage in a bronchopulmonary dysplasia model in preterm rabbits exposed to hyperoxia. Int J Mol Sci 17:1776

    Article  PubMed  PubMed Central  Google Scholar 

  13. Jin C, Jin Z, Zhang Y (2018) Glutamine inhibits the inflammation in preterm rats with lung injury induced by hyperoxia and its mechanism. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 34:1086–1090

    PubMed  Google Scholar 

  14. Ke R, Wang Y, Hong S, Xiao L (2020) Endoplasmic reticulum stress related factor IRE1α regulates TXNIP/NLRP3-mediated pyroptosis in diabetic nephropathy. Exp Cell Res 396:112293

    Article  CAS  PubMed  Google Scholar 

  15. Kim MH, Kim H (2017) The roles of glutamine in the intestine and its implication in intestinal diseases. Int J Mol Sci 18:1051

    Article  PubMed  PubMed Central  Google Scholar 

  16. Ko HM, Oh SH, Bang HS, Kang NI, Cho BH, Im SY, Lee HK (2009) Glutamine protects mice from lethal endotoxic shock via a rapid induction of MAPK phosphatase-1. J Immunol 182:7957–7962

    Article  CAS  PubMed  Google Scholar 

  17. Kondrikov D, Caldwell RB, Dong Z, Su Y (2011) Reactive oxygen species-dependent RhoA activation mediates collagen synthesis in hyperoxic lung fibrosis. Free Radic Biol Med 50:1689–1698

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kumar VH, Lakshminrusimha S, Kishkurno S, Paturi BS, Gugino SF, Nielsen L et al (2016) Neonatal hyperoxia increases airway reactivity and inflammation in adult mice. Pediatr Pulmonol 51:1131–1141

    Article  PubMed  Google Scholar 

  19. Lee CH, Kim HK, Jeong JS, Lee YD, Jin ZW, Im SY et al (2015) Mechanism of glutamine inhibition of cytosolic phospholipase a2 (cPLA2 ): evidence of physical interaction between glutamine-induced mitogen-activated protein kinase phosphatase-1 and cPLA2. Clin Exp Immunol 180:571–580

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Li W, Cao T, Luo C, Cai J, Zhou X, Xiao X et al (2020) Crosstalk between ER stress, NLRP3 inflammasome, and inflammation. Appl Microbiol Biotechnol 104:6129–6140

    Article  CAS  PubMed  Google Scholar 

  21. Liang Y, Liang L, Liu Z, Wang Y, Dong X, Qu L et al (2020) Inhibition of IRE1/JNK pathway in HK-2 cells subjected to hypoxia-reoxygenation attenuates mesangial cells-derived extracellular matrix production. J Cell Mol Med 24:13408–13420

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Liu XR, Cao L, Li T, Chen LL, Yu YY, Huang WJ et al (2017) Propofol attenuates H2O2-induced oxidative stress and apoptosis via the mitochondria- and ER-medicated pathways in neonatal rat cardiomyocytes. Apoptosis 22:639–646

    Article  CAS  PubMed  Google Scholar 

  23. Ozdemir R, Gokce IK, Taslidere AC, Tanbek K, Gul CC, Sandal S et al (2021) Does chrysin prevent severe lung damage in hyperoxia-induced lung injury model? Int Immunopharmacol 99:108033

    Article  CAS  PubMed  Google Scholar 

  24. Petry ÉR, Dresch DF, Carvalho C, Medeiros PC, Rosa TG, de Oliveira CM et al (2019) Oral glutamine supplementation attenuates inflammation and oxidative stress-mediated skeletal muscle protein content degradation in immobilized rats: Role of 70 kDa heat shock protein. Free Radic Biol Med 145:87–102

    Article  CAS  PubMed  Google Scholar 

  25. Sevastiadou S, Malamitsi-Puchner A, Costalos C, Skouroliakou M, Briana DD, Antsaklis A et al (2011) The impact of oral glutamine supplementation on the intestinal permeability and incidence of necrotizing enterocolitis/septicemia in premature neonates. J Matern Fetal Neonatal Med 24:1294–1300

    Article  CAS  PubMed  Google Scholar 

  26. Smith KM, Mrozek JD, Simonton SC, Bing DR, Meyers PA, Connett JE et al (1997) Prolonged partial liquid ventilation using conventional and high-frequency ventilatory techniques: gas exchange and lung pathology in an animal model of respiratory distress syndrome. Crit Care Med 25:1888–1897

    Article  CAS  PubMed  Google Scholar 

  27. Sun R, Zhao N, Wang Y, Su Y, Zhang J, Wang Y et al (2021) High concentration of hydrogen gas alleviates lipopolysaccharide-induced lung injury via activating Nrf2 signaling pathway in mice. Int Immunopharmacol 101:108198

    Article  CAS  PubMed  Google Scholar 

  28. Teng RJ, Jing X, Michalkiewicz T, Afolayan AJ, Wu TJ, Konduri GG (2017) Attenuation of endoplasmic reticulum stress by caffeine ameliorates hyperoxia-induced lung injury. Am J Physiol Lung Cell Mol Physiol 312:L586–L598

    Article  PubMed  PubMed Central  Google Scholar 

  29. Thébaud B, Goss KN, Laughon M, Whitsett JA, Abman SH, Steinhorn RH et al (2019) Bronchopulmonary dysplasia. Nat Rev Dis Primers 5:78

    Article  PubMed  PubMed Central  Google Scholar 

  30. Tracy MK, Berkelhamer SK (2019) Bronchopulmonary dysplasia and pulmonary outcomes of prematurity. Pediatr Ann 48:e148–e153

    Article  PubMed  Google Scholar 

  31. Vanoirbeek JA, Rinaldi M, De Vooght V, Haenen S, Bobic S, Gayan-Ramirez G et al (2010) Noninvasive and invasive pulmonary function in mouse models of obstructive and restrictive respiratory diseases. Am J Respir Cell Mol Biol 42:96–104

    Article  CAS  PubMed  Google Scholar 

  32. Wang CY, Li XD, Hao ZH, Xu D (2016) Insulin-like growth factor-1 improves diabetic cardiomyopathy through antioxidative and anti-inflammatory processes along with modulation of Akt/GSK-3β signaling in rats. Korean J Physiol Pharmacol 20:613–619

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wang H, Dong Y, Cai Y (2017) Alanyl-glutamine prophylactically protects against lipopolysaccharide-induced acute lung injury by enhancing the expression of HSP70. Mol Med Rep 16:2807–2813

    Article  CAS  PubMed  Google Scholar 

  34. Wang Y, Wang Q, Li J, Lu G, Liu Z (2019) Glutamine improves oxidative stress through the Wnt3a/β-catenin signaling pathway in Alzheimer’s disease in vitro and in vivo. Biomed Res Int 2019:4690280

    PubMed  PubMed Central  Google Scholar 

  35. Wu Q, Chong L, Shao Y, Chen S, Li C (2019) Lipoxin A4 reduces hyperoxia-induced lung injury in neonatal rats through PINK1 signaling pathway. Int Immunopharmacol 73:414–423

    Article  CAS  PubMed  Google Scholar 

  36. Xiong Y, Wang Y, Xiong Y, Gao W, Teng L (2020) Salidroside alleviated hypoxia-induced liver injury by inhibiting endoplasmic reticulum stress-mediated apoptosis via IRE1α/JNK pathway. Biochem Biophys Res Commun 529:335–340

    Article  CAS  PubMed  Google Scholar 

  37. Xu W, Gao L, Li T, Zheng J, Shao A, Zhang J (2018) Apelin-13 alleviates early brain injury after subarachnoid hemorrhage via suppression of endoplasmic reticulum stress-mediated apoptosis and blood-brain barrier disruption: possible involvement of ATF6/CHOP pathway. Neuroscience 388:284–296

    Article  CAS  PubMed  Google Scholar 

  38. Xu W, Li T, Gao L, Zheng J, Yan J, Zhang J et al (2019) Apelin-13/APJ system attenuates early brain injury via suppression of endoplasmic reticulum stress-associated TXNIP/NLRP3 inflammasome activation and oxidative stress in a AMPK-dependent manner after subarachnoid hemorrhage in rats. J Neuroinflammation 16:247

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zhu L, Chen X, Chong L, Kong L, Wen S, Zhang H et al (2019) Adiponectin alleviates exacerbation of airway inflammation and oxidative stress in obesity-related asthma mice partly through AMPK signaling pathway. Int Immunopharmacol 67:396–407

    Article  CAS  PubMed  Google Scholar 

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Funding

We are grateful for the financial support from the National Natural Science Foundation of China (No. 81860279) and Jilin Province Health and Health Science and Technology Capacity Enhancement Program Project (No. 2020Q001). This study was supported by the Department of Paediatrics of the Affiliated Hospital of Yanbian University and the Morphology Experimental Centre of Yanbian University.

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Author notes

  1. Shujian Zhang and Xuewei Li contributed equally to this work.

Authors and Affiliations

  1. Department of Emergency and Critical Care Medicine, Second Hospital of Jilin University, Changchun, Jilin Province, China

    Shujian Zhang, Xuewei Li & Jinliang Li

  2. Department of Pediatrics, Affiliated Hospital of Yanbian University, Yanji, Jilin, China

    Shujian Zhang, Can Jin & Zhengyong Jin

  3. Center of Morphological Experiment, Medical College of Yanbian University, Yanji, Jilin, China

    Tiezheng Yuan & Xiangyu Guo

  4. Department of Pediatrics, Second Hospital of Jilin University, Changchun, Jilin Province, China

    Zhengyong Jin

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  1. Shujian Zhang
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Contributions

The authors declare that all data were generated in-house and that no paper mill was used. SZ and TY conceived and designed the experiments; SZ and TY performed the experiments; CJ, XL, and XG analyzed the data; XG and TY contributed reagents, materials, and analysis tools; SZ, XL, and JL wrote the paper; ZJ and JL edited and approved the final draft.

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Correspondence to Zhengyong Jin or Jinliang Li.

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The authors declare no competing interests.

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All procedures were approved by the Medical Ethics Committee of the College of Medicine, Yanbian University (approval number: 20210429).

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Key points

1. Glutamine treatment reduces the levels of inflammatory cells and pro-inflammatory cytokines.

2. Glutamine treatment reduces levels of oxidative stress-related factors.

3. Glutamine treatment can improve lung function.

4. Glutamine is a potential drug for the treatment of BPD.

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Zhang, S., Li, X., Yuan, T. et al. Glutamine inhibits inflammation, oxidative stress, and apoptosis and ameliorates hyperoxic lung injury. J Physiol Biochem 79, 613–623 (2023). https://doi.org/10.1007/s13105-023-00961-5

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  • DOI: https://doi.org/10.1007/s13105-023-00961-5

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