Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Basic Science Article
  • Published:

L-citrulline attenuates lipopolysaccharide-induced inflammatory lung injury in neonatal rats

Pediatric Research volume 94, pages 1684–1695 (2023)Cite this article

Abstract

Background

Prenatal or postnatal lung inflammation and oxidative stress disrupt alveolo-vascular development leading to bronchopulmonary dysplasia (BPD) with and without pulmonary hypertension. L-citrulline (L-CIT), a nonessential amino acid, alleviates inflammatory and hyperoxic lung injury in preclinical models of BPD. L-CIT modulates signaling pathways mediating inflammation, oxidative stress, and mitochondrial biogenesis—processes operative in the development of BPD. We hypothesize that L-CIT will attenuate lipopolysaccharide (LPS)-induced inflammation and oxidative stress in our rat model of neonatal lung injury.

Methods

Newborn rats during the saccular stage of lung development were used to investigate the effect of L-CIT on LPS-induced lung histopathology and pathways involved in inflammatory, antioxidative processes, and mitochondrial biogenesis in lungs in vivo, and in primary culture of pulmonary artery smooth muscle cells, in vitro.

Results

L-CIT protected the newborn rat lung from LPS-induced: lung histopathology, ROS production, NFκB nuclear translocation, and upregulation of gene and protein expression of inflammatory cytokines (IL-1β, IL-8, MCP-1α, and TNF-α). L-CIT maintained mitochondrial morphology, increased protein levels of PGC-1α, NRF1, and TFAM (transcription factors involved in mitochondrial biogenesis), and induced SIRT1, SIRT3, and superoxide dismutases protein expression.

Conclusion

L-CIT may be efficacious in decreasing early lung inflammation and oxidative stress mitigating progression to BPD.

Impact

  • The nonessential amino acid L-citrulline (L-CIT) mitigated lipopolysaccharide (LPS)-induced lung injury in the early stage of lung development in the newborn rat.

  • This is the first study describing the effect of L-CIT on the signaling pathways operative in bronchopulmonary dysplasia (BPD) in a preclinical inflammatory model of newborn lung injury.

  • If our findings translate to premature infants, L-CIT could decrease inflammation, oxidative stress and preserve mitochondrial health in the lung of premature infants at risk for BPD.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: L-CIT effect on changes in lung morphology and lung collagen deposition, in vivo, in LPS-induced lung injury.
Fig. 2: Effect of L-CIT on LPS-induced changes of mitochondrial morphology and expression of mitochondrial proteins, in vivo.
Fig. 3: Effect of L-CIT on LPS-induced expression of inflammatory biomarkers and histopathology, in vivo.
Fig. 4: Effect of L-CIT on LPS-induced changes in oxidative markers, in vivo.
Fig. 5: Effect of L-CIT on anti-inflammatory and antioxidative signaling in neonatal rat PASMC.
Fig. 6: Effect of L-CIT on anti-inflammatory and antioxidative signaling in response to LPS, in vitro.

Similar content being viewed by others

Data availability

All collected and analyzed data from this study are included in this published article (and the Supplementary material) and are freely available to any researcher wishing to use them for non-commercial purposes.

References

  1. Shahzad, T., Radajewski, S., Chao, C. M., Bellusci, S. & Ehrhardt, H. Pathogenesis of bronchopulmonary dysplasia: when inflammation meets organ development. Mol. Cell. Pediatr. 3, 23 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  2. McEvoy, C. T. et al. Bronchopulmonary dysplasia: NHLBI Workshop on the Primary Prevention of Chronic Lung Diseases. Ann. Am. Thorac. Soc. 11, S146–S153 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Thebaud, B. et al. Bronchopulmonary dysplasia. Nat. Rev. Dis. Primers 5, 78 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Sahni, M. & Bhandari, V. Patho-mechanisms of the origins of bronchopulmonary dysplasia. Mol. Cell. Pediatr. 8, 21 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Baker, C. D. & Alvira, C. M. Disrupted lung development and bronchopulmonary dysplasia: opportunities for lung repair and regeneration. Curr. Opin. Pediatr. 26, 306–314 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Kalikkot Thekkeveedu, R., Guaman, M. C. & Shivanna, B. Bronchopulmonary dysplasia: a review of pathogenesis and pathophysiology. Respir. Med. 132, 170–177 (2017).

    Article  PubMed  Google Scholar 

  7. Michael, Z., Spyropoulos, F., Ghanta, S. & Christou, H. Bronchopulmonary dysplasia: an update of current pharmacologic therapies and new approaches. Clin. Med. Insights Pediatr. 12, 1179556518817322 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Pasha, A. B., Chen, X. Q. & Zhou, G. P. Bronchopulmonary dysplasia: pathogenesis and treatment. Exp. Ther. Med. 16, 4315–4321 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Allerton, T. D. et al. l-citrulline supplementation: impact on cardiometabolic health. Nutrients 10, 921. https://doi.org/10.3390/nu10070921 (2018).

  10. Montgomery, A. M. et al. Biochemical screening for pulmonary hypertension in preterm infants with bronchopulmonary dysplasia. Neonatology 109, 190–194 (2016).

    Article  CAS  PubMed  Google Scholar 

  11. Celik, I. H., Demirel, G., Canpolat, F. E. & Dilmen, U. Reduced plasma citrulline levels in low birth weight infants with necrotizing enterocolitis. J. Clin. Lab. Anal. 27, 328–332 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Zozaya, C. et al. Incidence, treatment, and outcome trends of necrotizing enterocolitis in preterm infants: a multicenter cohort study. Front. Pediatr. 8, 188 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Fanczal, E., Berecz, B., Szijarto, A., Gasparics, A. & Varga, P. The prognosis of preterm infants born at the threshold of viability: fog over the gray zone - population-based studies of extremely preterm infants. Med. Sci. Monit. 26, e926947 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Kandasamy, J., Olave, N., Ballinger, S. W. & Ambalavanan, N. Vascular endothelial mitochondrial function predicts death or pulmonary outcomes in preterm infants. Am. J. Respir. Crit. Care Med. 196, 1040–1049 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Vadivel, A. et al. L-citrulline attenuates arrested alveolar growth and pulmonary hypertension in oxygen-induced lung injury in newborn rats. Pediatr. Res. 68, 519–525 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Grisafi, D. et al. L-citrulline prevents alveolar and vascular derangement in a rat model of moderate hyperoxia-induced lung injury. Lung 190, 419–430 (2012).

    Article  CAS  PubMed  Google Scholar 

  17. Fike, C. D. et al. Rescue treatment with L-citrulline inhibits hypoxia-induced pulmonary hypertension in newborn pigs. Am. J. Respir. Cell. Mol. Biol. 53, 255–264 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Dedja, A. et al. Lipopolysaccharide-induced chorioamnionitis and postnatal lung injury: the beneficial effects of L-citrulline in newborn rats. Exp. Lung Res. 44, 226–240 (2018).

    Article  CAS  PubMed  Google Scholar 

  19. Xuan, C. et al. L-citrulline for protection of endothelial function from ADMA-induced injury in porcine coronary artery. Sci. Rep. 5, 10987 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Tsuboi, T., Maeda, M. & Hayashi, T. Administration of L-arginine plus L-citrulline or L-citrulline alone successfully retarded endothelial senescence. PLoS One 13, e0192252 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Lauterbach, R., Pawlik, D. & Lauterbach, J. P. L-citrulline supplementation in the treatment of pulmonary hypertension associated with bronchopulmonary dysplasia in preterm infant: a case report. SAGE Open Med. Case Rep. 6, 2050313X18778730 (2018).

    PubMed  PubMed Central  Google Scholar 

  22. Papadia, C., Osowska, S., Cynober, L. & Forbes, A. Citrulline in health and disease. Review on human studies. Clin. Nutr. 37, 1823–1828 (2018).

    Article  CAS  PubMed  Google Scholar 

  23. Lin, Y. J. et al. Inhaled nitric oxide enhances distal lung growth after exposure to hyperoxia in neonatal rats. Pediatr. Res. 58, 22–29 (2005).

    Article  CAS  PubMed  Google Scholar 

  24. Bland, R. D., Albertine, K. H., Carlton, D. P. & MacRitchie, A. J. Inhaled nitric oxide effects on lung structure and function in chronically ventilated preterm lambs. Am. J. Respir. Crit Care Med. 172, 899–906 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Rallis, D., Deierl, A., Atreja, G., Chaban, B. & Banerjee, J. The efficacy of inhaled nitric oxide treatment in premature infants with acute pulmonary hypertension. Early Hum. Dev. 127, 1–5 (2018).

    Article  CAS  PubMed  Google Scholar 

  26. Ham, D. J. et al. L-citrulline protects skeletal muscle cells from cachectic stimuli through an iNOS-dependent mechanism. PLoS One 10, e0141572 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Ginguay, A. et al. Citrulline prevents age-related LTP decline in old rats. Sci. Rep. 9, 20138 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Villareal, M. O., Matsukawa, T. & Isoda, H. L-citrulline supplementation-increased skeletal muscle PGC-1alpha expression is associated with exercise performance and increased skeletal muscle weight. Mol. Nutr. Food Res. 62, e1701043 (2018).

  29. Pham, J., Arul Nambi Rajan, K., Li, P. & Parast, M. M. The role of Sirtuin1-PPARgamma axis in placental development and function. J. Mol. Endocrinol. 60, R201–R212 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Man, A. W. C. et al. l-Citrulline ameliorates pathophysiology in a rat model of superimposed preeclampsia. Br. J. Pharmacol. 179, 3007–3023 (2022).

    Article  CAS  PubMed  Google Scholar 

  31. Rius-Perez, S., Torres-Cuevas, I., Millan, I., Ortega, A. L. & Perez, S. PGC-1alpha, inflammation, and oxidative stress: an integrative view in metabolism. Oxid. Med. Cell. Longev. 2020, 1452696 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Yang, K. & Dong, W. SIRT1-related signaling pathways and their association with bronchopulmonary dysplasia. Front. Med. (Lausanne) 8, 595634 (2021).

    Article  PubMed  Google Scholar 

  33. Ivanovska, J. et al. mTOR-Notch3 signaling mediates pulmonary hypertension in hypoxia-exposed neonatal rats independent of changes in autophagy. Pediatr. Pulmonol. 52, 1443–1454 (2017).

    Article  PubMed  Google Scholar 

  34. Jankov, R. P. & Keith Tanswell, A. Growth factors, postnatal lung growth and bronchopulmonary dysplasia. Paediatr. Respir. Rev. 5, S265–S275 (2004).

    Article  PubMed  Google Scholar 

  35. Aggarwal, S., Dimitropoulou, C., Lu, Q., Black, S. M. & Sharma, S. Glutathione supplementation attenuates lipopolysaccharide-induced mitochondrial dysfunction and apoptosis in a mouse model of acute lung injury. Front. Physiol. 3, 161 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Fu, C. et al. Dexmedetomidine attenuates lipopolysaccharide-induced acute lung injury by inhibiting oxidative stress, mitochondrial dysfunction and apoptosis in rats. Mol. Med. Rep. 15, 131–138 (2017).

    Article  CAS  PubMed  Google Scholar 

  37. Canto, C. & Auwerx, J. PGC-1alpha, SIRT1 and AMPK, an energy sensing network that controls energy expenditure. Curr. Opin. Lipidol. 20, 98–105 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Wang, G. et al. Activation of AMPK attenuates LPS-induced acute lung injury by upregulation of PGC1alpha and SOD1. Exp. Ther. Med. 12, 1551–1555 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kurundkar, D. et al. SIRT3 diminishes inflammation and mitigates endotoxin-induced acute lung injury. JCI Insight 4, e120722. https://doi.org/10.1172/jci.insight.120722 (2019).

  40. Tan, F. et al. Attenuated SUMOylation of sirtuin 1 in premature neonates with bronchopulmonary dysplasia. Mol. Med. Rep. 17, 1283–1288 (2018).

    CAS  PubMed  Google Scholar 

  41. 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) 246, 596–606 (2021).

    Article  CAS  PubMed  Google Scholar 

  42. de Wijs-Meijler, D. P. et al. Oxidative injury of the pulmonary circulation in the perinatal period: short- and long-term consequences for the human cardiopulmonary system. Pulm. Circ. 7, 55–66 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  43. Roberts, K., Stepanovich, G., Bhatt-Mehta, V. & Donn, S. M. New pharmacologic approaches to bronchopulmonary dysplasia. J. Exp. Pharmacol. 13, 377–396 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Jankov, R. P. et al. Fibroblast growth factor receptor-1 and neonatal compensatory lung growth after exposure to 95% oxygen. Am. J. Respir. Crit. Care Med. 167, 1554–1561 (2003).

    Article  PubMed  Google Scholar 

  45. McGrath-Morrow, S. A. et al. Immune response to intrapharyngeal LPS in neonatal and juvenile mice. Am. J. Respir. Cell. Mol. Biol. 52, 323–331 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Olmos, Y. et al. SirT1 regulation of antioxidant genes is dependent on the formation of a FoxO3a/PGC-1alpha complex. Antioxid. Redox Signal. 19, 1507–1521 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Brunet, A. et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 303, 2011–2015 (2004).

    Article  CAS  PubMed  Google Scholar 

  48. Merksamer, P. I. et al. The sirtuins, oxidative stress and aging: an emerging link. Aging (Albany NY) 5, 144–150 (2013).

    Article  CAS  PubMed  Google Scholar 

  49. Ren, Z. et al. The role of different SIRT1-mediated signaling pathways in toxic injury. Cell. Mol. Biol. Lett. 24, 36 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Mody, K. et al. Sirtuin1 in tracheal aspirate leukocytes: possible role in the development of bronchopulmonary dysplasia in premature infants. J. Matern. Fetal Neonatal Med. 25, 1483–1487 (2012).

    Article  CAS  PubMed  Google Scholar 

  51. Fu, C. et al. Activation of SIRT1 ameliorates LPS-induced lung injury in mice via decreasing endothelial tight junction permeability. Acta Pharmacol. Sin. 40, 630–641 (2019).

    Article  CAS  PubMed  Google Scholar 

  52. Kudo, M. et al. L-citrulline inhibits body weight gain and hepatic fat accumulation by improving lipid metabolism in a rat nonalcoholic fatty liver disease model. Food Sci. Nutr. 9, 4893–4904 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Kim, M. Y. et al. Resveratrol prevents renal lipotoxicity and inhibits mesangial cell glucotoxicity in a manner dependent on the AMPK-SIRT1-PGC1alpha axis in db/db mice. Diabetologia 56, 204–217 (2013).

    Article  CAS  PubMed  Google Scholar 

  54. Zu, Y. et al. SIRT1 promotes proliferation and prevents senescence through targeting LKB1 in primary porcine aortic endothelial cells. Circ. Res. 106, 1384–1393 (2010).

    Article  CAS  PubMed  Google Scholar 

  55. Xia, N. et al. Role of SIRT1 and FOXO factors in eNOS transcriptional activation by resveratrol. Nitric Oxide 32, 29–35 (2013).

    Article  CAS  PubMed  Google Scholar 

  56. Bai, B., Vanhoutte, P. M. & Wang, Y. Loss-of-SIRT1 function during vascular ageing: hyperphosphorylation mediated by cyclin-dependent kinase 5. Trends Cardiovasc. Med. 24, 81–84 (2014).

    Article  CAS  PubMed  Google Scholar 

  57. Zhang, W. et al. Sirt1 protects endothelial cells against LPS-induced barrier dysfunction. Oxid. Med. Cell. Longev. 2017, 4082102 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Ye, Q. et al. Overexpression of PGC-1alpha influences mitochondrial signal transduction of dopaminergic neurons. Mol. Neurobiol. 53, 3756–3770 (2016).

    Article  CAS  PubMed  Google Scholar 

  59. Wu, Z. et al. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98, 115–124 (1999).

    Article  CAS  PubMed  Google Scholar 

  60. Scarpulla, R. C. Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network. Biochim. Biophys. Acta 1813, 1269–1278 (2011).

    Article  CAS  PubMed  Google Scholar 

  61. Taherzadeh-Fard, E. et al. PGC-1alpha downstream transcription factors NRF-1 and TFAM are genetic modifiers of Huntington disease. Mol. Neurodegener. 6, 32 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Ten, V. S. & Ratner, V. Mitochondrial bioenergetics and pulmonary dysfunction: current progress and future directions. Paediatr. Respir. Rev. 34, 37–45 (2020).

    PubMed  Google Scholar 

  63. Xuefei, Y. et al. Effects of hyperoxia on mitochondrial homeostasis: are mitochondria the hub for bronchopulmonary dysplasia? Front. Cell. Dev. Biol. 9, 642717 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Ratner, V. et al. Hypoxic stress exacerbates hyperoxia-induced lung injury in a neonatal mouse model of bronchopulmonary dysplasia. Neonatology 95, 299–305 (2009).

    Article  CAS  PubMed  Google Scholar 

  65. Moinard, C. et al. Citrulline supplementation induces changes in body composition and limits age-related metabolic changes in healthy male rats. J. Nutr. 145, 1429–1437 (2015).

    Article  CAS  PubMed  Google Scholar 

  66. Wadley, G. D. & McConell, G. K. Effect of nitric oxide synthase inhibition on mitochondrial biogenesis in rat skeletal muscle. J. Appl. Physiol. (1985) 102, 314–320 (2007).

    Article  CAS  PubMed  Google Scholar 

  67. Suliman, H. B., Carraway, M. S., Welty-Wolf, K. E., Whorton, A. R. & Piantadosi, C. A. Lipopolysaccharide stimulates mitochondrial biogenesis via activation of nuclear respiratory factor-1. J. Biol. Chem. 278, 41510–41518 (2003).

    Article  CAS  PubMed  Google Scholar 

  68. Kong, X. et al. Sirtuin 3, a new target of PGC-1alpha, plays an important role in the suppression of ROS and mitochondrial biogenesis. PLoS One 5, e11707 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  69. Morigi, M. et al. Sirtuin 3-dependent mitochondrial dynamic improvements protect against acute kidney injury. J. Clin. Invest. 125, 715–726 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  70. Marcus, J. M. & Andrabi, S. A. SIRT3 regulation under cellular stress: making sense of the ups and downs. Front. Neurosci. 12, 799 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Perrone, S., Tataranno, M. L. & Buonocore, G. Oxidative stress and bronchopulmonary dysplasia. J. Clin. Neonatol. 1, 109–114 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Alvira, C. M. Nuclear factor-kappa-B signaling in lung development and disease: one pathway, numerous functions. Birth Defects Res. A Clin. Mol. Teratol. 100, 202–216 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Jones, C. V. et al. M2 macrophage polarisation is associated with alveolar formation during postnatal lung development. Respir. Res. 14, 41 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Hirani, D. et al. Macrophage-derived IL-6 trans-signalling as a novel target in the pathogenesis of bronchopulmonary dysplasia. Eur. Respir. J. 59, 2002248. https://doi.org/10.1183/13993003.02248-2020 (2022).

Download references

Acknowledgements

We thank Sonia Dos Santos for the excellent technical assistance and Dr Douglas Watson for editing the manuscript.

Funding

The study was supported by the Women’s Auxiliary Chair in Neonatology at The Hospital for Sick Children.

Author information

Authors and Affiliations

  1. Translational Medicine and Cell Biology Programs, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, ON, Canada

    Nikola Ivanovski, Huanhuan Wang, Harvard Tran, Julijana Ivanovska, Jingyi Pan, Emily Miraglia, Sharon Leung, Melanie Posiewko, Daniel Li, Atefeh Mohammadi, Randa Higazy, Peter Kim, Giles Santyr, Jaques Belik, Nades Palaniyar & Estelle B. Gauda

  2. Department of Physiology, University of Toronto, Toronto, ON, Canada

    Nikola Ivanovski & Jaques Belik

  3. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada

    Harvard Tran, Atefeh Mohammadi, Anita Nagy, Nades Palaniyar & Estelle B. Gauda

  4. Department of Biochemistry, University of Toronto, Toronto, ON, Canada

    Emily Miraglia & Peter Kim

  5. Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada

    Randa Higazy

  6. Division of Anatomical Pathology, The Hospital for Sick Children, Toronto, ON, Canada

    Anita Nagy

  7. Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada

    Giles Santyr

  8. Division of Neonatology, The Hospital for Sick Children, Toronto, ON, Canada

    Jaques Belik & Estelle B. Gauda

Authors
  1. Nikola Ivanovski
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Huanhuan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Harvard Tran
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Julijana Ivanovska
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jingyi Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Emily Miraglia
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sharon Leung
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Melanie Posiewko
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Daniel Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Atefeh Mohammadi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Randa Higazy
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Anita Nagy
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Peter Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Giles Santyr
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Jaques Belik
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Nades Palaniyar
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Estelle B. Gauda
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

N.I.: substantial contributions to conception and design; acquisition, analysis and interpretation of data; drafting and revising the article. H.W., H.T., J.I., J.P., E.M., S.L., M.P., D.L., A.M. and R.H.: substantial contributions to acquisition, analysis and interpretation of data. A.N., P.K., G.S., J.B. and N.P.: substantial contributions to conception and design; interpretation of data; critical revision for important intellectual content. E.B.G.: substantial contributions to conception and design, and interpretation of data; drafting the article or revising it critically for important intellectual content; final approval of the version to be published.

Corresponding author

Correspondence to Estelle B. Gauda.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ivanovski, N., Wang, H., Tran, H. et al. L-citrulline attenuates lipopolysaccharide-induced inflammatory lung injury in neonatal rats. Pediatr Res 94, 1684–1695 (2023). https://doi.org/10.1038/s41390-023-02684-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41390-023-02684-1

Search

Advanced search

Quick links