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Inflammation Potentiates Cochlear Uptake of Ototoxins and Drug-Induced Hearing Loss

  • Peter S. Steyger
Chapter

Abstract

Serious bacterial infections are often treated with aminoglycosides, especially when the cause of systemic infection is unknown. Severe infections trigger specific systemic inflammatory response pathways. Aminoglycosides are primarily trafficked across the cochlear blood-labyrinth barrier into the stria vascularis, prior to clearance into endolymph and entry into hair cells with subsequent cytotoxicity and loss of auditory function: cochleotoxicity. Systemic inflammation potentiates cochlear uptake of aminoglycosides and increases the risk of hearing loss in both preclinical models and human studies. Here, we review the data that establishes the above narrative, and articulate the need for translational studies to promote ototoxicity monitoring in neonatal intensive care units and cystic fibrosis clinics.

Keywords

Aminoglycosides Ototoxicity Stria vascularis Drug trafficking Infection 

Notes

Acknowledgements

Figures drafted by Karen Thiebes, of Simplified Science Publishing, LLC. I thank lab members for discussion on the manuscript. This research was supported by R01 awards (DC004555, DC12588) from the National Institute of Deafness and Other Communication Disorders. The content is solely the responsibility of the author and does not represent the official views of the NIH, Oregon Health & Science University or the VA Portland Health Care System. The author declares no existing or potential conflict of interest.

This work was supported by NIDCD R01 awards DC04555 and DC012588.

References

  1. Abbott NJ, Ronnback L, Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci. 2006;7:41–53.CrossRefPubMedGoogle Scholar
  2. Ahmed RM, Hannigan IP, Macdougall HG, Chan RC, et al. Gentamicin ototoxicity: a 23-year selected case series of 103 patients. Med J Aust. 2012;196:701–4.CrossRefPubMedGoogle Scholar
  3. Alharazneh A, Luk L, Huth M, Monfared A, et al. Functional hair cell mechanotransducer channels are required for aminoglycoside ototoxicity. PLoS One. 2011;6:e22347.CrossRefPubMedPubMedCentralGoogle Scholar
  4. Al-Malky G, Dawson SJ, Sirimanna T, Bagkeris E, et al. High-frequency audiometry reveals high prevalence of aminoglycoside ototoxicity in children with cystic fibrosis. J Cyst Fibros. 2015;14:248–54.CrossRefPubMedGoogle Scholar
  5. Balogh K Jr, Hiraide F, Ishii D. Distribution of radioactive dihydrostreptomycin in the cochlea. An autoradiographic study. Ann Otol Rhinol Laryngol. 1970;79:641–52.CrossRefPubMedGoogle Scholar
  6. Bhatt SM, Lauretano A, Cabellos C, Halpin C, et al. Progression of hearing loss in experimental pneumococcal meningitis: correlation with cerebrospinal fluid cytochemistry. J Infect Dis. 1993;167:675–83.CrossRefPubMedGoogle Scholar
  7. Campbell KC, Martin SM, Meech RP, Hargrove TL, et al. D-methionine (d-met) significantly reduces kanamycin-induced ototoxicity in pigmented Guinea pigs. Int J Audiol. 2016;55:273–8.CrossRefPubMedGoogle Scholar
  8. Caye-Thomasen P, Dam MS, Omland SH, Mantoni M. Cochlear ossification in patients with profound hearing loss following bacterial meningitis. Acta Otolaryngol. 2012;132:720–5.CrossRefPubMedGoogle Scholar
  9. Coffin AB, Reinhart KE, Owens KN, Raible DW, et al. Extracellular divalent cations modulate aminoglycoside-induced hair cell death in the zebrafish lateral line. Hear Res. 2009;253:42–51.CrossRefPubMedPubMedCentralGoogle Scholar
  10. Cohen-Salmon M, Regnault B, Cayet N, Caille D, et al. Connexin30 deficiency causes instrastrial fluid-blood barrier disruption within the cochlear stria vascularis. Proc Natl Acad Sci U S A. 2007;104:6229–34.CrossRefPubMedPubMedCentralGoogle Scholar
  11. Cross CP, Liao S, Urdang ZD, Srikanth P, et al. Effect of sepsis and systemic inflammatory response syndrome on neonatal hearing screening outcomes following gentamicin exposure. Int J Pediatr Otorhinolaryngol. 2015;79:1915–9.CrossRefPubMedPubMedCentralGoogle Scholar
  12. Crouch JJ, Sakaguchi N, Lytle C, Schulte BA. Immunohistochemical localization of the na-k-cl co-transporter (nkcc1) in the gerbil inner ear. J Histochem Cytochem. 1997;45:773–8.CrossRefPubMedGoogle Scholar
  13. Dai CF, Steyger PS. A systemic gentamicin pathway across the stria vascularis. Hear Res. 2008;235:114–24.CrossRefPubMedGoogle Scholar
  14. Dai CF, Mangiardi D, Cotanche DA, Steyger PS. Uptake of fluorescent gentamicin by vertebrate sensory cells in vivo. Hear Res. 2006;213:64–78.CrossRefPubMedPubMedCentralGoogle Scholar
  15. Darrow DH, Keithley EM, Harris JP. Effects of bacterial endotoxin applied to the Guinea pig cochlea. Laryngoscope. 1992;102:683–8.CrossRefPubMedGoogle Scholar
  16. Desjardins-Giasson S, Beaubien AR. Correlation of amikacin concentrations in perilymph and plasma of continuously infused Guinea pigs. Antimicrob Agents Chemother. 1984;26:87–90.CrossRefPubMedPubMedCentralGoogle Scholar
  17. Ebsr A. Evidence-based systematic review: drug-induced hearing loss—gentamicin [Online]. 2010. Available: www.asha.org/uploadedFiles/EBSRGentamicin.pdf [Accessed].
  18. Fian R, Grasser E, Treiber F, Schmidt R, et al. The contribution of trpv4-mediated calcium signaling to calcium homeostasis in endothelial cells. J Recept Signal Transduct Res. 2007;27:113–24.CrossRefPubMedGoogle Scholar
  19. Figueroa VA, Retamal MA, Cea LA, Salas JD, et al. Extracellular gentamicin reduces the activity of connexin hemichannels and interferes with purinergic ca(2+) signaling in hela cells. Front Cell Neurosci. 2014;8:265.CrossRefPubMedPubMedCentralGoogle Scholar
  20. Forge A, Schacht J. Aminoglycoside antibiotics. Audiol Neurootol. 2000;5:3–22.CrossRefPubMedGoogle Scholar
  21. Fox DJ, Cooper MD, Speil CA, Roberts MH, et al. D-methionine reduces tobramycin-induced ototoxicity without antimicrobial interference in animal models. J Cyst Fibros. 2016;15:518–30.CrossRefPubMedGoogle Scholar
  22. Francis SP, Cunningham LL. Non-autonomous cellular responses to ototoxic drug-induced stress and death. Front Cell Neurosci. 2017;11:252.CrossRefPubMedPubMedCentralGoogle Scholar
  23. Fujioka M, Okano H, Ogawa K. Inflammatory and immune responses in the cochlea: potential therapeutic targets for sensorineural hearing loss. Front Pharmacol. 2014;5:287.CrossRefPubMedPubMedCentralGoogle Scholar
  24. Garinis AC, Cross CP, Srikanth P, Carroll K, et al. The cumulative effects of intravenous antibiotic treatments on hearing in patients with cystic fibrosis. J Cyst Fibros. 2017a;16:401–9.CrossRefPubMedPubMedCentralGoogle Scholar
  25. Garinis AC, Liao S, Cross CP, Galati J, et al. Effect of gentamicin and levels of ambient sound on hearing screening outcomes in the neonatal intensive care unit: a pilot study. Int J Pediatr Otorhinolaryngol. 2017b;97:42–50.CrossRefPubMedPubMedCentralGoogle Scholar
  26. Garinis AC, Kemph A, Tharpe AM, Weitkamp JH, et al. Monitoring neonates for ototoxicity. Int J Audiol. 2018. (in press). https://doi.org/10.1080/14992027.2017.1339130. PMID: 28949262 and PMCID: PMC5741535 [Available on 2018-12-22].
  27. Henry KR, Guess MB, Chole RA. Hyperthermia increases aminoglycoside ototoxicity. Acta Otolaryngol. 1983;95:323–7.CrossRefPubMedGoogle Scholar
  28. Hiel H, Erre JP, Aurousseau C, Bouali R, et al. Gentamicin uptake by cochlear hair cells precedes hearing impairment during chronic treatment. Audiology. 1993;32:78–87.CrossRefPubMedGoogle Scholar
  29. Hirose K, Discolo CM, Keasler JR, Ransohoff R. Mononuclear phagocytes migrate into the murine cochlea after acoustic trauma. J Comp Neurol. 2005;489:180–94.CrossRefPubMedGoogle Scholar
  30. Hirose K, Hartsock JJ, Johnson S, Santi P, et al. Systemic lipopolysaccharide compromises the blood-labyrinth barrier and increases entry of serum fluorescein into the perilymph. J Assoc Res Otolaryngol. 2014a;15:707–19.CrossRefPubMedPubMedCentralGoogle Scholar
  31. Hirose K, Li SZ, Ohlemiller KK, Ransohoff RM. Systemic lipopolysaccharide induces cochlear inflammation and exacerbates the synergistic ototoxicity of kanamycin and furosemide. J Assoc Res Otolaryngol. 2014b;15:555–70.CrossRefPubMedPubMedCentralGoogle Scholar
  32. Huang CJ, Favre I, Moczydlowski E. Permeation of large tetra-alkylammonium cations through mutant and wild-type voltage-gated sodium channels as revealed by relief of block at high voltage. J Gen Physiol. 2000;115:435–54.CrossRefPubMedPubMedCentralGoogle Scholar
  33. Ikeda K, Sakagami M, Morizono T, Juhn SK. Permeability of the round window membrane to middle-sized molecules in purulent otitis media. Arch Otolaryngol Head Neck Surg. 1990;116:57–60.CrossRefPubMedGoogle Scholar
  34. Imamura S, Adams JC. Distribution of gentamicin in the Guinea pig inner ear after local or systemic application. J Assoc Res Otolaryngol. 2003;4:176–95.CrossRefPubMedPubMedCentralGoogle Scholar
  35. Iwano T, Yamamoto A, Omori K, Akayama M, et al. Quantitative immunocytochemical localization of na+,k+−atpase alpha-subunit in the lateral wall of rat cochlear duct. J Histochem Cytochem. 1989;37:353–63.CrossRefPubMedGoogle Scholar
  36. Jiang M, Wang Q, Karasawa T, Koo JW, et al. Sodium-glucose transporter-2 (sglt2; slc5a2) enhances cellular uptake of aminoglycosides. PLoS One. 2014;9:e108941.CrossRefPubMedPubMedCentralGoogle Scholar
  37. Jiang M, Johnson A, Karasawa T, Kachelmeier A et al. Role of transient receptor potential vanilloid 1 (trpv1) in the cellular uptake of aminoglycosides. ARO Midwinter Meeting Abstracts. 2015;38:PS-582.Google Scholar
  38. Karasawa T, Wang Q, Fu Y, Cohen DM, et al. Trpv4 enhances the cellular uptake of aminoglycoside antibiotics. J Cell Sci. 2008;121:2871–9.CrossRefPubMedPubMedCentralGoogle Scholar
  39. Kaur T, Hirose K, Rubel EW, Warchol ME. Macrophage recruitment and epithelial repair following hair cell injury in the mouse utricle. Front Cell Neurosci. 2015a;9:150.CrossRefPubMedPubMedCentralGoogle Scholar
  40. Kaur T, Zamani D, Tong L, Rubel EW, et al. Fractalkine signaling regulates macrophage recruitment into the cochlea and promotes the survival of spiral ganglion neurons after selective hair cell lesion. J Neurosci. 2015b;35:15050–61.CrossRefPubMedPubMedCentralGoogle Scholar
  41. Kawauchi H, Demaria TF, Lim DJ. Endotoxin permeability through the round window. Acta Otolaryngol Suppl. 1989;457:100–15.PubMedGoogle Scholar
  42. Koo JW, Quintanilla-Dieck L, Jiang M, Liu J, et al. Endotoxemia-mediated inflammation potentiates aminoglycoside-induced ototoxicity. Sci Transl Med. 2015;7:298ra118.CrossRefPubMedPubMedCentralGoogle Scholar
  43. Kroese AB, Das A, Hudspeth AJ. Blockage of the transduction channels of hair cells in the bullfrog’s sacculus by aminoglycoside antibiotics. Hear Res. 1989;37:203–17.CrossRefPubMedGoogle Scholar
  44. Kruger M, Boney R, Ordoobadi AJ, Sommers TF, et al. Natural bizbenzoquinoline derivatives protect zebrafish lateral line sensory hair cells from aminoglycoside toxicity. Front Cell Neurosci. 2016;10:83.CrossRefPubMedPubMedCentralGoogle Scholar
  45. Kushner B, Allen PD, Crane BT. Frequency and demographics of gentamicin use. Otol Neurotol. 2015;37:190–5.CrossRefGoogle Scholar
  46. Li H, Steyger PS. Systemic aminoglycosides are trafficked via endolymph into cochlear hair cells. Sci Rep. 2011;1:159.CrossRefPubMedPubMedCentralGoogle Scholar
  47. Macarthur CJ, Hausman F, Kempton JB, Trune DR. Murine middle ear inflammation and ion homeostasis gene expression. Otol Neurotol. 2011;32:508–15.CrossRefPubMedPubMedCentralGoogle Scholar
  48. Macarthur C, Hausman F, Kempton B, Trune DR. Intratympanic steroid treatments may improve hearing via ion homeostasis alterations and not immune suppression. Otol Neurotol. 2015;36(6):1089–95.CrossRefPubMedPubMedCentralGoogle Scholar
  49. Marcotti W, Van Netten SM, Kros CJ. The aminoglycoside antibiotic dihydrostreptomycin rapidly enters mouse outer hair cells through the mechano-electrical transducer channels. J Physiol. 2005;567:505–21.CrossRefPubMedPubMedCentralGoogle Scholar
  50. Marcus DC, Wu T, Wangemann P, Kofuji P. Kcnj10 (kir4.1) potassium channel knockout abolishes endocochlear potential. Am J Physiol Cell Physiol. 2002;282:C403–7.CrossRefPubMedGoogle Scholar
  51. Monzack EL, May LA, Roy S, Gale JE, et al. Live imaging the phagocytic activity of inner ear supporting cells in response to hair cell death. Cell Death Differ. 2015;22:1995–2005.CrossRefPubMedPubMedCentralGoogle Scholar
  52. Moore RD, Smith CR, Lietman PS. Risk factors for the development of auditory toxicity in patients receiving aminoglycosides. J Infect Dis. 1984;149:23–30.CrossRefPubMedGoogle Scholar
  53. Nicol KM, Hackney CM, Evans EF, Pratt SR. Behavioural evidence for recovery of auditory function in Guinea pigs following kanamycin administration. Hear Res. 1992;61:117–31.CrossRefPubMedGoogle Scholar
  54. Nin F, Hibino H, Doi K, Suzuki T, et al. The endocochlear potential depends on two k+ diffusion potentials and an electrical barrier in the stria vascularis of the inner ear. Proc Natl Acad Sci U S A. 2008;105:1751–6.CrossRefPubMedPubMedCentralGoogle Scholar
  55. Oh GS, Kim HJ, Choi JH, Shen A, et al. Activation of lipopolysaccharide-tlr4 signaling accelerates the ototoxic potential of cisplatin in mice. J Immunol. 2011;186:1140–50.CrossRefPubMedGoogle Scholar
  56. Oh S, Woo JI, Lim DJ, Moon SK. Erk2-dependent activation of c-Jun is required for nontypeable haemophilus influenzae-induced cxcl2 upregulation in inner ear fibrocytes. J Immunol. 2012;188:3496–505.CrossRefPubMedPubMedCentralGoogle Scholar
  57. Oishi N, Duscha S, Boukari H, Meyer M, et al. Xbp1 mitigates aminoglycoside-induced endoplasmic reticulum stress and neuronal cell death. Cell Death Dis. 2015;6:e1763.CrossRefPubMedPubMedCentralGoogle Scholar
  58. Perny M, Roccio M, Grandgirard D, Solyga M, et al. The severity of infection determines the localization of damage and extent of sensorineural hearing loss in experimental pneumococcal meningitis. J Neurosci. 2016;36:7740–9.CrossRefPubMedGoogle Scholar
  59. Pober JS, Sessa WC. Evolving functions of endothelial cells in inflammation. Nat Rev Immunol. 2007;7:803–15.CrossRefPubMedGoogle Scholar
  60. Quintanilla-Dieck L, Larrain B, Trune D, Steyger PS. Effect of systemic lipopolysaccharide-induced inflammation on cytokine levels in the murine cochlea: a pilot study. Otolaryngol Head Neck Surg. 2013;149:301–3.CrossRefPubMedGoogle Scholar
  61. Richardson MP, Reid A, Tarlow MJ, Rudd PT. Hearing loss during bacterial meningitis. Arch Dis Child. 1997;76:134–8.CrossRefPubMedPubMedCentralGoogle Scholar
  62. Rizzi MD, Hirose K. Aminoglycoside ototoxicity. Curr Opin Otolaryngol Head Neck Surg. 2007;15:352–7.CrossRefPubMedGoogle Scholar
  63. Rock KL, Latz E, Ontiveros F, Kono H. The sterile inflammatory response. Annu Rev Immunol. 2010;28:321–42.CrossRefPubMedPubMedCentralGoogle Scholar
  64. Stamatovic SM, Johnson AM, Keep RF, Andjelkovic AV. Junctional proteins of the blood-brain barrier: new insights into function and dysfunction. Tissue Barriers. 2016;4:e1154641.CrossRefPubMedPubMedCentralGoogle Scholar
  65. Stearns GS, Keithley EM, Harris JP. Development of high endothelial venule-like characteristics in the spiral modiolar vein induced by viral labyrinthitis. Laryngoscope. 1993;103:890–8.CrossRefPubMedGoogle Scholar
  66. Stepanyan RS, Indzhykulian AA, Velez-Ortega AC, Boger ET, et al. Trpa1-mediated accumulation of aminoglycosides in mouse cochlear outer hair cells. J Assoc Res Otolaryngol. 2011;12:729–40.CrossRefPubMedPubMedCentralGoogle Scholar
  67. Steyger PS. Is auditory synaptopathy a result of drug-induced hearing loss? Hearing J. 2017;70:8–9.CrossRefGoogle Scholar
  68. Takeuchi S, Ando M. Marginal cells of the stria vascularis of gerbils take up glucose via the facilitated transporter glut: application of autofluorescence. Hear Res. 1997;114:69–74.CrossRefPubMedGoogle Scholar
  69. Takeuchi S, Ando M. Dye-coupling of melanocytes with endothelial cells and pericytes in the cochlea of gerbils. Cell Tissue Res. 1998;293:271–5.CrossRefPubMedGoogle Scholar
  70. Takeuchi S, Ando M, Sato T, Kakigi A. Three-dimensional and ultrastructural relationships between intermediate cells and capillaries in the gerbil stria vascularis. Hear Res. 2001;155:103–12.CrossRefPubMedGoogle Scholar
  71. Takumida M, Anniko M. Localization of endotoxin in the inner ear following inoculation into the middle ear. Acta Otolaryngol. 2004;124(7):772.CrossRefPubMedGoogle Scholar
  72. Tarlow MJ, Comis SD, Osborne MP. Endotoxin induced damage to the cochlea in Guinea pigs. Arch Dis Child. 1991;66:181–4.CrossRefPubMedPubMedCentralGoogle Scholar
  73. Tieu C, Campbell KC. Current pharmacologic otoprotective agents in or approaching clinical trials: how they elucidate mechanisms of noise-induced hearing loss. Otolaryngology. 2012;3:130.Google Scholar
  74. Tran Ba Huy P, Bernard P, Schacht J. Kinetics of gentamicin uptake and release in the rat. Comparison of inner ear tissues and fluids with other organs. J Clin Invest. 1986;77:1492–500.CrossRefPubMedPubMedCentralGoogle Scholar
  75. Trune DR, Kempton B, Hausman FA, Larrain BE, et al. Correlative mrna and protein expression of middle and inner ear inflammatory cytokines during mouse acute otitis media. Hear Res. 2015;326:49–58.CrossRefPubMedPubMedCentralGoogle Scholar
  76. Vu AA, Nadaraja GS, Huth ME, Luk L, et al. Integrity and regeneration of mechanotransduction machinery regulate aminoglycoside entry and sensory cell death. PLoS One. 2013;8:e54794.CrossRefPubMedPubMedCentralGoogle Scholar
  77. Wang Q, Steyger PS. Trafficking of systemic fluorescent gentamicin into the cochlea and hair cells. J Assoc Res Otolaryngol. 2009;10:205–19.CrossRefPubMedPubMedCentralGoogle Scholar
  78. Yamane H, Nakai Y, Konishi K. Furosemide-induced alteration of drug pathway to cochlea. Acta Otolaryngol Suppl. 1988;447:28–35.CrossRefPubMedGoogle Scholar
  79. Yoshihara T, Satoh M, Yamamura Y, Itoh H, et al. Ultrastructural localization of glucose transporter 1 (glut1) in Guinea pig stria vascularis and vestibular dark cell areas: an immunogold study. Acta Otolaryngol. 1999;119:336–40.CrossRefPubMedGoogle Scholar
  80. Zager RA. Endotoxemia, renal hypoperfusion, and fever: interactive risk factors for aminoglycoside and sepsis-associated acute renal failure. Am J Kidney Dis. 1992;20:223–30.CrossRefPubMedGoogle Scholar
  81. Zhang W, Dai M, Fridberger A, Hassan A, et al. Perivascular-resident macrophage-like melanocytes in the inner ear are essential for the integrity of the intrastrial fluid-blood barrier. Proc Natl Acad Sci U S A. 2012;109:10388–93.CrossRefPubMedPubMedCentralGoogle Scholar
  82. Zhao HB, Yu N, Fleming CR. Gap junctional hemichannel-mediated atp release and hearing controls in the inner ear. Proc Natl Acad Sci U S A. 2005;102:18724–9.CrossRefPubMedPubMedCentralGoogle Scholar

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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Oregon Hearing Research CenterOregon Health & Science UniversityOregonUSA

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