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Hasan Bayram, MD, PhD .

Molecular M echanisms in C orticosteroid R esistance ; H istone A cetylation and D eacetylation. Hasan Bayram, MD, PhD . Department of Chest Diseases , School of Medicine , University of Gaziantep E-mail: bayram@ gantep .edu.tr.

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Hasan Bayram, MD, PhD .

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  1. Molecular Mechanisms in CorticosteroidResistance; HistoneAcetylation and Deacetylation Hasan Bayram, MD, PhD. Department of ChestDiseases, School of Medicine, University of Gaziantep E-mail: bayram@gantep.edu.tr TTS 15th AnnualCongress, Antalya 11-15 April 2012

  2. I have no conflict of interest to declare with regards to my presentation.

  3. Contents • How do steroids work? • How does steroid resistance occur? • Histoneacetylation and deacetylation • HDAC abnormality in diseases • The effect of increased HDAC activity in treatment • Summary

  4. GlucocorticoidActivation of Anti-inflammatory GeneExpression Barnes PJ, J Steroid Biochem Mol Biol. 2010

  5. GlucocorticoidSuppression of ActivatedInflammatoryGenes Barnes PJ, J Steroid Biochem Mol Biol. 2010

  6. Possible MolecularMechanisms of SteroidResistance Barnes PJ, J Steroid Biochem Mol Biol. 2010

  7. Mechanism of GlucocorticoidResistance in COPD, SevereAsthma and SmokingAsthma Barnes PJ, J Steroid Biochem Mol Biol. 2010

  8. MolecularMechanisms of SteroidResistance • Defectivehistoneacetylation • Reducedacetylation of lysine 5 on histone 4 • Reducedhistonedeacetylase 2 • Increasedoxidativestress • Increasedphosphoinositide-3-kinase-δ activation • Increased P-glycoprotein • Increasedefflux of steroids Barnes PJ, Adcock IA, Lancet 2009

  9. (4m DNA nükleusta paketlenir 50,000x kısaltılarak))

  10. H2A R R * * * * H2B * H2B * * * * * H4 * * * H4 * * * M * * DNA * * * M M * * * * H3 H2A H3 P P * * * * M M * =Acetylation sites: Lysine residues NucleosomalStructure: DNA is wrapped around the histoneoctamer Wolffe AP, Haynes J: Nucl Acids Res 1999 (Courtesy of I Adcock)

  11. Histone acetylation/deacetylation controls gene expression HistoneDeacetylation (Gene silencing) Histone Deacetylase (transcriptional activation) Histone Acetylation Histone Acetyltransferase P300/CBP, PCAF, TAFs, SRC-1, ACTR, TIP60 4 classes: HDAC 1 - 11sirtuins 1-7 (Courtesy of I Adcock)

  12. Histon deasetilazların (HDAC) sınıflandırılması

  13. Abnormal Expression of HDACs in AirwaysDisease

  14. DiseaseswithAbnormal HDAC Expression • Asthma (smokers) • COPD • Others; rheumatoid arthritis, inflammatory bowel disease • AdenocarcinomapatientswithCushing’ syndrome has lowlevel of HDAC1 1Bilodeau S, et al, Genes Dev. 2006; Barnes PJ, Adcock IA, Lancet 2009

  15. protein) ** # # HDAC activity (dpm/mg 125 r2 = 0.7803 100 As +ICS As +ICS p< 0.0001 1 75 FEV 50 0 100 200 300 HDAC activity (dpm) HAT and HDAC activity in asthmatic biopsies HAT activity HDAC activity 7500 150 ** 5000 ** 100 HAT activity (dpm) 2500 50 0 0 As -ICS N As -ICS N (Courtesy of I. Adcock) Ito K, et al, AJRCCM. 2002

  16. HDAC and HAT Expression in PBMCs of Normal andAsthmaticIndividuals HDAC HAT Hew M, et al., AJRCCM 2006

  17. Relationship BetweenEndogenous HDAC and HAT Activitiesand BHR in Asthmatic Children Su RC, et al,. JACI 2009

  18. HAT andHDAC Activitiesin Peripheral Lung Tissue from Patientswith COPD HAT HDAC KOAH evre KOAH evre PN: Pnumonia CF: Cytsticfibrosis Ito K, et al, NEJM. 2005

  19. TheCorrelationBetween HDAC Activityand FEV1/FVC Ito K, et al, NEJM. 2005

  20. HDAC Expression in PeripheralLungTissue. GOLD Stage HDAC 1-8 gene expression, real time PCR (* VS non-smokerand s0.) Ito K, et al, NEJM. 2005

  21. 6 weeks TSA Kontrol

  22. Can We Enhance HDAC Activity and Restore ‘Normal’ Cell Function?

  23. Effect of Prednisoloneon Activity and Expression ofHDAC in PBMCs (30 mg/daily 3-weektreatment) Cosio BG, et al, Am J RespirCrit Care 2004

  24. Activity and Expression of HDACs and HATs in BAL Macrophages HAT HDAC Cosio BG, et al, Am J RespirCrit Care 2004

  25. Effect of Dexamethasone on Release of IL-8 and GM-CSF fromBronchialEpithelialCells of COPD Patients

  26. Reversal of CorticosteroidInsensitivity by Theophylline in SmokingMice To Y, et al. Am J RespirCrit Care Med. 2010

  27. Effect of Theophylline on HDAC Activity and DexamethasoneSensitivity in AlveolarMacrophages (U937 Hücreleri) Cosio BG, et al J ExpMed. 2004

  28. Change in PeakExpiratoryFlow (PEF)Following 28 days of Treatment Spears M, et al. EurRespir J. 2009

  29. Effect of FP+LowDoseTheophylline on HDAC Activity in PBMCs (Courtesy of I Adcock) Ford PA, et al. Chest 2010

  30. FP/Theo ImprovesSputumNeutrophilia andLungFunction (Courtesy of I Adcock) Ford PA, et al. Chest 2010

  31. Summary • Steroid resistance is an important problem • Histone acetylation and deacetylation is important • The interventions to induce HDAC activity (i.e. Theophylline) may contribute to the treatment

  32. ThankYou

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