L-citrulline attenuates arrested alveolar growth and pulmonary hypertension in oxygen-induced lung injury in newborn rats
Arul Vadivel, Judy L Aschner, Gloria J Rey-Parra, Jordan Magarik, Heng Zeng, Marshall Summar, Farah Eaton, Bernard Thébaud, Arul Vadivel, Judy L Aschner, Gloria J Rey-Parra, Jordan Magarik, Heng Zeng, Marshall Summar, Farah Eaton, Bernard Thébaud
Abstract
Bronchopulmonary dysplasia (BPD) is characterized by arrested alveolar development and complicated by pulmonary hypertension (PH). NO promotes alveolar growth. Inhaled NO (iNO) ameliorates the BPD phenotype in experimental models and in some premature infants. Arginosuccinate synthetase (ASS) and arginosuccinate lyase (ASL) convert L-citrulline to L-arginine; L-citrulline is regenerated during NO synthesis from L-arginine. Plasma levels of these NO precursors are low in PH. We hypothesized that L-citrulline prevents experimental O2-induced BPD in newborn rats. Rat pups were assigned from birth through postnatal day (P) 14 to room air (RA), RA + L-citrulline, 95% hyperoxia (BPD model), and 95%O2 + L-citrulline. Rat pups exposed to hyperoxia had fewer and enlarged air spaces and decreased capillary density, mimicking human BPD. This was associated with decreased plasma L-arginine and L-citrulline concentrations on P7. L-citrulline treatment significantly increased plasma L-arginine and L-citrulline concentrations and increased ASL protein expression in hyperoxia. L-citrulline preserved alveolar and vascular growth in O2-exposed pups and decreased pulmonary arterial medial wall thickness (MWT) and right ventricular hypertrophy (RVH). Increased lung arginase (ARG) activity in O2-exposed pups was reversed by L-citrulline treatment. L-citrulline supplementation prevents hyperoxia-induced lung injury and PH in newborn rats. L-citrulline may represent a novel therapeutic alternative to iNO for prevention of BPD.
Figures
![Figure 1. Schematic of the citrulline-arginine-NO pathway…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3132222/bin/nihms279436f1.jpg)
![Figure 2. Effect of L-citrulline administration from…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3132222/bin/nihms279436f2.jpg)
![Figure 3. L-Citrulline prevents alveolar simplification in…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3132222/bin/nihms279436f3.jpg)
![Figure 4. L-Citrulline improves lung angiogenesis in…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3132222/bin/nihms279436f4.jpg)
Figure 5. L-Citrulline prevents pulmonary hypertension in…
Figure 5. L-Citrulline prevents pulmonary hypertension in O 2 -induced BPD in newborn rats
A. Hyperoxia-exposed rats…
Figure 6. Effects of hyperoxia and postnatal…
Figure 6. Effects of hyperoxia and postnatal age on protein abundance in rat lung homogenates
Figure 7. Effects of L-citrulline treatment on…
Figure 7. Effects of L-citrulline treatment on the abundance of proteins in the citrulline, arginine,…
Figure 8. Effects of hyperoxia and L-citrulline…
Figure 8. Effects of hyperoxia and L-citrulline treatment on protein abundance of arginase II and…
- Inhibition of β-catenin signaling improves alveolarization and reduces pulmonary hypertension in experimental bronchopulmonary dysplasia.Alapati D, Rong M, Chen S, Hehre D, Hummler SC, Wu S. Alapati D, et al. Am J Respir Cell Mol Biol. 2014 Jul;51(1):104-13. doi: 10.1165/rcmb.2013-0346OC. Am J Respir Cell Mol Biol. 2014. PMID: 24484510
- Sildenafil improves alveolar growth and pulmonary hypertension in hyperoxia-induced lung injury.Ladha F, Bonnet S, Eaton F, Hashimoto K, Korbutt G, Thébaud B. Ladha F, et al. Am J Respir Crit Care Med. 2005 Sep 15;172(6):750-6. doi: 10.1164/rccm.200503-510OC. Epub 2005 Jun 9. Am J Respir Crit Care Med. 2005. PMID: 15947285
- L-citrulline prevents alveolar and vascular derangement in a rat model of moderate hyperoxia-induced lung injury.Grisafi D, Tassone E, Dedja A, Oselladore B, Masola V, Guzzardo V, Porzionato A, Salmaso R, Albertin G, Artusi C, Zaninotto M, Onisto M, Milan A, Macchi V, De Caro R, Fassina A, Bordigato MA, Chiandetti L, Filippone M, Zaramella P. Grisafi D, et al. Lung. 2012 Aug;190(4):419-30. doi: 10.1007/s00408-012-9382-z. Epub 2012 Mar 20. Lung. 2012. PMID: 22430123
- Phosphodiesterase 4 inhibition attenuates persistent heart and lung injury by neonatal hyperoxia in rats.de Visser YP, Walther FJ, Laghmani el H, Steendijk P, Middeldorp M, van der Laarse A, Wagenaar GT. de Visser YP, et al. Am J Physiol Lung Cell Mol Physiol. 2012 Jan 1;302(1):L56-67. doi: 10.1152/ajplung.00041.2011. Epub 2011 Sep 23. Am J Physiol Lung Cell Mol Physiol. 2012. PMID: 21949154 Free PMC article.
- The Role of Sphingolipid Signaling in Oxidative Lung Injury and Pathogenesis of Bronchopulmonary Dysplasia.Thomas JM, Sudhadevi T, Basa P, Ha AW, Natarajan V, Harijith A. Thomas JM, et al. Int J Mol Sci. 2022 Jan 23;23(3):1254. doi: 10.3390/ijms23031254. Int J Mol Sci. 2022. PMID: 35163176 Free PMC article. Review.
- The Effect of L-Citrulline Supplementation on Outcomes of Critically Ill Patients under Mechanical Ventilation; a Double-Blind Randomized Controlled Trial.Asgary MR, Mirghazanfari SM, Hazrati E, Hadi V, Mehri Ardestani M, Bani Yaghoobi F, Hadi S. Asgary MR, et al. Arch Acad Emerg Med. 2023 Jan 1;11(1):e11. doi: 10.22037/aaem.v11i1.1774. eCollection 2023. Arch Acad Emerg Med. 2023. PMID: 36620736 Free PMC article.
- PGC-1α activity and mitochondrial dysfunction in preterm infants.Mohammadi A, Higazy R, Gauda EB. Mohammadi A, et al. Front Physiol. 2022 Sep 26;13:997619. doi: 10.3389/fphys.2022.997619. eCollection 2022. Front Physiol. 2022. PMID: 36225305 Free PMC article. Review.
- Progressive Metabolic Abnormalities Associated with the Development of Neonatal Bronchopulmonary Dysplasia.Ye C, Wu J, Reiss JD, Sinclair TJ, Stevenson DK, Shaw GM, Chace DH, Clark RH, Prince LS, Ling XB, Sylvester KG. Ye C, et al. Nutrients. 2022 Aug 28;14(17):3547. doi: 10.3390/nu14173547. Nutrients. 2022. PMID: 36079804 Free PMC article.
- Stem-Cell Therapy for Bronchopulmonary Dysplasia (BPD) in Newborns.Omar SA, Abdul-Hafez A, Ibrahim S, Pillai N, Abdulmageed M, Thiruvenkataramani RP, Mohamed T, Madhukar BV, Uhal BD. Omar SA, et al. Cells. 2022 Apr 9;11(8):1275. doi: 10.3390/cells11081275. Cells. 2022. PMID: 35455954 Free PMC article. Review.
- Pharmacotherapy in Bronchopulmonary Dysplasia: What Is the Evidence?Sakaria RP, Dhanireddy R. Sakaria RP, et al. Front Pediatr. 2022 Mar 9;10:820259. doi: 10.3389/fped.2022.820259. eCollection 2022. Front Pediatr. 2022. PMID: 35356441 Free PMC article. Review.
- Animals
- Animals, Newborn*
- Arginine / blood
- Bronchopulmonary Dysplasia / blood
- Bronchopulmonary Dysplasia / pathology
- Bronchopulmonary Dysplasia / physiopathology*
- Bronchopulmonary Dysplasia / prevention & control*
- Citrulline / blood
- Citrulline / pharmacology
- Citrulline / therapeutic use*
- Disease Models, Animal
- Humans
- Hypertension, Pulmonary / physiopathology
- Hypertension, Pulmonary / prevention & control*
- Infant, Newborn
- Lung / pathology
- Lung / physiopathology
- Lung Injury
- Nitric Oxide / blood
- Pulmonary Alveoli / drug effects
- Pulmonary Alveoli / growth & development*
- Pulmonary Alveoli / physiopathology
- Rats
- Citrulline
- Nitric Oxide
- Arginine
- Full Text Sources
- Other Literature Sources
- Medical
- Miscellaneous
NCBI Literature Resources
The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.
National Library of Medicine
8600 Rockville Pike
Bethesda, MD 20894
![Figure 5. L-Citrulline prevents pulmonary hypertension in…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3132222/bin/nihms279436f5.jpg)
Figure 6. Effects of hyperoxia and postnatal…
Figure 6. Effects of hyperoxia and postnatal age on protein abundance in rat lung homogenates
Figure 7. Effects of L-citrulline treatment on…
Figure 7. Effects of L-citrulline treatment on the abundance of proteins in the citrulline, arginine,…
Figure 8. Effects of hyperoxia and L-citrulline…
Figure 8. Effects of hyperoxia and L-citrulline treatment on protein abundance of arginase II and…
- Inhibition of β-catenin signaling improves alveolarization and reduces pulmonary hypertension in experimental bronchopulmonary dysplasia.Alapati D, Rong M, Chen S, Hehre D, Hummler SC, Wu S. Alapati D, et al. Am J Respir Cell Mol Biol. 2014 Jul;51(1):104-13. doi: 10.1165/rcmb.2013-0346OC. Am J Respir Cell Mol Biol. 2014. PMID: 24484510
- Sildenafil improves alveolar growth and pulmonary hypertension in hyperoxia-induced lung injury.Ladha F, Bonnet S, Eaton F, Hashimoto K, Korbutt G, Thébaud B. Ladha F, et al. Am J Respir Crit Care Med. 2005 Sep 15;172(6):750-6. doi: 10.1164/rccm.200503-510OC. Epub 2005 Jun 9. Am J Respir Crit Care Med. 2005. PMID: 15947285
- L-citrulline prevents alveolar and vascular derangement in a rat model of moderate hyperoxia-induced lung injury.Grisafi D, Tassone E, Dedja A, Oselladore B, Masola V, Guzzardo V, Porzionato A, Salmaso R, Albertin G, Artusi C, Zaninotto M, Onisto M, Milan A, Macchi V, De Caro R, Fassina A, Bordigato MA, Chiandetti L, Filippone M, Zaramella P. Grisafi D, et al. Lung. 2012 Aug;190(4):419-30. doi: 10.1007/s00408-012-9382-z. Epub 2012 Mar 20. Lung. 2012. PMID: 22430123
- Phosphodiesterase 4 inhibition attenuates persistent heart and lung injury by neonatal hyperoxia in rats.de Visser YP, Walther FJ, Laghmani el H, Steendijk P, Middeldorp M, van der Laarse A, Wagenaar GT. de Visser YP, et al. Am J Physiol Lung Cell Mol Physiol. 2012 Jan 1;302(1):L56-67. doi: 10.1152/ajplung.00041.2011. Epub 2011 Sep 23. Am J Physiol Lung Cell Mol Physiol. 2012. PMID: 21949154 Free PMC article.
- The Role of Sphingolipid Signaling in Oxidative Lung Injury and Pathogenesis of Bronchopulmonary Dysplasia.Thomas JM, Sudhadevi T, Basa P, Ha AW, Natarajan V, Harijith A. Thomas JM, et al. Int J Mol Sci. 2022 Jan 23;23(3):1254. doi: 10.3390/ijms23031254. Int J Mol Sci. 2022. PMID: 35163176 Free PMC article. Review.
- The Effect of L-Citrulline Supplementation on Outcomes of Critically Ill Patients under Mechanical Ventilation; a Double-Blind Randomized Controlled Trial.Asgary MR, Mirghazanfari SM, Hazrati E, Hadi V, Mehri Ardestani M, Bani Yaghoobi F, Hadi S. Asgary MR, et al. Arch Acad Emerg Med. 2023 Jan 1;11(1):e11. doi: 10.22037/aaem.v11i1.1774. eCollection 2023. Arch Acad Emerg Med. 2023. PMID: 36620736 Free PMC article.
- PGC-1α activity and mitochondrial dysfunction in preterm infants.Mohammadi A, Higazy R, Gauda EB. Mohammadi A, et al. Front Physiol. 2022 Sep 26;13:997619. doi: 10.3389/fphys.2022.997619. eCollection 2022. Front Physiol. 2022. PMID: 36225305 Free PMC article. Review.
- Progressive Metabolic Abnormalities Associated with the Development of Neonatal Bronchopulmonary Dysplasia.Ye C, Wu J, Reiss JD, Sinclair TJ, Stevenson DK, Shaw GM, Chace DH, Clark RH, Prince LS, Ling XB, Sylvester KG. Ye C, et al. Nutrients. 2022 Aug 28;14(17):3547. doi: 10.3390/nu14173547. Nutrients. 2022. PMID: 36079804 Free PMC article.
- Stem-Cell Therapy for Bronchopulmonary Dysplasia (BPD) in Newborns.Omar SA, Abdul-Hafez A, Ibrahim S, Pillai N, Abdulmageed M, Thiruvenkataramani RP, Mohamed T, Madhukar BV, Uhal BD. Omar SA, et al. Cells. 2022 Apr 9;11(8):1275. doi: 10.3390/cells11081275. Cells. 2022. PMID: 35455954 Free PMC article. Review.
- Pharmacotherapy in Bronchopulmonary Dysplasia: What Is the Evidence?Sakaria RP, Dhanireddy R. Sakaria RP, et al. Front Pediatr. 2022 Mar 9;10:820259. doi: 10.3389/fped.2022.820259. eCollection 2022. Front Pediatr. 2022. PMID: 35356441 Free PMC article. Review.
- Animals
- Animals, Newborn*
- Arginine / blood
- Bronchopulmonary Dysplasia / blood
- Bronchopulmonary Dysplasia / pathology
- Bronchopulmonary Dysplasia / physiopathology*
- Bronchopulmonary Dysplasia / prevention & control*
- Citrulline / blood
- Citrulline / pharmacology
- Citrulline / therapeutic use*
- Disease Models, Animal
- Humans
- Hypertension, Pulmonary / physiopathology
- Hypertension, Pulmonary / prevention & control*
- Infant, Newborn
- Lung / pathology
- Lung / physiopathology
- Lung Injury
- Nitric Oxide / blood
- Pulmonary Alveoli / drug effects
- Pulmonary Alveoli / growth & development*
- Pulmonary Alveoli / physiopathology
- Rats
- Citrulline
- Nitric Oxide
- Arginine
- Full Text Sources
- Other Literature Sources
- Medical
- Miscellaneous
NCBI Literature Resources
The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.
National Library of Medicine
8600 Rockville Pike
Bethesda, MD 20894
![Figure 6. Effects of hyperoxia and postnatal…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3132222/bin/nihms279436f6.jpg)
Figure 7. Effects of L-citrulline treatment on…
Figure 7. Effects of L-citrulline treatment on the abundance of proteins in the citrulline, arginine,…
Figure 8. Effects of hyperoxia and L-citrulline…
Figure 8. Effects of hyperoxia and L-citrulline treatment on protein abundance of arginase II and…
- Inhibition of β-catenin signaling improves alveolarization and reduces pulmonary hypertension in experimental bronchopulmonary dysplasia.Alapati D, Rong M, Chen S, Hehre D, Hummler SC, Wu S. Alapati D, et al. Am J Respir Cell Mol Biol. 2014 Jul;51(1):104-13. doi: 10.1165/rcmb.2013-0346OC. Am J Respir Cell Mol Biol. 2014. PMID: 24484510
- Sildenafil improves alveolar growth and pulmonary hypertension in hyperoxia-induced lung injury.Ladha F, Bonnet S, Eaton F, Hashimoto K, Korbutt G, Thébaud B. Ladha F, et al. Am J Respir Crit Care Med. 2005 Sep 15;172(6):750-6. doi: 10.1164/rccm.200503-510OC. Epub 2005 Jun 9. Am J Respir Crit Care Med. 2005. PMID: 15947285
- L-citrulline prevents alveolar and vascular derangement in a rat model of moderate hyperoxia-induced lung injury.Grisafi D, Tassone E, Dedja A, Oselladore B, Masola V, Guzzardo V, Porzionato A, Salmaso R, Albertin G, Artusi C, Zaninotto M, Onisto M, Milan A, Macchi V, De Caro R, Fassina A, Bordigato MA, Chiandetti L, Filippone M, Zaramella P. Grisafi D, et al. Lung. 2012 Aug;190(4):419-30. doi: 10.1007/s00408-012-9382-z. Epub 2012 Mar 20. Lung. 2012. PMID: 22430123
- Phosphodiesterase 4 inhibition attenuates persistent heart and lung injury by neonatal hyperoxia in rats.de Visser YP, Walther FJ, Laghmani el H, Steendijk P, Middeldorp M, van der Laarse A, Wagenaar GT. de Visser YP, et al. Am J Physiol Lung Cell Mol Physiol. 2012 Jan 1;302(1):L56-67. doi: 10.1152/ajplung.00041.2011. Epub 2011 Sep 23. Am J Physiol Lung Cell Mol Physiol. 2012. PMID: 21949154 Free PMC article.
- The Role of Sphingolipid Signaling in Oxidative Lung Injury and Pathogenesis of Bronchopulmonary Dysplasia.Thomas JM, Sudhadevi T, Basa P, Ha AW, Natarajan V, Harijith A. Thomas JM, et al. Int J Mol Sci. 2022 Jan 23;23(3):1254. doi: 10.3390/ijms23031254. Int J Mol Sci. 2022. PMID: 35163176 Free PMC article. Review.
- The Effect of L-Citrulline Supplementation on Outcomes of Critically Ill Patients under Mechanical Ventilation; a Double-Blind Randomized Controlled Trial.Asgary MR, Mirghazanfari SM, Hazrati E, Hadi V, Mehri Ardestani M, Bani Yaghoobi F, Hadi S. Asgary MR, et al. Arch Acad Emerg Med. 2023 Jan 1;11(1):e11. doi: 10.22037/aaem.v11i1.1774. eCollection 2023. Arch Acad Emerg Med. 2023. PMID: 36620736 Free PMC article.
- PGC-1α activity and mitochondrial dysfunction in preterm infants.Mohammadi A, Higazy R, Gauda EB. Mohammadi A, et al. Front Physiol. 2022 Sep 26;13:997619. doi: 10.3389/fphys.2022.997619. eCollection 2022. Front Physiol. 2022. PMID: 36225305 Free PMC article. Review.
- Progressive Metabolic Abnormalities Associated with the Development of Neonatal Bronchopulmonary Dysplasia.Ye C, Wu J, Reiss JD, Sinclair TJ, Stevenson DK, Shaw GM, Chace DH, Clark RH, Prince LS, Ling XB, Sylvester KG. Ye C, et al. Nutrients. 2022 Aug 28;14(17):3547. doi: 10.3390/nu14173547. Nutrients. 2022. PMID: 36079804 Free PMC article.
- Stem-Cell Therapy for Bronchopulmonary Dysplasia (BPD) in Newborns.Omar SA, Abdul-Hafez A, Ibrahim S, Pillai N, Abdulmageed M, Thiruvenkataramani RP, Mohamed T, Madhukar BV, Uhal BD. Omar SA, et al. Cells. 2022 Apr 9;11(8):1275. doi: 10.3390/cells11081275. Cells. 2022. PMID: 35455954 Free PMC article. Review.
- Pharmacotherapy in Bronchopulmonary Dysplasia: What Is the Evidence?Sakaria RP, Dhanireddy R. Sakaria RP, et al. Front Pediatr. 2022 Mar 9;10:820259. doi: 10.3389/fped.2022.820259. eCollection 2022. Front Pediatr. 2022. PMID: 35356441 Free PMC article. Review.
- Animals
- Animals, Newborn*
- Arginine / blood
- Bronchopulmonary Dysplasia / blood
- Bronchopulmonary Dysplasia / pathology
- Bronchopulmonary Dysplasia / physiopathology*
- Bronchopulmonary Dysplasia / prevention & control*
- Citrulline / blood
- Citrulline / pharmacology
- Citrulline / therapeutic use*
- Disease Models, Animal
- Humans
- Hypertension, Pulmonary / physiopathology
- Hypertension, Pulmonary / prevention & control*
- Infant, Newborn
- Lung / pathology
- Lung / physiopathology
- Lung Injury
- Nitric Oxide / blood
- Pulmonary Alveoli / drug effects
- Pulmonary Alveoli / growth & development*
- Pulmonary Alveoli / physiopathology
- Rats
- Citrulline
- Nitric Oxide
- Arginine
- Full Text Sources
- Other Literature Sources
- Medical
- Miscellaneous
![Figure 7. Effects of L-citrulline treatment on…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3132222/bin/nihms279436f7.jpg)
Figure 8. Effects of hyperoxia and L-citrulline…
Figure 8. Effects of hyperoxia and L-citrulline treatment on protein abundance of arginase II and…
![Figure 8. Effects of hyperoxia and L-citrulline…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3132222/bin/nihms279436f8.jpg)
Source: PubMed