Abstract
Background
Brain hypoxic–ischemic (HI) damage induces distant inflammatory lung damage in newborn pigs. We aimed to investigate the effects of cannabidiol (CBD) on lung damage in this scenario.
Methods
Newborn piglets received intravenous vehicle, CBD, or CBD+WAY100635 (5-HT1A receptor antagonist) after HI brain damage (carotid flow interruption and FiO2 0.10 for 30 min). Total lung compliance (TLC), oxygenation index (OI), and extravascular lung water content (EVLW) were monitored for 6 h. Histological damage, interleukin (IL)-1β concentration, and oxidative stress were assessed in brain and lung tissue. Total protein content was determined in bronchoalveolar lavage fluid (BALF).
Results
CBD prevented HI-induced deleterious effects on TLC and OI and reduced lung histological damage, modulating inflammation (decreased leukocyte infiltration and IL-1 concentration) and reducing protein content in BALF and EVLW. These effects were related to CBD-induced anti-inflammatory changes in the brain. HI did not increase oxidative stress in the lungs. In the lungs, WAY100635 blunted the beneficial effects of CBD on histological damage, IL-1 concentration, and EVLW.
Conclusions
CBD reduced brain HI-induced distant lung damage, with 5-HT1A receptor involvement in these effects. Whether the effects of CBD on the lungs were due to the anti-inflammatory effects on the brain or due to the direct effects on the lungs remains to be elucidated.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Martín-Ancel A, García-Alix A, Gayá F, Cabañas F, Burgueros M, Quero J . Multiple organ involvement in perinatal asphyxia. J Pediatr 1995;127:786–793.
Shah P, Riphagen S, Beyene J, Perlman M . Multiorgan dysfunction in infants with post-asphyxial hypoxic-ischaemic encephalopathy. Arch Dis Child Fetal Neonatal Ed 2004;89:F152–F155.
Bocking AD, Gagnon R, White SE, Homan J, Milne KM, Richardson BS . Circulatory responses to prolonged hypoxemia in fetal sheep. Am J Obstet Gynecol 1988;159:1418–24.
Arruza L, Pazos MR, Mohammed N et al, Hypoxic-ischemic brain damage induces distant inflammatory lung injury in newborn piglets. Pediatr Res 2015;79:401–8.
Hampson AJ, Grimaldi M, Axelrod J, Wink D . Cannabidiol and (-)Delta9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci USA 1998;95:8268–73.
Mechoulam R, Peters M, Murillo-Rodriguez E, Hanus LO . Cannabidiol—recent advances. Chem Biodivers 2007;4:1678–92.
Pertwee R. The pharmacology and therapeutic potential of cannabidiol. In: Di Marzo V, ed. Cannabinoids. New York: Kluwer Academic/Plenum Publishers, 2004:32–83.
Castillo A, Tolón MR, Fernández-Ruiz J, Romero J, Martinez-Orgado J . The neuroprotective effect of cannabidiol in an in vitro model of newborn hypoxic-ischemic brain damage in mice is mediated by CB2 and adenosine receptors. Neurobiol Dis 2010;37:434–440.
Alvarez FJ, Lafuente H, Rey-Santano MC et al, Neuroprotective effects of the nonpsychoactive cannabinoid cannabidiol in hypoxic-ischemic newborn piglets. Pediatr Res 2008;64:653–8.
Lafuente H, Alvarez FJ, Pazos MR et al, Cannabidiol reduces brain damage and improves functional recovery after acute hypoxia-ischemia in newborn pigs. Pediatr Res 2011;70:272–7.
Pazos MR, Cinquina V, Gómez A et al, Cannabidiol administration after hypoxia-ischemia to newborn rats reduces long-term brain injury and restores neurobehavioral function. Neuropharmacology 2012;63:776–83.
Pazos MR, Mohammed N, Lafuente H et al, Mechanisms of cannabidiol neuroprotection in hypoxic-ischemic newborn pigs: role of 5HT(1A) and CB2 receptors. Neuropharmacology 2013;71:282–91.
Lafuente H, Pazos MR, Alvarez A et al, Effects of cannabidiol and hypothermia on short-term brain damage in new-born piglets after acute hypoxia-ischemia. Front Neurosci 2016;10:323.
Russo EB, Burnett A, Hall B, Parker KK . Agonistic properties of cannabidiol at 5-HT1a receptors. Neurochem Res 2005;30:1037–43.
Mishima K, Hayakawa K, Abe K et al, Cannabidiol prevents cerebral infarction via a serotonergic 5-hydroxytryptamine1A receptor-dependent mechanism. Stroke 2005;36:1071–1076.
Ribeiro A, Ferraz-de-Paula V, Pinheiro ML et al, Cannabidiol, a non-psychotropic plant-derived cannabinoid, decreases inflammation in a murine model of acute lung injury: role for the adenosine A(2A) receptor. Eur J Pharmacol 2012;678:78–85.
Ribeiro A, Almeida VI, Costola-de-Souza C et al, Cannabidiol improves lung function and inflammation in mice submitted to LPS-induced acute lung injury. Immunopharmacol Immunotoxicol 2015;37:35–41.
Muhammad S, Barakat W, Stoyanov S et al, The HMGB1 receptor RAGE mediates ischemic brain damage. J Neurosci 2008;28:12023–31.
Liesz A, Dalpke A, Mracsko E et al, DAMP signaling is a key pathway inducing immune modulation after brain injury. J Neurosci 2015;35:583–98.
Koutsoukou A, Katsiari M, Orfanos SE et al, Respiratory mechanics in brain injury: a review. World J Crit Care Med 2016;5:65.
Hayakawa K, Irie K, Sano K et al, Therapeutic time window of cannabidiol treatment on delayed ischemic damage via high-mobility group box1-inhibiting mechanism. Biol Pharm Bull 2009;32:1538–44.
Vuolo F, Petronilho F, Sonai B et al, Evaluation of serum cytokines levels and the role of cannabidiol treatment in animal model of asthma. Mediators Inflamm 2015;2015:538670.
Kim YE, Park WS, Sung DK et al, Intratracheal transplantation of mesenchymal stem cells simultaneously attenuates both lung and brain injuries in hyperoxic newborn rats. Pediatr Res 2016;80:415–24.
Seeley EJ . A dry lung is a happy lung: More supporting evidence. J Thorac Cardiovasc Surg 2015;149:321–2.
Johnston MV, Fatemi A, Wilson MA, Northington F . Treatment advances in neonatal neuroprotection and neurointensive care. Lancet Neurol 2011;10:372–82.
Gdovin MJ, Zamora DA, Ravindran CRM, Leiter JC . Serotonergic modulation of respiratory rhythmogenesis and central chemoreception. Ethn Dis 2010;20:S1–39-44.
Barrett KT, Kinney HC, Li A, Daubenspeck JA, Leiter JC, Nattie EE . Subtle alterations in breathing and heart rate control in the 5-HT1A receptor knockout mouse in early postnatal development. J Appl Physiol 2012;113:1585–93.
Skinner MR, Ramage AG, Jordan D . Modulation of reflexly evoked vagal bradycardias by central 5-HT1A receptors in anaesthetized rabbits. Br J Pharmacol 2002;137:861–73.
Ramage AG, Villalón CM . 5-Hydroxytryptamine and cardiovascular regulation. Trends Pharmacol Sci 2008;29:472–81.
Dudášová A, Keir SD, Parsons ME, Molleman A, Page CP . The effects of cannabidiol on the antigen-induced contraction of airways smooth muscle in the guinea-pig. Pulm Pharmacol Ther 2013;26:373–9.
Acknowledgements
Technical and human support provided by María Dolores Molina Corzo is gratefully acknowledged. We are also indebted to Francisco Tendillo, MD, PhD, for his help with performing this experiment. Finally, we thank Jason Willis-Lee MITI for author’s editing services provided during preparation of the final manuscript.
Statement of financial support
This work was supported by grants from the Research Institute Carlos III (ISCIII) according to the Spanish Plan for RI+D+I 2008–2011, the Spanish Plan for Scientific and Technical Research and Innovation 2013–2016, with co-funding from European Regional Development Funds (FEDER) (FIS PI12/00852, PS12/00192, and PI13/01722), the Biomedicine Program, Community of Madrid (S2010/BMD-2308), and GW Research (Cambridge, UK; GWCRI09119). None of the funding sources were involved in the study design, collection, analysis, and interpretation of data or the decision to submit the article for publication.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
Jose Martinez-Orgado has a Research Agreement with GW Research (Cambridge, UK). The remaining authors declare no conflict of interest.
Rights and permissions
About this article
Cite this article
Arruza, L., Pazos, M., Mohammed, N. et al. Cannabidiol reduces lung injury induced by hypoxic–ischemic brain damage in newborn piglets. Pediatr Res 82, 79–86 (2017). https://doi.org/10.1038/pr.2017.104
Received:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/pr.2017.104
This article is cited by
-
Cannabidiol and Sports Performance: a Narrative Review of Relevant Evidence and Recommendations for Future Research
Sports Medicine - Open (2020)
