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Chronic Intermittent Hypoxia in Premature Infants: The Link Between Low Fat Stores, Adiponectin Receptor Signaling and Lung Injury

  • Na-Young Kang
  • Julijana Ivanovska
  • Liran Tamir-Hostovsky
  • Jaques Belik
  • Estelle B. GaudaEmail author
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1071)

Abstract

Premature infants have chronic intermittent hypoxia (CIH) that increases morbidity, and the youngest and the smallest premature infants are at the greatest risk. The combination of lung injury from inflammation/oxidative stress causing low functional residual capacity combined with frequent short apneas leads to CIH. Adiponectin (APN) is an adipose-derived adipokine that protects the lung from inflammation and oxidative stress. Premature and small for gestational age (SGA) infants have minimal body fat and low levels of circulating APN. To begin to understand the potential role of APN in lung protection during lung development, we characterized the developmental profile of APN and APN receptors (AdipoR1 and AdipoR2) protein and mRNA expression in the newborn rat lung at fetal day (FD) 19, and postnatal days (PD) 1, 4, 7, 10, 14, 21, and 28. Protein levels in lung homogenates were measured by western blot analyses; relative mRNA expression was detected by quantitative PCR (qPCR); and serum high molecular weight (HMW) APN was measured using enzyme-linked immunosorbent assay (ELISA). Results: APN protein and mRNA levels were lowest at FD19 and PD1, increased 2.2-fold at PD4, decreased at PD10, and then increased again at PD21. AdipoR1 protein and mRNA levels peaked at PD1, followed by a threefold drop by PD4, and remained low until PD21. AdipoR2 protein and mRNA levels also peaked at PD1, but remained high at PD4, followed by a 1.7-fold drop by PD10 that remained low by PD21. Serum APN levels detected by ELISA did not differ from PD4 to PD28. To date, this is the first report characterizing APN and APN receptor protein and mRNA expression in the rat lung during development. The developmental stage of the newborn rat lung models that of the premature human infant; both are in the saccular stage of lung development. In the newborn rat lung, alveolarization begins at PD4, peaks at PD10, and ends at PD21. Importantly, we found that AdipoR1 receptor protein and mRNA expression is lowest during lung alveolarization (PD4 to PD21). Thus, we speculate that low levels of AdipoR1 during lung alveolarization contributes to the increased susceptibility to developing acute lung edema and chronic lung injury such as bronchopulmonary dysplasia (BPD) in premature human infants.

Keywords

Adiponectin Alveolarization Bronchopulmonary dysplasia Developmental profile Lung development 

References

  1. Bianco A, Mazzarella G, Turchiarelli V, Nigro E, Corbi G, Scudiero O, Sofia M, Daniele A (2013) Adiponectin: an attractive marker for metabolic disorders in chronic obstructive pulmonary disease (COPD). Nutrients 5(10):4115–4125CrossRefGoogle Scholar
  2. Chen C, Huang J, Li H, Zhang C, Huang X, Tong G, Xu Y (2015) MicroRNA-221 regulates endothelial nitric oxide production and inflammatory response by targeting adiponectin receptor 1. Gene 565(2):246–251CrossRefGoogle Scholar
  3. Chen H, Yang C, Chang J, Wu C, Sia K, Lin W (2016) AdipoR-increased intracellular ROS promoted cPLA2and COX-2 expression via activation of PKC and p300 in adiponectin-stimulated human alveolar type II cells. Am J Physiol Lung Cell Mol Physiol 311(2):L255–L269CrossRefGoogle Scholar
  4. Di Fiore JM, Martin RJ, Gauda EB (2013) Apnea of prematurity – perfect storm. Respir Physiol Neurobiol 189(2):213–222CrossRefGoogle Scholar
  5. Gauda EB, Master Z (2017) Contribution of relative leptin and adiponectin deficiencies in premature infants to chronic intermittent hypoxia: exploring a new hypothesis. Respir Physio Neurobiol (Epub ahead of print).  https://doi.org/10.1016/j.resp.2017.12.003 CrossRefGoogle Scholar
  6. Hansen-Pupp I, Hellgren G, Hård AL, Smith L, Hellström A, Löfqvist C (2015) Early surge in circulatory adiponectin is associated with improved growth at near term in very preterm infants. J Clin Endocrinol Metab 100(6):2380–2387CrossRefGoogle Scholar
  7. Jobe AH, Ikegami M (2000) Lung development and function in preterm infants in the surfactant treatment era. Annu Rev Physiol 62(1):825–846CrossRefGoogle Scholar
  8. Luo Y, Liu M (2016) Adiponectin: a versatile player of innate immunity. J Mol Cell Biol 8(2):120–128CrossRefGoogle Scholar
  9. Miller M, Cho JY, Pham A, Ramsdell J, Broide DH (2009) Adiponectin and functional adiponectin receptor 1 are expressed by airway epithelial cells in chronic obstructive pulmonary disease. J Immunol 182(1):684–691CrossRefGoogle Scholar
  10. Morales E, Sakurai R, Husain S, Paek D, Gong M, Ibe B, Li Y, Husain M, Torday JS, Rehan VK (2014) Nebulized PPARγ agonists: a novel approach to augment neonatal lung maturation and injury repair in rats. Pediatr Res 75(5):631–640CrossRefGoogle Scholar
  11. Nigro E, Scudiero O, Sarnataro D, Mazzarella G, Sofia M, Bianco A, Daniele A (2013) Adiponectin affects lung epithelial A549 cell viability counteracting TNFa and IL-1ß toxicity through AdipoR1. Int J Biochem Cell Biol 45(6):1145–1153CrossRefGoogle Scholar
  12. Sliman SM, Patel RB, Cruff JP, Kotha SR, Newland CA, Schrader CA, Sherwani SI, Gurney TO, Magalang UJ, Parinandi NL (2013) Adiponectin protects against hyperoxic lung injury and vascular leak. Cell Biochem Biophys 67(2):399–414CrossRefGoogle Scholar
  13. Speer CP (2003) Inflammation and bronchopulmonary dysplasia. Semin Neonatol 8(1):29–38CrossRefGoogle Scholar
  14. Weng M, Raher MJ, Leyton P, Combs TP, Scherer PE, Bloch KD, Medoff BD (2011) Adiponectin decreases pulmonary arterial remodeling in murine models of pulmonary hypertension. Am J Respir Cell Mol Biol 45(2):340–347CrossRefGoogle Scholar
  15. Xu L, Bao H, Si Y, Han L, Zhang R, Cai M, Shen Y (2013) Effects of adiponectin on acute lung injury in cecal ligation and puncture–induced sepsis rats. J Surg Res 183(2):752–759CrossRefGoogle Scholar
  16. Zana-Taieb E, Pham H, Franco-Montoya ML, Jacques S, Letourneur F, Baud O, Jarreau PH, Vaiman D (2015) Impaired alveolarization and intra-uterine growth restriction in rats: a postnatal genome-wide analysis. J Pathol 235(3):420–430CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Na-Young Kang
    • 1
  • Julijana Ivanovska
    • 1
  • Liran Tamir-Hostovsky
    • 1
  • Jaques Belik
    • 1
  • Estelle B. Gauda
    • 2
    Email author
  1. 1.The Hospital for Sick Children, Division of NeonatologyUniversity of TorontoTorontoCanada
  2. 2.Department of Pediatrics, The Hospital for Sick ChildrenUniversity of TorontoTorontoCanada

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