HIF–VEGF Pathways Are Critical for Chronic Otitis Media in and Mouse Mutants

English version České info

Otitis media with effusion (OME) is the commonest cause of hearing loss in children, yet the underlying genetic pathways and mechanisms involved are incompletely understood. Ventilation of the middle ear with tympanostomy tubes is the commonest surgical procedure in children and the best treatment for chronic OME, but the mechanism by which they work remains uncertain. As hypoxia is a common feature of inflamed microenvironments, moderation of hypoxia may be a significant contributory mechanism. We have investigated the occurrence of hypoxia and hypoxia-inducible factor (HIF) mediated responses in Junbo and Jeff mouse mutant models, which develop spontaneous chronic otitis media. We found that Jeff and Junbo mice labeled in vivo with pimonidazole showed cellular hypoxia in inflammatory cells in the bulla lumen, and in Junbo the middle ear mucosa was also hypoxic. The bulla fluid inflammatory cell numbers were greater and the upregulation of inflammatory gene networks were more pronounced in Junbo than Jeff. Hif-1α gene expression was elevated in bulla fluid inflammatory cells, and there was upregulation of its target genes including Vegfa in Junbo and Jeff. We therefore investigated the effects in Junbo of small-molecule inhibitors of VEGFR signaling (PTK787, SU-11248, and BAY 43-9006) and destabilizing HIF by inhibiting its chaperone HSP90 with 17-DMAG. We found that both classes of inhibitor significantly reduced hearing loss and the occurrence of bulla fluid and that VEGFR inhibitors moderated angiogenesis and lymphangiogenesis in the inflamed middle ear mucosa. The effectiveness of HSP90 and VEGFR signaling inhibitors in suppressing OM in the Junbo model implicates HIF–mediated VEGF as playing a pivotal role in OM pathogenesis. Our analysis of the Junbo and Jeff mutants highlights the role of hypoxia and HIF–mediated pathways, and we conclude that targeting molecules in HIF–VEGF signaling pathways has therapeutic potential in the treatment of chronic OM.

Vyšlo v časopise: HIF–VEGF Pathways Are Critical for Chronic Otitis Media in and Mouse Mutants. PLoS Genet 7(10): e32767. doi:10.1371/journal.pgen.1002336
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1002336

Souhrn

Zdroje

1. DavidsonJHydeMLAlbertiPW 1989 Epidemiologic patterns in childhood hearing loss: a review. Int J Ped Otorhinolaryngol 17 239 266

2. KubbaHPearsonJPBirchallJP 2000 The aetiology of otitis media with effusion: a review. Clin Otolaryngol Allied Sci 25 181 194

3. RosenfeldRMCulpepperLDoyleKJGrundfastKMHobermanA 2004 Clinical practice guideline: otitis media with effusion. Otolaryngol Head Neck Surg 130 S95 S118

4. LousJBurtonMJFeldingJUOvesenTRoversMM 2005 Grommets (ventilation tubes) for hearing loss associated with otitis media with effusion in children. Cochrane Database Syst Rev CD001801

5. FredeSBerchner-PfannschmidtUFandreyJ 2007 Regulation of hypoxia-inducible factors during inflammation. Meth Enzymol 435 405 419

6. DehneNBrüneB 2009 HIF-1 in the inflammatory microenvironment. Exp Cell Res 315 1791 1797

7. DoedensAJohnsonRS 2007 Transgenic models to understand hypoxia-inducible factor function. Meth Enzymol 435 87 105

8. WalmsleySRPrintCFarahiNPeyssonnauxCJohnsonRS 2005 Hypoxia-induced neutrophil survival is mediated by HIF-1alpha-dependent NF-kappaB activity. J Exp Med 201 105 115

9. RiusJGumaMSchachtrupCAkassoglouKZinkernagelAS 2008 NF-κB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1α. Nature 453 807 811

10. TaylorCT 2008 Interdependent roles for hypoxia inducible factor and nuclear factor-kappaB in hypoxic inflammation. J Physiol 586 4055 4059

11. ZinkernagelAJohnsonRNizetV 2007 Hypoxia inducible factor (HIF) function in innate immunity and infection. J Mol Med 85 1339 1346

12. OliverKTaylorCCumminsE 2009 Hypoxia. Regulation of NFκB signalling during inflammation: the role of hydroxylases. Arthritis Res Ther 11 215

13. GrosiosKWoodJEsserRRaychaudhuriADawsonJ 2004 Angiogenesis inhibition by the novel VEGF receptor tyrosine kinase inhibitor, PTK787/ZK222584, causes significant anti-arthritic effects in models of rheumatoid arthritis. Inflamm Res 53 133 142

14. IngelstedtSJonsonBRundcrantzH 1975 Gas tension and pH in middle ear effusion. Otol Rhinol Laryngol 84 198 202

15. HergilsLMagnusonB 1997 Middle ear gas composition in pathologic conditions: mass spectrometry in otitis media with effusion and atelectasis. Ann Otol Rhinol Laryngol 106 743 745

16. TakahashiMNiwaHYanagitaN 1990 PO2 levels in middle ear effusions and middle ear mucosa. Acta Otolaryngol Suppl 471 39 42

17. KimTHChaeSWKimHJJungHH 2005 Effect of recombinant vascular endothelial growth factor on experimental otitis media with effusion. Acta Otolaryngol 125 256 259

18. JungHHKimMWLeeJHKimYTKimNH 1999 Expression of vascular endothelial growth factor in otitis media. Acta Otolaryngol 119 801 808

19. ChaeSWKimSJKimJLJungHH 2003 Expression of vascular endothelial growth factor receptors in experimental otitis media in the rat. Acta Otolaryngol 123 559 563

20. TruneDRLarrainBEHausmanFAKemptonJBMacArthurCJ 2010 Simultaneous measurement of multiple ear proteins with multiplex ELISA assays. Hear Res 2010 Dec 7 doi:10.1016/j.heares.2010.11.009

21. SekiyamaKOhoriJMatsuneSKuronoY 2011 The role of vascular endothelial growth factor in pediatric otitis media with effusion. Auris Nasus Larynx 3 319 24 Epub 2011 Jan 11

22. CasselbrantMLMandelEMRocketteHEKurs-LaskyMFallPA 2004 The genetic component of middle ear disease in the first 5 years of life. Arch Otolaryngol Head Neck Surg 130 273 278

23. DalyKABrownWMSegadeFBowdenDWKeatsBJ 2004 Chronic and recurrent otitis media: a genome scan for susceptibility loci. Am J Hum Genet 75 988 997

24. SegadeFDalyKAAllredDHicksPJCoxM 2006 Association of the FBXO11 gene with chronic otitis media with effusion and recurrent otitis media: The Minnesota COME/ROM family study. Arch Otolaryngol Head Neck Surg 132 729 733

25. RyeMSWiertsemaSPScamanESHOommenJSunW 2011 FBXO11, a regulator of the TGFβ pathway, is associated with severe otitis media in Western Australian children. Genes Immun 2011 Feb 3. Epub ahead of print doi:10.1038/gene.2011.2

26. DalyKAHoffmanHJKvaernerKJKvestadECasselbrantML 2010 Epidemiology, natural history, and risk factors: panel report from the ninth international research conference on otitis media. Int J Ped Otorhinolaryngol 74 231 240

27. RyeMSBhuttaMFCheesemanMTBurgnerDBlackwellJM 2010 Unraveling the genetics of otitis media - from mouse to human and back again. Mammalian Genome 22 66 82

28. Hardisty-HughesRETateossianHMorseSARomeroMRMiddletonA 2006 A mutation in the F-box gene, Fbxo11, causes otitis media in the Jeff mouse. Hum Mol Genet 15 3273 3279

29. ParkinsonNHardisty-HughesRETateossianHTsaiHTBrookerD 2006 Mutation at the Evi1 Locus in Junbo mice causes susceptibility to otitis media. PLoS Genet 2 e149 doi:10.1371/journal.pgen.0020149

30. WalmsleySRCadwalladerKAChilversER 2005 The role of HIF-1alpha in myeloid cell inflammation. Trends Immunol 26 434 439

31. HuangfuMSaundersJ 1983 Auditory development in the mouse: structural maturation of the middle ear. J Morphol 176 249 259

32. GiebinkGSJuhnSKWeberMLLeCT 1982 The bacteriology and cytology of chronic otitis media with effusion. Ped Infect Dis 1 98 103

33. SipiläPKarmaP 1982 Inflammatory cells in mucoid effusion of secretory otitis media. Acta Otolaryngol 94 467 472

34. SadéJArA 1997 Middle ear and auditory tube: middle ear clearance, gas exchange, and pressure regulation. Otolaryngol Head Neck Surg 116 499 524

35. FeldingJURasmussenJBLildholdtT 1987 Gas composition of the normal and the ventilated middle ear cavity. Scand J Clin Lab Invest Suppl 186 31 41

36. KerschnerJE 2007 Mucin gene expression in human middle ear epithelium. Laryngoscope 117 1666 1676

37. YoungHWWilliamsOWChandraDBellinghausenLKPérezG 2007 Central role of Muc5ac expression in mucous metaplasia and its regulation by conserved 5′ elements. Am J Respir Cell Mol Biol 37 273 290

38. JuhnSKJungMKHoffmanMDDrewBRPreciadoDA 2008 The role of inflammatory mediators in the pathogenesis of otitis media and sequelae. Clin Exp Otorhinolaryngol 1 117 138

39. IinoYKakizakiKKatanoHSaigusaHKanegasakiS 2005 Eosinophil chemoattractants in the middle ear of patients with eosinophilic otitis media. Clin Exp Allergy 35 1370 1376

40. NonakaMOgiharaNFukumotoASakanushiAPawankarR 2009 Poly(I∶C) synergizes with Th2 cytokines to induce TARC/CCL17 in middle ear fibroblasts established from mucosa of otitis media with effusion. Acta Otolaryngol Suppl 562 57 62

41. MoonSKWooJILeeHYParkRShimadaJ 2007 Toll-like receptor 2-dependent NF-kappaB activation is involved in nontypeable Haemophilus influenzae-induced monocyte chemotactic protein 1 up-regulation in the spiral ligament fibrocytes of the inner ear. Infect Immun 75 3361 3372

42. LeichtleAHernandezMEbmeyerJYamasakiKLaiY 2010 CC chemokine ligand 3 overcomes the bacteriocidal and phagocytic defect of macrophages and hastens recovery from experimental otitis media in TNF−/− mice. J Immunol 184 3087 3097

43. TongHHLongJPShannonPADeMariaTF 2003 Expression of cytokine and chemokine genes by human middle ear epithelial cells induced by influenza A virus and Streptococcus pneumoniae opacity variants. Infect Immun 71 4289 4296

44. KitaHHimiT 1999 Cytokine and chemokine induction using cell wall component and toxin derived from gram-positive bacteria in the rat middle ear. Acta Otolaryngol 119 446 452

45. HarimayaAFujiiNHimiT 2009 Preliminary study of proinflammatory cytokines and chemokines in the middle ear of acute otitis media due to Alloiococcus otitidis. Int J Pediatr Otorhinolaryngol 73 677 680

46. KariyaSOkanoMFukushimaKNomiyaSKataokaY 2008 Expression of inflammatory mediators in the otitis media induced by Helicobacter pylori antigen in mice. Clin Exp Immunol 154 134 140

47. SkovbjergSRoosKNowrouzianFLindhMHolmSE 2010 High cytokine levels in perforated acute otitis media exudates containing live bacteria. Clin Microbiol Infect 16 1382 1388

48. ZhaoSQLiJLiuHZhangQGWangY 2009 Role of interleukin-10 and transforming growth factor beta 1 in otitis media with effusion. Chin Med J (Engl) 122 2149 2154

49. LongJPTongHHShannonPADeMariaTF 2003 Differential expression of cytokine genes and inducible nitric oxide synthase induced by opacity phenotype variants of Streptococcus pneumoniae during acute otitis media in the rat. Infect Immun 71 5531 5540

50. EmontsMVeenhovenRHWiertsemaSPHouwing-DuistermaatJJWalravenV 2007 Genetic polymorphisms in immunoresponse genes TNFA, IL6, IL10, and TLR4 are associated with recurrent acute otitis media. Pediatrics 120 814 823

51. MatkovićSVojvodićDBaljosevicI 2007 Cytokine levels in groups of patients with different duration of chronic secretory otitis. Eur Arch Otorhinolaryngol 264 1283 1287

52. MattilaPSNykänenAElorantaMTarkkanenJ 2002 Adenoids provide a microenvironment for the generation of CD4(+), CD45RO(+), L-selectin(−), CXCR4(+), CCR5(+) T lymphocytes, a lymphocyte phenotype found in the middle ear effusion. Int Immunol 12 1235 1243

53. LeichtleAHernandezMPakKYamasakiKChengCF 2009 TLR4-mediated induction of TLR2 signaling is critical in the pathogenesis and resolution of otitis media. Innate Immun 15 205 215

54. KingPNguiJOppedisanoFRobins-BrowneRHolmesP 2008 Effect of interferon gamma and CD40 ligation on intracellular monocyte survival of nontypeable Haemophilus influenzae. APMIS 116 1043 1049

55. RezesSKésmárkiKSipkaSSziklaiI 2007 Characterization of otitis media with effusion based on the ratio of albumin and immunoglobulin G concentrations in the effusion. Otol Neurotol 28 663 667

56. HongCKParkDCKimSWChaCIChaSH 2008 Effect of paranasal sinusitis on the development of otitis media with effusion: influence of Eustachian tube function and adenoid immunity. Int J Pediatr Otorhinolaryngol 72 1609 1618

57. SabharwalVRamSFigueiraMParkIHPeltonSI 2009 Role of complement in host defense against pneumococcal otitis media. Infect Immun 77 1121 1127

58. JaatinenTRuuskanenOTruedssonLLokkiML 1999 Homozygous deletion of the CYP21A-TNXA-RP2-C4B gene region conferring C4B deficiency associated with recurrent respiratory infections. Hum Immunol 60 707 714

59. ChenALiHSHebdaPAZeeviASwartsJD 2005 Gene expression profiles of early pneumococcal otitis media in the rat. Int J Pediatr Otorhinolaryngol 69 1383 1393

60. HernandezMLeichtleAPakKEbmeyerJEuteneuerS 2008 Myeloid differentiation primary response gene 88 is required for the resolution of otitis media. J Infect Dis 198 1862 1869

61. LiHSDoyleWJSwartsJDLoCYHebdaPA 2003 Mucosal expression of genes encoding possible upstream regulators of Na+ transport during pneumococcal otitis media. Acta Otolaryngol 123 575 582

62. GranathAUddmanRCardellLO 2010 Increased TLR7 expression in the adenoids among children with otitis media with effusion. Acta Otolaryngol 130 57 61

63. KamimuraMHimiTKatauraA 1996 Cell adhesion molecules of experimental otitis media in the rat. Acta Otolaryngol 116 857 862

64. AngeloLSKurzrockR 2007 Vascular endothelial growth factor and its relationship to inflammatory mediators. Clin Cancer Res 13 2825 2830

65. NagyJBenjaminLZengHDvorakADvorakH 2008 Vascular permeability, vascular hyperpermeability and angiogenesis. Angiogenesis 11 109 119

66. PenhaREscadaP 2007 Interrelations between the middle and inner ear in otitis media. Int Tinnitis J 9 87 91

67. JuhnSKHamaguchiYGoycooleaM 2009 Review of round window membrane permeability. Acta Otolaryngol 105 s457 43 48

68. OlssonAKDimbergAKreugerJClaesson-WelshL 2006 VEGF receptor signalling - in control of vascular function. Nat Rev Mol Cell Biol 7 359 371

69. KiselyovABalakinKVTkachenkoSE 2006 VEGF/VEGFR signalling as a target for inhibiting angiogenesis. Expert Opin Investig Drugs 16 83 107

70. van der BiltJDSoetersMEDuyvermanAMNijkampMWWitteveenPO 2007 Perinecrotic hypoxia contributes to ischemia/reperfusion-accelerated outgrowth of colorectal micrometastases. Am J Pathol 170 1379 1388

71. MilkiewiczMDoyleJLFudalewskiTIspanovicEAghasiM 2007 HIF-1α and HIF-2α play a central role in stretch-induced but not shear-stress-induced angiogenesis in rat skeletal muscle. J Physiol 583 753 766

72. FukuyoYHuntCRHorikoshiN 2010 Geldanamycin and its anti-cancer activities. Cancer Lett 290 24 35

73. DuvalMLe BoeufFHuotJGrattonJP 2007 Src-mediated phosphorylation of Hsp90 in response to vascular endothelial growth factor (VEGF) is required for VEGF receptor-2 signaling to endothelial NO synthase. Mol Biol Cell 18 4659 4668

74. Madrigal-MatuteJLópez-FrancoOBlanco-ColioLMMuñoz-GarcíaBRamos-MozoP 2010 Heat shock protein 90 inhibitors attenuate inflammatory responses in atherosclerosis. Cardiovasc Res 86 330 337

75. TateossianHHardisty-HughesREMorseSRomeroMRHiltonH 2009 Regulation of TGF-β signalling by Fbxo11, the gene mutated in the Jeff otitis media mouse mutant. PathoGenet Published online 2009 July 6. doi: 10.1186/1755-8417-2-5

76. GoyamaSKurokawaM 2009 Pathogenetic significance of ecotropic viral integration site-1 in hematological malignancies. Cancer Sci 100 990 995

77. JeonSHChaeBCKimHASeoGYSeoDW 2007 Mechanisms underlying TGF-beta1-induced expression of VEGF and Flk-1 in mouse macrophages and their implications for angiogenesis. J Leukoc Biol 81 557 566

78. Sánchez-ElsnerTBotellaLMVelascoBCorbíAAttisanoL 2001 Synergistic cooperation between hypoxia and transforming growth factor-beta pathways on human vascular endothelial growth factor gene expression. J Biol Chem 276 38527 38535

79. MorishitaKParkerDSMucenskiMLJenkinsNACopelandNG 1988 Retroviral activation of a novel gene encoding a zinc finger protein in IL-3-dependent myeloid leukemia cell lines. Cell 54 831 840

80. TanakaTNishidaJMitaniKOgawaSYazakiY 1994 Evi-1 raises AP-1 activity and stimulates c-fos promoter transactivation with dependence on the second zinc finger domain. J Biol Chem 269 24020 24026

81. LaderouteKR 2005 The interaction between HIF-1 and AP-1 transcription factors in response to low oxygen. Semin Cell Dev Biol 16 502 513

82. YuBMiaoZHJiangYLiMHYangN 2009 c-Jun protects hypoxia-inducible factor-1alpha from degradation via its oxygen-dependent degradation domain in a nontranscriptional manner. Cancer Res 69 7704 7712

83. ZenzREferlRScheineckerCRedlichKSmolenJ 2008 Activator protein 1 (Fos/Jun) functions in inflammatory bone and skin disease. Arthritis Res Ther 2008;10 1 201 Epub 2008 Jan 18

84. TrepelJMollapourMGiacconeGNeckersL 2010 Targeting the dynamic HSP90 complex in cancer. Nat Rev Cancer 10 537 549

85. ZhengQYJohnsonKRErwayLC 1999 Assessment of hearing in 80 inbred strains of mice by ABR threshold analyses. Hearing Res 130 94 107