Abstract
Pulmonary NEB, widely distributed within the airway mucosa of mammalian lungs, are presumed hypoxia sensitive airway O2 sensors responding to changes in airway gas concentration. NEB cell hyperplasia has been reported after exposure to chronic hypoxia and in a variety of paediatric and adult lung disorders. Prolyl hydroxylases (PHD 1–3) regulate the stability of hypoxia-inducible factors (HIF’s) in an O2-dependent manner and function as intrinsic oxygen sensors. To determine a possible role of PHD-1in NEB cells we have quantitated NEB’s in lungs of neonatal (P2) and adult (2 months) PHD-1-deficient mice and compared them to wild type (WT) control mice. Lung tissues fixed in formalin and embedded in paraffin were processed for immunoperoxidase method and frozen sections for multilabel immunoflourescence using antibodies for NEB markers synaptophysin, synaptic vesicle protein 2 and the peptide CGRP. The frequency and size of NEB in lungs of PHD-1 deficient neonatal mice (P2) and at 2 months was increased significantly compared to WT controls (p < 0.01). The present data suggests an important role for PHD enzymes in NEB cell biology deserving further studies. Since the PHD-1 deficient mouse appears to be the first animal model showing NEB cell hyperplasia it may be useful for studies of NEB physiology and pathobiology.
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References
Appelhoff RJ, Tian Ya-Min, Raval RR et al (2004) Differential function of the prolyl hydroxylases PHD 1, PHD 2, and PHD 3 in the regulation of hypoxia –inducible factor. J Biol Chem 279:38458–38465
Aragones J, Schneider M, VanGeyte K et al (2008) Deficiency or inhibition of oxygen sensor PHD 1 induces hypoxia tolerance by reprogramming basal metabolism. Nat Genet 40:170–189
Borges MW, Linnoila RI, van de Velde HJ et al (1997) An achaete-scute homologue essential for neuroendocrine differentiation in the lung. Nature 386:852–855
Cutz E, Gillan JE, Bryan AC (1985) Neuroendocrine cells in the developing human lung: morphologic and functional considerations. Pediatr Pulmonol 1:S21–S29
Cutz E, Yeger H, Pan J (2007a) Pulmonary neuroendocrine cell system in pediatric lung disease-recent advances. Pediatr Dev Pathol 10:419–435
Cutz E, Perrin DG, Pan J, Haas EA, Krous FK (2007b) Pulmonary neuroendocrine cells and neuroepithelial bodies in sudden infant death syndrome: potential markers of airway chemoreceptor dysfunction. Ped Dev Pathol 10:106–116
Cutz E, Yeger H, Pan J, Ito T (2008) Pulmonary neuroendocrine cell system in health and disease. Curr Respir Med Rev 4:174–183
Fu XW, Wang D, Nurse CA, Dinauer MC, Cutz E (2000) NADPH oxidase in an O2 sensor in airway chemoreceptors: evidence from K+ current modulation in wild type and oxidase deficient mice. Proc Natl Acad Sci U S A 97:4374–4379
Kaelin WG, Ratcliffe PJ (2008) Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell 30:393–402
Kazemian P, Stephenson R, Yeger H, Cutz E (2001) Respiratory control in neonatal mice with NADPH oxidase deficiency. Respir Physiol 126:89–100
McGovern S, Pan J, Oliver G, Cutz E, Yeger H (2010) The role of hypoxia and neurogenic genes(Mash-1 and Prox-1) in the developmental programming and maturation of pulmonary neuroendocrine cells in fetal mouse lung. Lab Invest 90:180–195
Pan J, Luk C, Kent G, Cutz E, Yeger H (2006) Pulmonary neuroendocrine cells, airway innervation and smooth muscle are altered in Cftr null mice. Am J Respir Cell Mol Biol 35(3):320–6
Semenza G (2009) Regulation of oxygen homeostasis by hypoxia-inducible factor. Physiology 24:97–106
Seth P, Krop L, Porter D, Polyak K (2002) Novel estrogen and tamoxifen induced genes identified by SAGE (Serial analysis of gene expression). Oncogene 21:836–843
Sorokin SP, Hoyt RF Jr, Shaffer MJ (1997) Ontogeny of neuroepithelial bodies: correlations with mitogenesis and innervation. Microsc Res Tech 37:43–61
Wang D, Youngson C, Wong V et al (1996) NADPH oxidase and hydrogen peroxide-sensitive K+ channel may function as an oxygen sensor complex in airway chemoreceptors and small cell carcinoma cell lines. Proc Natl Acad Sci U S A 93:13182–13187
Weir EK, Lopez-Barneo J, Buckler KJ, Archer SL (2005) Acute oxygen sensing mechanisms. N Engl J Med 353:2042–2055
Youngson C, Nurse C, Yeger H, Cutz E (1993) Oxygen sensing in airway chemoreceptors. Nature 365:153–156
Acknowledgements
Supported by grants from the Canadian Institutes for Health Research (MOP 15270) and Canadian Cystic Fibrosis to E.C. and H.Y and Wellcome Trust (Programme grant #091857 ) to P.R. and T.B.
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Pan, J., Yeger, H., Ratcliffe, P., Bishop, T., Cutz, E. (2012). Hyperplasia of Pulmonary Neuroepithelial Bodies (NEB) in Lungs of Prolyl Hydroxylase −1(PHD-1) Deficient Mice. In: Nurse, C., Gonzalez, C., Peers, C., Prabhakar, N. (eds) Arterial Chemoreception. Advances in Experimental Medicine and Biology, vol 758. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-4584-1_21
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DOI: https://doi.org/10.1007/978-94-007-4584-1_21
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