Cellular and Molecular Neurobiology

, Volume 34, Issue 4, pp 523–538 | Cite as

Differential Expression of Transcription Factors and Inflammation-, ROS-, and Cell Death-Related Genes in Organotypic Cultures in the Modiolus, the Organ of Corti and the Stria Vascularis of Newborn Rats

  • Johann Gross
  • Heidi Olze
  • Birgit Mazurek
Original Research


Cells respond to injury and hypoxia by changing gene expression. To study how the main compartments of the cochlea, the stria vascularis (SV), the organ of Corti (OC), and the modiolus (MOD), respond to such stress, we analyzed the expression of selected genes using microarray analysis. Organotypic cultures of SV, OC, and MOD from newborn rats were used as an experimental model. In the present study, we compare the expression of a total of 50 genes involved in apoptosis and necrosis, reactive oxygen species (ROS) metabolism, inflammation as well as selected transcription factors (TF) and analyze their role for the different cell death patterns observed in the three regions. MOD, OC, and SV differ not only in their basal gene profiles but also in their ability to respond to injury and hypoxia. The results provide two coexpression clusters across the three regions, a Hif-1a coexpression cluster and a cluster around the cell death-associated transcripts Casp3, Capn1, Capn2, and Capns1. These clusters include the TF Jun, Bmyc, Nfyc, Foxd3, Hes1, the ROS-associated molecules Sod3, and Nos2, and the inflammatory chemokine Ccl20. The evidence of both clusters indicates the complex and regulated character of gene expression following injury and hypoxia across the three regions SV, OC, and MOD. The high vulnerability of spiral ganglion neurons in the MOD region, previously explained on the basis of the availability of neuro-trophic factors, is associated with the increased endogenous production of ROS and nitric oxide and inadequate activation of protective acting genes.


Cell death Culture Gene expression Hypoxia Inflammation Inner ear Microarray Modiolus Organ of Corti Reactive oxygen species Spiral ganglion neurons Stria vascularis 



We would like to thank the University Hospital Charité for support. It gives us great pleasure to thank Johannes Wendt for his generous help in critically reading and correcting this article.


  1. Abi-Hachem RN, Zine A, Van de Water TR (2010) The injured cochlea as a target for inflammatory processes, initiation of cell death pathways and application of related otoprotectives strategies. Recent Pat CNS Drug Discov 5:147–163PubMedGoogle Scholar
  2. Alam SA, Robinson BK, Huang J, Green SH (2007) Prosurvival and proapoptotic intracellular signaling in rat spiral ganglion neurons in vivo after the loss of hair cells. J Comp Neurol 503:832–852PubMedGoogle Scholar
  3. Alavian KN, Li H, Collis L, Bonanni L, Zeng L, Sacchetti S, Lazrove E, Nabili P, Flaherty B, Graham M, Chen Y, Messerli SM, Mariggio MA, Rahner C, McNay E, Shore GC, Smith PJ, Hardwick JM, Jonas EA (2011) Bcl-xL regulates metabolic efficiency of neurons through interaction with the mitochondrial F1FO ATP synthase. Nat Cell Biol 13:1224–1233PubMedCentralPubMedGoogle Scholar
  4. Alexander JJ, Jacob A, Bao L, Macdonald RL, Quigg RJ (2005) Complement-dependent apoptosis and inflammatory gene changes in murine lupus cerebritis. J Immunol 175:8312–8319PubMedGoogle Scholar
  5. Alfranca A, Gutierrez MD, Vara A, Aragones J, Vidal F, Landazuri MO (2002) c-Jun and hypoxia-inducible factor 1 functionally cooperate in hypoxia-induced gene transcription. Mol Cell Biol 22:12–22PubMedCentralPubMedGoogle Scholar
  6. Asangani IA, Rasheed SA, Leupold JH, Post S, Allgayer H (2008) NRF-1, and AP-1 regulate the promoter of the human calpain small subunit 1 (CAPNS1) gene. Gene 410:197–206PubMedGoogle Scholar
  7. Barclay M, Ryan AF, Housley GD (2011) Type I vs type II spiral ganglion neurons exhibit differential survival and neuritogenesis during cochlear development. Neural Dev 6:33PubMedCentralPubMedGoogle Scholar
  8. Bas E, Gupta C, Van de Water TR (2012) A novel organ of corti explant model for the study of cochlear implantation trauma. Anat Rec 295:1944–1956Google Scholar
  9. Batts SA, Shoemaker CR, Raphael Y (2009) Notch signaling and Hes labeling in the normal and drug-damaged organ of Corti. Hear Res 249:15–22PubMedCentralPubMedGoogle Scholar
  10. Blengio F, Raggi F, Pierobon D, Cappello P, Eva A, Giovarelli M, Varesio L, Bosco MC (2013) The hypoxic environment reprograms the cytokine/chemokine expression profile of human mature dendritic cells. Immunobiology 218:76–89PubMedGoogle Scholar
  11. Borutaite V, Morkuniene R, Arandarcikaite O, Jekabsone A, Barauskaite J, Brown GC (2009) Nitric oxide protects the heart from ischemia-induced apoptosis and mitochondrial damage via protein kinase G mediated blockage of permeability transition and cytochrome c release. J Biomed Sci 16:70PubMedCentralPubMedGoogle Scholar
  12. Branney PA, Faas L, Steane SE, Pownall ME, Isaacs HV (2009) Characterisation of the fibroblast growth factor dependent transcriptome in early development. PLoS One 4:e4951PubMedCentralPubMedGoogle Scholar
  13. Burton RA, Mattila S, Taparowsky EJ, Post CB (2006) B-myc: N-terminal recognition of myc binding proteins. Biochemistry 45:9857–9865PubMedGoogle Scholar
  14. Calzolari D, Paternostro G, Harrington PL Jr, Piermarocchi C, Duxbury PM (2007) Selective control of the apoptosis signaling network in heterogeneous cell populations. PLoS One 2:e547PubMedCentralPubMedGoogle Scholar
  15. Cesaro A, Abakar-Mahamat A, Brest P, Lassalle S, Selva E, Filippi J, Hebuterne X, Hugot JP, Doglio A, Galland F, Naquet P, Vouret-Craviari V, Mograbi B, Hofman PM (2009) Differential expression and regulation of ADAM17 and TIMP3 in acute inflamed intestinal epithelia. Am J Physiol Gastrointest Liver Physiol 296:G1332–G1343PubMedGoogle Scholar
  16. Chalaris A, Adam N, Sina C, Rosenstiel P, Lehmann-Koch J, Schirmacher P, Hartmann D, Cichy J, Gavrilova O, Schreiber S, Jostock T, Matthews V, Hasler R, Becker C, Neurath MF, Reiss K, Saftig P, Scheller J, Rose-John S (2010) Critical role of the disintegrin metalloprotease ADAM17 for intestinal inflammation and regeneration in mice. J Exp Med 207:1617–1624PubMedCentralPubMedGoogle Scholar
  17. Chandel NS, Budinger GR (2007) The cellular basis for diverse responses to oxygen. Free Radic Biol Med 42:165–174PubMedGoogle Scholar
  18. Charlier N, Leclere N, Felderhoff U, Heldt J, Kietzmann T, Obladen M, Gross J (2002) Hypoxia-induced cell death and changes in hypoxia-inducible factor-1 activity in PC12 cells upon exposure to nerve growth factor. Brain Res Mol Brain Res 104:21–30PubMedGoogle Scholar
  19. Chatterjee PK, Brown PA, Cuzzocrea S, Zacharowski K, Stewart KN, Mota-Filipe H, McDonald MC, Thiemermann C (2001) Calpain inhibitor-1 reduces renal ischemia/reperfusion injury in the rat. Kidney Int 59:2073–2083PubMedGoogle Scholar
  20. Chen W, Ostrowski RP, Obenaus A, Zhang JH (2009) Prodeath or prosurvival: two facets of hypoxia inducible factor-1 in perinatal brain injury. Exp Neurol 216:7–15PubMedCentralPubMedGoogle Scholar
  21. Cheng WC, Shu WY, Li CY, Tsai ML, Chang CW, Chen CR, Cheng HT, Wang TH, Hsu IC (2012) Intra- and inter-individual variance of gene expression in clinical studies. PLoS One 7:e38650PubMedCentralPubMedGoogle Scholar
  22. Chi JT, Wang Z, Nuyten DS, Rodriguez EH, Schaner ME, Salim A, Wang Y, Kristensen GB, Helland A, Borresen-Dale AL, Giaccia A, Longaker MT, Hastie T, Yang GP, van de Vijver MJ, Brown PO (2006) Gene expression programs in response to hypoxia: cell type specificity and prognostic significance in human cancers. PLoS Med 3:e47PubMedCentralPubMedGoogle Scholar
  23. Citron BA, Arnold PM, Sebastian C, Qin F, Malladi S, Ameenuddin S, Landis ME, Festoff BW (2000) Rapid upregulation of caspase-3 in rat spinal cord after injury: mRNA, protein, and cellular localization correlates with apoptotic cell death. Exp Neurol 166:213–226PubMedGoogle Scholar
  24. Demarchi F, Schneider C (2007) The calpain system as a modulator of stress/damage response. Cell Cycle 6:136–138PubMedGoogle Scholar
  25. Du J, Chen Y, Li Q, Han X, Cheng C, Wang Z, Danielpour D, Dunwoodie SL, Bunting KD, Yang YC (2012) HIF-1alpha deletion partially rescues defects of hematopoietic stem cell quiescence caused by Cited2 deficiency. Blood 119:2789–2798PubMedCentralPubMedGoogle Scholar
  26. Duchen MR (2004) Mitochondria in health and disease: perspectives on a new mitochondrial biology. Mol Aspects Med 25:365–451PubMedGoogle Scholar
  27. Eltzschig HK, Carmeliet P (2011) Hypoxia and inflammation. N Engl J Med 364:656–665PubMedCentralPubMedGoogle Scholar
  28. Fahling M, Persson AB, Klinger B, Benko E, Steege A, Kasim M, Patzak A, Persson PB, Wolf G, Bluthgen N, Mrowka R (2012) Multilevel regulation of HIF-1 signaling by TTP. Mol Biol Cell 23:4129–4141PubMedCentralPubMedGoogle Scholar
  29. Fu LM, Fu-Liu CS (2005) Evaluation of gene importance in microarray data based upon probability of selection. BMC Bioinformatics 6:67PubMedCentralPubMedGoogle Scholar
  30. Fujioka M, Kanzaki S, Okano HJ, Masuda M, Ogawa K, Okano H (2006) Proinflammatory cytokines expression in noise-induced damaged cochlea. J Neurosci Res 83:575–583PubMedGoogle Scholar
  31. Gao X, Daugherty RL, Tourtellotte WG (2007) Regulation of low affinity neurotrophin receptor (p75(NTR)) by early growth response (Egr) transcriptional regulators. Mol Cell Neurosci 36:501–514PubMedCentralPubMedGoogle Scholar
  32. Gatti DM, Barry WT, Nobel AB, Rusyn I, Wright FA (2010) Heading down the wrong pathway: on the influence of correlation within gene sets. BMC Genom 11:574Google Scholar
  33. Gautier L, Cope L, Bolstad BM, Irizarry RA (2004) Affy–analysis of Affymetrix GeneChip data at the probe level. Bioinformatics 20:307–315PubMedGoogle Scholar
  34. Giaccia AJ, Simon MC, Johnson R (2004) The biology of hypoxia: the role of oxygen sensing in development, normal function, and disease. Genes Dev 18:2183–2194PubMedCentralPubMedGoogle Scholar
  35. Griffiths MR, Gasque P, Neal JW (2010) The regulation of the CNS innate immune response is vital for the restoration of tissue homeostasis (repair) after acute brain injury: a brief review. Int J Inflam 2010:151097PubMedCentralPubMedGoogle Scholar
  36. Gross J, Rheinlander C, Fuchs J, Mazurek B, Machulik A, Andreeva N, Kietzmann T (2003) Expression of hypoxia-inducible factor-1 in the cochlea of newborn rats. Hear Res 183:73–83PubMedGoogle Scholar
  37. Gross J, Machulik A, Amarjargal N, Moller R, Ungethum U, Kuban RJ, Fuchs FU, Andreeva N, Fuchs J, Henke W, Pohl EE, Szczepek AJ, Haupt H, Mazurek B (2007) Expression of apoptosis-related genes in the organ of Corti, modiolus and stria vascularis of newborn rats. Brain Res 1162:56–68PubMedGoogle Scholar
  38. Gross J, Machulik A, Moller R, Fuchs J, Amarjargal N, Ungethuem U, Kuban RJ, Szczepek AJ, Haupt H, Mazurek B (2008) mRNA expression of members of the IGF system in the organ of Corti, the modiolus and the stria vascularis of newborn rats. Growth Factors 26:180–191PubMedGoogle Scholar
  39. Gross J, Moller R, Amarjargal N, Machulik A, Fuchs J, Ungethum U, Kuban RJ, Henke W, Haupt H, Mazurek B (2009) Expression of erythropoietin and angiogenic growth factors following inner ear injury of newborn rats. Prague Med Rep 110:310–331PubMedGoogle Scholar
  40. Gygi SP, Rochon Y, Franza BR, Aebersold R (1999) Correlation between protein and mRNA abundance in yeast. Mol Cell Biol 19:1720–1730PubMedCentralPubMedGoogle Scholar
  41. Heinrich UR, Helling K (2012) Nitric oxide: a versatile key player in cochlear function and hearing disorders. Nitric Oxide 27:106–116PubMedGoogle Scholar
  42. Heinrich UR, Brieger J, Selivanova O, Feltens R, Eimermacher A, Schafer D, Mann WJ (2006) COX-2 expression in the guinea pig cochlea is partly altered by moderate sound exposure. Neurosci Lett 394:121–126PubMedGoogle Scholar
  43. Helton R, Cui J, Scheel JR, Ellison JA, Ames C, Gibson C, Blouw B, Ouyang L, Dragatsis I, Zeitlin S, Johnson RS, Lipton SA, Barlow C (2005) Brain-specific knock-out of hypoxia-inducible factor-1alpha reduces rather than increases hypoxic-ischemic damage. J Neurosci 25:4099–4107PubMedGoogle Scholar
  44. Hosokawa Y, Hosokawa I, Ozaki K, Nakae H, Matsuo T (2005) Increase of CCL20 expression by human gingival fibroblasts upon stimulation with cytokines and bacterial endotoxin. Clin Exp Immunol 142:285–291PubMedCentralPubMedGoogle Scholar
  45. Ido Y, Yamamoto T, Yoshitomi T, Yamamoto A, Obana E, Ohkura K, Shinohara Y (2012) Pseudogenes of rat VDAC1: 16 gene segments in the rat genome show structural similarities with the cDNA encoding rat VDAC1, with 8 slightly expressed in certain tissues. Mamm Genome 23:286–293PubMedGoogle Scholar
  46. Iijima N, Suzuki N, Oguchi T, Hashimoto S, Takumi Y, Sugahara K, Okuda T, Yamashita H, Usami S (2004) The effect of hypergravity on the inner ear: CREB and syntaxin are up-regulated. Neuroreport 15:965–969PubMedGoogle Scholar
  47. Ikedo H, Tamaki K, Ueda S, Kato S, Fujii M, Ten DP, Okuda S (2003) Smad protein and TGF-beta signaling in vascular smooth muscle cells. Int J Mol Med 11:645–650PubMedGoogle Scholar
  48. Jacobs CM, Boldingh KA, Slagsvold HH, Thoresen GH, Paulsen RE (2004) ERK2 prohibits apoptosis-induced subcellular translocation of orphan nuclear receptor NGFI-B/TR3. J Biol Chem 279:50097–50101PubMedGoogle Scholar
  49. Jha S, Srivastava SY, Brickey WJ, Iocca H, Toews A, Morrison JP, Chen VS, Gris D, Matsushima GK, Ting JP (2010) The inflammasome sensor, NLRP3, regulates CNS inflammation and demyelination via caspase-1 and interleukin-18. J Neurosci 30:15811–15820PubMedGoogle Scholar
  50. Kennedy CL, Smith DJ, Lyras D, Chakravorty A, Rood JI (2009) Programmed cellular necrosis mediated by the pore-forming alpha-toxin from Clostridium septicum. PLoS Pathog 5:e1000516. doi: 10.1371/journal.ppat.1000516 PubMedCentralPubMedGoogle Scholar
  51. Kfoury N, Kapatos G (2009) Identification of neuronal target genes for CCAAT/enhancer binding proteins. Mol Cell Neurosci 40:313–327PubMedCentralPubMedGoogle Scholar
  52. Khan M, Szczepek AJ, Haupt H, Olze H, Mazurek B (2010) Expression of the proinflammatory cytokines in cochlear explant cultures: influence of normoxia and hypoxia. Neurosci Lett 479:249–252PubMedGoogle Scholar
  53. Kielian T, Syed MM, Liu S, Phulwani NK, Phillips N, Wagoner G, Drew PD, Esen N (2008) The synthetic peroxisome proliferator-activated receptor-gamma agonist ciglitazone attenuates neuroinflammation and accelerates encapsulation in bacterial brain abscesses. J Immunol 180:5004–5016PubMedCentralPubMedGoogle Scholar
  54. Krysko DV, Agostinis P, Krysko O, Garg AD, Bachert C, Lambrecht BN, Vandenabeele P (2011) Emerging role of damage-associated molecular patterns derived from mitochondria in inflammation. Trends Immunol 32:157–164PubMedGoogle Scholar
  55. Lawrence T (2009) The nuclear factor NF-kappaB pathway in inflammation. Cold Spring Harb Perspect Biol 1:a001651PubMedCentralPubMedGoogle Scholar
  56. Lefebvre PP, Weber T, Rigo JM, Staecker H, Moonen G, Van de Water TR (1992) Peripheral and central target-derived trophic factor(s) effects on auditory neurons. Hear Res 58:185–192PubMedGoogle Scholar
  57. Lefebvre PP, Malgrange B, Lallemend F, Staecker H, Moonen G, Van de Water TR (2002) Mechanisms of cell death in the injured auditory system: otoprotective strategies. Audiol Neurootol 7:165–170PubMedGoogle Scholar
  58. Li X, Fang P, Mai J, Choi ET, Wang H, Yang XF (2013) Targeting mitochondrial reactive oxygen species as novel therapy for inflammatory diseases and cancers. J Hematol Oncol 6:19PubMedCentralPubMedGoogle Scholar
  59. Liu Y, Labosky PA (2008) Regulation of embryonic stem cell self-renewal and pluripotency by Foxd3. Stem Cells 26:2475–2484PubMedCentralPubMedGoogle Scholar
  60. Lorenzen I, Lokau J, Dusterhoft S, Trad A, Garbers C, Scheller J, Rose-John S, Grotzinger J (2012) The membrane-proximal domain of A Disintegrin and Metalloprotease 17 (ADAM17) is responsible for recognition of the interleukin-6 receptor and interleukin-1 receptor II. FEBS Lett 586:1093–1100PubMedGoogle Scholar
  61. Lu S, Fan Z, Xu W, Han Y, Zhang G, Liu W, Bai X, Wang X, Xin H, Li J, Wang H (2011) l-Cysteine attenuates peroxynitrite-elicited cytotoxicity to spiral ganglion neurons: possible relation to hearing loss. Neurol Res 33:935–941PubMedGoogle Scholar
  62. Manzanero S, Santro T, Arumugam TV (2013) Neuronal oxidative stress in acute ischemic stroke: sources and contribution to cell injury. Neurochem Int 62:712–718PubMedGoogle Scholar
  63. Marin-Hernandez A, Gallardo-Perez JC, Ralph SJ, Rodriguez-Enriquez S, Moreno-Sanchez R (2009) HIF-1alpha modulates energy metabolism in cancer cells by inducing over-expression of specific glycolytic isoforms. Mini Rev Med Chem 9:1084–1101PubMedGoogle Scholar
  64. Mazurek B, Rheinlander C, Fuchs FU, Amarjargal N, Kuban RJ, Ungethum U, Haupt H, Kietzmann T, Gross J (2006a) Influence of ischemia/hypoxia on the HIF-1 activity and expression of hypoxia-dependent genes in the cochlea of the newborn rat. HNO 54:689–697PubMedGoogle Scholar
  65. Mazurek B, Amarjargal N, Haupt H, Fuchs J, Olze H, Machulik A, Gross J (2011) Expression of genes implicated in oxidative stress in the cochlea of newborn rats. Hear Res 277:54–60PubMedGoogle Scholar
  66. Mazurek B, Machulik A, Amarjargal N, Kuban RJ, Ungethuem U, Fuchs J, Haupt H, Gross J (2006b). Gene expression of organ of Corti (OC), modiolus (MOD) and stria vascularis (SV) of newborn rats. Gene expression omnibus (GEO). Accessed 28 Feb 2014
  67. McGeough MD, Pena CA, Mueller JL, Pociask DA, Broderick L, Hoffman HM, Brydges SD (2012) Cutting edge: IL-6 is a marker of inflammation with no direct role in inflammasome-mediated mouse models. J Immunol 189:2707–2711PubMedCentralPubMedGoogle Scholar
  68. Mense SM, Sengupta A, Zhou M, Lan C, Bentsman G, Volsky DJ, Zhang L (2006) Gene expression profiling reveals the profound upregulation of hypoxia-responsive genes in primary human astrocytes. Physiol Genomics 25:435–449PubMedGoogle Scholar
  69. Mincheva-Tasheva S, Soler RM (2013) NF-kappaB signaling pathways: role in nervous system physiology and pathology. Neuroscientist 19:175–194PubMedGoogle Scholar
  70. Mirabelli-Badenier M, Braunersreuther V, Viviani GL, Dallegri F, Quercioli A, Veneselli E, Mach F, Montecucco F (2011) CC and CXC chemokines are pivotal mediators of cerebral injury in ischaemic stroke. Thromb Haemost 105:409–420PubMedGoogle Scholar
  71. Moritz W, Meier F, Stroka DM, Giuliani M, Kugelmeier P, Nett PC, Lehmann R, Candinas D, Gassmann M, Weber M (2002) Apoptosis in hypoxic human pancreatic islets correlates with HIF-1alpha expression. FASEB J 16:745–747PubMedGoogle Scholar
  72. Munoz A, Costa M (2013) Nutritionally mediated oxidative stress and inflammation. Oxid Med Cell Longev 2013:610950PubMedCentralPubMedGoogle Scholar
  73. Palumbo S, Toscano CD, Parente L, Weigert R, Bosetti F (2011) Time-dependent changes in the brain arachidonic acid cascade during cuprizone-induced demyelination and remyelination. Prostaglandins Leukot Essent Fatty Acids 85:29–35PubMedCentralPubMedGoogle Scholar
  74. Pan PH, Cardinal J, Li ML, Hu CP, Tsung A (2013) Interferon regulatory factor-1 mediates the release of high mobility group box-1 in endotoxemia in mice. Chin Med J 126:918–924PubMedGoogle Scholar
  75. Perez P, Bao J (2011) Why do hair cells and spiral ganglion neurons in the cochlea die during aging? Aging Dis 2:231–241PubMedCentralPubMedGoogle Scholar
  76. Popovich PG, Longbrake EE (2008) Can the immune system be harnessed to repair the CNS? Nat Rev Neurosci 9:481–493PubMedGoogle Scholar
  77. Raphael Y, Altschuler RA (2003) Structure and innervation of the cochlea. Brain Res Bull 60:397–422PubMedGoogle Scholar
  78. Ringger NC, Tolentino PJ, McKinsey DM, Pike BR, Wang KK, Hayes RL (2004) Effects of injury severity on regional and temporal mRNA expression levels of calpains and caspases after traumatic brain injury in rats. J Neurotrauma 21:829–841PubMedGoogle Scholar
  79. Rohnert P, Schroder UH, Ziabreva I, Tager M, Reymann KG, Striggow F (2012) Insufficient endogenous redox buffer capacity may underlie neuronal vulnerability to cerebral ischemia and reperfusion. J Neurosci Res 90:193–202PubMedGoogle Scholar
  80. Ruan RS (2002) Possible roles of nitric oxide in the physiology and pathophysiology of the mammalian cochlea. Ann NY Acad Sci 962:260–274PubMedGoogle Scholar
  81. Rubbia-Brandt L, Tauzin S, Brezault C, Delucinge-Vivier C, Descombes P, Dousset B, Majno PE, Mentha G, Terris B (2011) Gene expression profiling provides insights into pathways of oxaliplatin-related sinusoidal obstruction syndrome in humans. Mol Cancer Ther 10:687–696PubMedGoogle Scholar
  82. Sang L, Roberts JM, Coller HA (2010) Hijacking HES1: how tumors co-opt the anti-differentiation strategies of quiescent cells. Trends Mol Med 16:17–26PubMedCentralPubMedGoogle Scholar
  83. Savaskan NE, Fingerle-Rowson G, Buchfelder M, Eyupoglu IY (2012) Brain miffed by macrophage migration inhibitory factor. Int J Cell Biol 2012:139573PubMedCentralPubMedGoogle Scholar
  84. Schodel J, Mole DR, Ratcliffe PJ (2013) Pan-genomic binding of hypoxia-inducible transcriptionfactors. Biol Chem 394:507–517PubMedGoogle Scholar
  85. Seidman MD, Tang W, Shirwany N, Bai U, Rubin CJ, Henig JP, Quirk WS (2009) Anti-intercellular adhesion molecule-1 antibody’s effect on noise damage. Laryngoscope 119:707–712PubMedGoogle Scholar
  86. Semenza GL (2001) Hypoxia-inducible factor 1: control of oxygen homeostasis in health and disease. Pediatr Res 49:614–617PubMedGoogle Scholar
  87. Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3:721–732PubMedGoogle Scholar
  88. Semenza GL (2011) Hypoxia-inducible factor 1: regulator of mitochondrial metabolism and mediator of ischemic preconditioning. Biochim Biophys Acta 1813:1263–1268PubMedCentralPubMedGoogle Scholar
  89. Sermeus A, Michiels C (2011) Reciprocal influence of the p53 and the hypoxic pathways. Cell Death Dis 2:e164PubMedCentralPubMedGoogle Scholar
  90. Sha SH, Taylor R, Forge A, Schacht J (2001) Differential vulnerability of basal and apical hair cells is based on intrinsic susceptibility to free radicals. Hear Res 155:1–8PubMedGoogle Scholar
  91. Sharaf el DO, Gallerne C, Brenner C, Lemaire C (2012) Increased expression of VDAC1 sensitizes carcinoma cells to apoptosis induced by DNA cross-linking agents. Biochem Pharmacol 83:1172–1182Google Scholar
  92. Shaw PJ, Eggett CJ (2000) Molecular factors underlying selective vulnerability of motor neurons to neurodegeneration in amyotrophic lateral sclerosis. J Neurol 247(Suppl 1):I17–I27PubMedGoogle Scholar
  93. Shen YC, Thompson DL, Kuah MK, Wong KL, Wu KL, Linn SA, Jewett EM, Shu-Chien AC, Barald KF (2012) The cytokine macrophage migration inhibitory factor (MIF) acts as a neurotrophin in the developing inner ear of the zebrafish, Danio rerio. Dev Biol 363:84–94PubMedCentralPubMedGoogle Scholar
  94. Shi X, Nuttall AL (2003) Upregulated iNOS and oxidative damage to the cochlear stria vascularis due to noise stress. Brain Res 967:1–10PubMedGoogle Scholar
  95. Shi X, Dai C, Nuttall AL (2003) Altered expression of inducible nitric oxide synthase (iNOS) in the cochlea. Hear Res 177:43–52PubMedGoogle Scholar
  96. Shrivastava K, Llovera G, Recasens M, Chertoff M, Gimenez-Llort L, Gonzalez B, Acarin L (2013) Temporal expression of cytokines and signal transducer and activator of transcription factor 3 activation after neonatal hypoxia/ischemia in mice. Dev Neurosci 35:212–225PubMedGoogle Scholar
  97. Sun X, Wang X, Chen T, Li T, Cao K, Lu A, Chen Y, Sun D, Luo J, Fan J, Young W, Ren Y (2010) Myelin activates FAK/Akt/NF-kappaB pathways and provokes CR3-dependent inflammatory response in murine system. PLoS One 5:e9380PubMedCentralPubMedGoogle Scholar
  98. van de Water TR, Lallemend F, Eshraghi AA, Ahsan S, He J, Guzman J, Polak M, Malgrange B, Lefebvre PP, Staecker H, Balkany TJ (2004) Caspases, the enemy within, and their role in oxidative stress-induced apoptosis of inner ear sensory cells. Otol Neurotol 25:627–632Google Scholar
  99. van Deel ED, Lu Z, Xu X, Zhu G, Hu X, Oury TD, Bache RJ, Duncker DJ, Chen Y (2008) Extracellular superoxide dismutase protects the heart against oxidative stress and hypertrophy after myocardial infarction. Free Radic Biol Med 44:1305–1313PubMedCentralPubMedGoogle Scholar
  100. Verrier F, Deniaud A, Lebras M, Metivier D, Kroemer G, Mignotte B, Jan G, Brenner C (2004) Dynamic evolution of the adenine nucleotide translocase interactome during chemotherapy-induced apoptosis. Oncogene 23:8049–8064PubMedGoogle Scholar
  101. Wakabayashi K, Fujioka M, Kanzaki S, Okano HJ, Shibata S, Yamashita D, Masuda M, Mihara M, Ohsugi Y, Ogawa K, Okano H (2010) Blockade of interleukin-6 signaling suppressed cochlear inflammatory response and improved hearing impairment in noise-damaged mice cochlea. Neurosci Res 66:345–352PubMedGoogle Scholar
  102. Wang B, Liu Y, Zhu X, Chi F, Zhang Y, Yang M (2011) Up-regulation of cochlear Hes1 expression in response to noise exposure. Acta Neurobiol Exp (Wars) 71:256–262Google Scholar
  103. Waxman AB, Kolliputi N (2009) IL-6 protects against hyperoxia-induced mitochondrial damage via Bcl-2-induced Bak interactions with mitofusins. Am J Respir Cell Mol Biol 41:385–396PubMedCentralPubMedGoogle Scholar
  104. Yamashima T (2012) Hsp70.1 and related lysosomal factors for necrotic neuronal death. J Neurochem 120:477–494PubMedGoogle Scholar
  105. Yang Y, Sharma R, Zimniak P, Awasthi YC (2002) Role of alpha class glutathione S-transferases as antioxidant enzymes in rodent tissues. Toxicol Appl Pharmacol 182:105–115PubMedGoogle Scholar
  106. Ying YL, Balaban CD (2009) Regional distribution of manganese superoxide dismutase 2 (Mn SOD2) expression in rodent and primate spiral ganglion cells. Hear Res 253:116–124PubMedGoogle Scholar
  107. Yoo YG, Yeo MG, Kim DK, Park H, Lee MO (2004) Novel function of orphan nuclear receptor Nur77 in stabilizing hypoxia-inducible factor-1alpha. J Biol Chem 279:53365–53373PubMedGoogle Scholar
  108. Zheng JL, Shou J, Guillemot F, Kageyama R, Gao WQ (2000) Hes1 is a negative regulator of inner ear hair cell differentiation. Development 127:4551–4560PubMedGoogle Scholar

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© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Molecular Biology Research Laboratory, Department of OtorhinolaryngologyCharité-Universitätsmedizin BerlinBerlinGermany
  2. 2.Department of OtorhinolaryngologyCharité-Universitätsmedizin BerlinBerlinGermany

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