INFLAMAÇÃO E ADESÃO CELULAR NA ANEMIA FALCIFORME E SEU REFLEXO NO TRATAMENTO
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1 INFLAMAÇÃO E ADESÃO CELULAR NA ANEMIA FALCIFORME E SEU REFLEXO NO TRATAMENTO
2 - Durável - Flexível HEMÁCIA - Elevada concentração de hemoglobina - Máxima eficiência no transporte de oxigênio - Vida média : 120 dias - 550,6 quilômetros
3 Hemoglobina
4 The Pathophysiology of Sickle Cell Anemia Costa: Hematologia, Fundamentos e Prática 2001
5 Vaso-occlusion in Sickle Cell Disease Vascular Occlusion HbS Tissue Infarction Hemolytic Anemia Pain episodes Splenic Hypofunction Infections Acute chest syndrome Pulmonary hypertension Stroke Multi-organ damage
6 Vaso-occlusion in Sickle Cell Disease HbS Vascular Occlusion HU therapy Tissue Infarction Hemolytic Anemia Pain episodes Splenic Hypofunction Infections Acute chest syndrome Pulmonary hypertension Stroke Multi-organ damage
7 Vaso-occlusion in Sickle Cell Disease HbS Vascular Occlusion HU therapy Tissue Infarction Hemolytic Anemia Pain episodes Splenic Hypofunction Infections Acute chest syndrome Pulmonary hypertension Stroke Multi-organ damage
8 Vaso-occlusion pathophysiology: Role of endothelial activation, vascular inflammation and cell adhesion Hypoxia ROS ET-1 NO
9 Vaso-occlusion pathophysiology: Role of endothelial activation, vascular inflammation and cell adhesion Hypoxia ROS ET-1 Adhesion molecule expression NO
10 Vaso-occlusion pathophysiology: Role of endothelial activation, vascular inflammation and cell adhesion Hypoxia ROS ET-1 NO IL-8 IL-1 TNF Adhesion molecule expression
11 Vaso-occlusion pathophysiology: Role of endothelial activation, vascular inflammation and cell adhesion Hypoxia ROS ET-1 NO IL-8 IL-1 TNF TF PAF vwf Adhesion molecule expression
12 Vaso-occlusion pathophysiology: Role of endothelial activation, vascular inflammation and cell adhesion
13 Vaso-occlusion pathophysiology: Role of endothelial activation, vascular inflammation and cell adhesion
14 Targeting Vaso-occlusion: Reduce Hemolysis Reduce Inflammation Reduce Endothelial Activation Reduce Red Cell Adhesion Reduce Neutrophil Adhesion Increase NO Bioavailability Reduce Oxidative Stress
15 Targeting Vaso-occlusion: Reduce Hemolysis Reduce Inflammation Reduce Endothelial Activation Reduce Red Cell Adhesion Reduce Neutrophil Adhesion Increase NO Bioavailability Reduce Oxidative Stress
16 TNF- (pg/ml) Targeting Vascular Inflammation: Plasma Inflammatory Proteins in SCD TNF-α Control SCA SCAHU P=0.006 P=0.006 Lanaro et al., 2009
17 IL-8 (pg/ml) Targeting Vascular Inflammation: Plasma Inflammatory Proteins in SCD IL Control SCA SCAHU P< Lanaro et al., 2009; Garrido, in submissão
18 IL-8 (pg/ml) Targeting Vascular Inflammation: Plasma Inflammatory Proteins in SCD IL Control SCA SCAHU P< Lanaro et al., 2009; Garrido, in submissão
19 plasma IL-6 Targeting Vascular Inflammation: Plasma Inflammatory Proteins in SCD 15 IL-6 (pg/ml) CTRL SS SSHU Fertrin, unpublished
20 Tissue Factor (pg/ml) Targeting Vascular Inflammation: Pro-coagulant factors in SCD Tissue Factor Control SCA SCAHU P<0.001 Garrido, in submission
21 sicam-1 (ng/ml) svcam-1 (ng/ml) Targeting Vascular Inflammation: Endothelial Adhesion Molecules Plasma ICAM-1 Plasma VCAM Control SCA SCAHU 0 Control SCA SCAHU P<0.05 P<0.05 P<0.001 Garrido, in submission; Conran, 2004
22 The Endothelium and Vascular Inflammation TNF- SS RBC Contact Heme Hypoxia ROS NO
23 The Endothelium and Vascular Inflammation NF B Vasoconstriction ET-1 ET-3 enos function XO BH4 TNF- SS RBC Contact Heme Hypoxia ROS NO
24 The Endothelium and Vascular Inflammation Cell Adhesion Adhesion Molecule Expression NF B Vasoconstriction ET-1 ET-3 enos function XO BH4 TNF-
25 The Endothelium and Vascular Inflammation Cell Adhesion Adhesion Molecule Expression Leukocyte Activation NF B IL-1, IL-8, GM-CSF, IL-6 Inflammation CRP Vasoconstriction ET-1 ET-3 enos function XO BH4 TNF-
26 The Endothelium and Vascular Inflammation Cell Adhesion Adhesion Molecule Expression Leukocyte Activation NF B IL-1, IL-8, GM-CSF, IL-6 Inflammation CRP Vasoconstriction ET-1 ET-3 enos function XO BH4 vwf, TXA2, PAF, Tissue Factor Coagulation TNF-
27 The Endothelium and Vascular Inflammation Cell Adhesion Adhesion Molecule Expression Leukocyte Activation NF B IL-1, IL-8, GM-CSF, IL-6 Inflammation CRP Vasoconstriction ET-1 ET-3 enos function XO BH4 vwf, TXA2, PAF, Tissue Factor Coagulation TNF- Thrombin CD40L LIGHT Platelets
28 The Endothelium and Vascular Inflammation Cell Adhesion Adhesion Molecule Expression Leukocyte Activation NF B IL-1, IL-8, GM-CSF, IL-6 Inflammation CRP Vasoconstriction ET-1 ET-3 enos function XO BH4 vwf, TXA2, PAF, Tissue Factor Coagulation TNF- Thrombin CD40L LIGHT Platelets
29 Hydroxyurea Therapy and Vascular Inflammation Cell Adhesion Adhesion Molecule Expression Leukocyte Activation NF B IL-1, IL-8, GM-CSF, IL-6 Inflammation CRP Vasoconstriction ET-1 ET-3 enos function XO BH4 vwf, TXA2, PAF, Tissue Factor Coagulation TNF- Thrombin CD40L LIGHT Platelets
30 Targeting Vaso-occlusion: Reduce Hemolysis Reduce Inflammation Reduce Endothelial Activation Reduce Red Cell Adhesion Reduce Neutrophil Adhesion Increase NO Bioavailability and cgmp signalling Reduce Oxidative Stress
31 % Adhesion to ICAM-1 % Adhesion to FN % neutrophil adhesion to HUVEC SCA Neutrophil adhesion properties are increased in vitro *** FN # HUVEC 9 50 * Control SCD SCDHU * # * ICAM-1 # 10 0 Basal 10nM TNF- Basal 10nM TNF- Control SCD 5 0 Control SCD SCDHU Canalli et al., 2008; 2011
32 Targeting Vaso-occlusion: Reduce Hemolysis Reduce Inflammation Reduce Endothelial Activation Reduce Red Cell Adhesion Reduce Neutrophil Adhesion Increase NO Bioavailability and cgmp signalling Reduce Oxidative Stress
33 NO-cGMP pathway in SCD NO Soluble guanylate cyclase (sgc) GTP cgmp PKG RED CELLS -globin WHITE CELLS Cell adhesion HbF Almeida et al., 2008; Cokic et al., 2003; Ikuta et al., 2001
34 % Adhesion to ICAM-1 % Adhesion to FN NO donors reduce SCD neutrophil adhesive properties in vitro 15 *** ## BASAL DEANO BASAL DEANO Control SCD 25 ** ## Basal Control DEANO Basal SCD DEANO Canalli et al., 2008
35 The cgmp-dependent pathway as a potential therapeutic target for SCA vaso-occlusion NO Hydroxyurea Soluble guanylate cyclase (sgc) GTP cgmp PKG Erythrocytic lineage cells -globin HbF Leukocytes Cell adhesion King, 2004
36 The cgmp-dependent pathway as a potential therapeutic target for SCA vaso-occlusion NO Hydroxyurea Soluble guanylate cyclase (sgc) GTP cgmp PDE 9 PKG Erythrocytic lineage cells -globin Leukocytes Cell adhesion HbF Almeida et al., 2008
37 CD34 Reticulocytes Neutrophils K562 - erythroid cells + Brain T98G colon Heart Kidney Liver Lung Lymphnode Mammary Ovary Skeletal Muscle Relative PDE9A Gene Expression Skin Spleen Testicle Uterus The cgmp-dependent pathway as a potential therapeutic target for SCA vaso-occlusion Almeida et al., 2008
38 The cgmp-dependent pathway as a potential therapeutic target for SCA vaso-occlusion NO Hydroxyurea Soluble guanylate cyclase (sgc) GTP cgmp PDE 9 BAY PKG Erythrocytic lineage cells -globin Leukocytes Cell adhesion HbF Almeida et al., 2008
39 % Adhesion to FN Inhibition of PDE9 decreases neutrophil adhesion to FN, in vitro 30 A *** Basal BAY73 Basal BAY73 CONTROL SCD Miguel et al., 2011
40 Sickle Cell Mouse Inflammatory Vaso-occlusive Model Blood flow 3h post -TNF-α Frenette Laboratory Albert Einstein College of Medicine, NY Cremaster Muscle Measure: leukocyte Adhesion, rolling and extravasation
41 Effects of HU and BAY on leukocyte recruitment in TNF-α-treated SCD mice Frenette Laboratory Albert Einstein College of Medicine, NY
42 Effects of HU and BAY on leukocyte recruitment in TNF-α-treated SCD mice Vehicle BAY HU HU + BAY Frenette Laboratory Albert Einstein College of Medicine, NY 10μm Blood flow
43 BAY decreases WBC-RBC interactions Frenette Laboratory Albert Einstein College of Medicine, NY
44 Co-administration of HU and BAY improves SCD mouse survival in the setting of vaso-occlusion Frenette Laboratory Albert Einstein College of Medicine, NY
45 NOVEL HYBRID OF HYDROXYUREA AND THALIDOMIDE BASED PHARMACOPHORES INDUCE FETAL HEMOGLOBIN AND BLOCK MONOCYTE ACTIVATION
46 Thalidomide Thalidomide and its recently developed IMiD (immunoodulatory derivates of thalidomide) derivatives (such as pomalidomide and lenalidomide) potently inhibit cytokine release from activated monocytes and suppress adhesion molecule expression on vascular endothelium; These properties are critically linked to the phthalimide ring in the thalidomide molecule.
47 Molecular Hybridization Hydroxyurea Thalidomide Molecular Hybridization Nitric oxide Spacer
48 Aim The aim of this study was to evaluate the effects of a novel hybrid compound Lapdesf 1 (2-[4-(1,3-dioxo-1,3-dihydro-2Hisoindol-2-yl)phenyl]ethyl nitrate) on γ-globin gene expression in cells culture, fetal hemoglobin levels in sickle cell transgenic mice and cytokine release from activated monocytes.
49 -globin gene expression (U.A.) Results K562 Cell Culture Human K562 cells were maintained in DMEM with 10% FBS, Pen/Strep, in humidified air (5% CO 2, 37 C). -globin gene expression was analyzed by qrt-pcr and quantified using the Gnorm program. -globin gene expression (U.A.) A 24h Ctrl 5uM 30uM 60uM 100uM -globin gene expression (U.A.) B h Ctrl 5uM 30uM 60uM 100uM C 72h * Ctrl 5uM 30uM 60uM 100uM -globin gene expression (U.A.) D h Ctrl 5uM 30uM 60uM 100uM K562 Cell Culture incubated with Lapdesf 1, n 3, * P<0.05, compared to control.
50 Erythroid Cell Culture CD34 + cells were isolated from healthy donors and cultived with EPO, Stem cell factor and IL-3. The cells were treated on day 9 and collected after 4 days (day13). -globin gene expression (U.A.) 3 2 * * 1 0 Ctrl DMSO 100uM HU 5uM 30uM 60uM Lapdesf1
51 Sickle Cell Transgenic Mice Chronic Treatment Transgenic KT sickle mice were treated i.p. for 8 weeks with test drug and levels of fetal hemoglobin determined by HPLC, n 6, * P<0.05. Veh: Vehicle PL: Pomalidomide HU: Hydroxyurea C/HD: High-dose (10mg/Kg PL and 100mg/Kg HU) C/LD: Low-dose (10mg/Kg PL and 10mg/HU) Mieler et al.; 2011; Blood
52 Monocyte stimulation Levels of pro-inflammatory mediators determined by ELISA in the supernatant of mononuclear culture from sickle cell transgenic mice treated with LPS and co-incubated with test drugs (24H). Dexamethasone (1µM) was used a positive anti-inflammatory control (A) TNF-α. (B) IL-1β. (C) IL-6. (D) KC. n 5, * P<0.05, compared to LPS.
53 Santos J.et al:j.med.chem,2011 Our results support the hypothesis that Lapdesf 1 can augment HbF synthesis. In addition, this compound has the ability to inhibit TNF-α production and other inflammatory cytokines and could help reduce chronic inflammation in sickle-cell patients, thus reducing or preventing clinical complications associated with SCD. These data suggest that Lapdesf 1 represents a novel drug worthy of additional study for SCD and β thalassemia and perhaps certain other diseases associated with chronic inflammation.
54 Decreasing Endothelial Interactions and Vascular Inflammation in SCD Statins Hypoxia ROS ET-1 NO IL-8 IL-1 TNF Adhesion molecule expression
55 % SCD neutophil adhesion Statins reduce SCD neutrophil adhesion to endothelial cells in vitro *** Basal Sim TNF TNF/Sim Canalli et al., 2011
56 HEREDITARY PERSISTENCE OF FETAL HEMOGLOBIN
57 Hereditary Persistence of Fetal Hemoglobin (HPFH) HPFH is a genetic disorder that results in the increased levels of fetal hemoglobin in adult life. Types: deletional - involving the beta globin gene cluster (dhpfh) non-deletional point mutations in the gamma globin gene promoter (ndhpfh) (Forget, 1998; Steinberg et al., 2001).
58 Brazilian Type Hereditary Persistence of Fetal Hemoglobin Costa et al., 1990
59 A. Wild Type NFE1/YY1...CTTCCCCACACTAT... promoter A globin gene A Globin Gene Expression Repressed B. Brazilian Type ndhpfh FOXO3a + NFE1/YY1 PAX1...CTTCCGCACACTAT... promoter A globin gene A Globin Gene Expression Reactivation Roversi et al., 2011
60 Brazilian Type of ndhpfh
61 18 November 2011: Vol no pp Correction of sickle cell disease in adult mice by interference with fetal hemoglobin silencing. Xu J, Peng C, Sankaran VG, Shao Z, Esrick EB, Chong BG, Ippolito GC, Fujiwara Y, Ebert BL, Tucker PW, Orkin SH. Children's Hospital Boston Department of Pediatric Oncology Dana-Farber Cancer Institute Harvard Medical School, Boston, MA, USA.
62 BCL11A Transcriptional repressor of HbF production; Contributes to HbF silencing in primary human erythroid cells; Regulator of globin switching in development. AIMS Investigate the contribution of BCL11A to -silencing in adults through conditional inactivation of this gene in mice carrying the human -globin gene cluster.
63 Inactivation of BCL11A rescues sickle cell defects in humanized SCD mice. Representative blood smears of control, SCD, and SCD/Bcl11a / mice are shown at 1000x magnification.
64 Conclusion The correction of SCD in mice by genetic manipulation of a single component involved in globin gene regulation constitutes a requisite step in translating new insights in HbF silencing into mechanism-based, improved therapy for the major hemoglobin disorders.
65 Summary Vascular inflammatory molecule production may contribute to vaso-occlusion in SCD, by activating the endothelium and blood cells; Approaches to reduce vascular inflammation should be further investigated; Inhibition of leukocyte adhesion to the vessel wall may be an important approach for the prevention of sickle cell vaso-occlusion; - STATINS - Selectin Inhibitors (GMI-1070)
66 Summary HU may have important HbF-independent effects that could play a role in the prevention of leukocyte adhesion and vaso-occlusion; Drugs that amplify the cgmp-dependent effects of HU should be further studied; Inhibition of the PDE9 enzyme may represent a relatively tissue-specific drug target in SCD, with potential for increasing both HbF production and decreasing leukocyte adhesion
67 Sara Saad Nicola Conran Vanessa Garrido Carla Franco-Penteado Andreia Canalli Lediana Miguel Carol Lanaro Fabiola Traina Kleber Fertrin New York: Albert Einstein College of Medicine Paul Frenette Christoph Scheiermman Jungan Jang Camila Almeida
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70 Targeting Vascular Inflammation: Plasma Inflammatory Modulators in SCD PGE 1 PGE 2 Lanaro et al., 2009; Conran et al., 2007
71 Decreasing Endothelial Interactions and Vascular Inflammation in SCD Hypoxia ROS ET-1 NO HU NO donating drugs cgmp-elevating drugs
72 Decreasing Endothelial Interactions and Vascular Inflammation in SCD Hypoxia ROS ET-1 NO ACE inhibitors
73 Decreasing Endothelial Interactions and Vascular Inflammation in SCD Hypoxia ROS ET-1 NO IL-8 IL-1 TNF TF PAF vwf Adhesion molecule expression Anti-platelet drugs - Eptifibatide
74 Decreasing Endothelial Interactions and Vascular Inflammation in SCD Statins
75 Decreasing Endothelial Interactions and Vascular Inflammation in SCD Statins HU
76 Decreasing Endothelial Interactions and Vascular Inflammation in SCD GMI-1070 HU cgmp-elevating drugs
77 Decreasing Endothelial Interactions and Vascular Inflammation in SCD possible approaches Hypoxia ROS ET-1 NO HU Red cell hydration
78 Statins reduce SCD neutrophil adhesion to endothelial cells in vitro Role for Adhesion Molecule Expression ICAM-1 expression on HUVEC VCAM-1 expression on HUVEC Canalli et al., 2011
79 Statins reduce SCD neutrophil adhesion to endothelial cells in vitro Role for NO production Canalli et al., 2011
80 Disclosures No affiliations to declare
81 Targeting Vascular Inflammation: HC and Plasma Inflammatory Proteins in SCD IL-6 IL-8 C-reactive protein TNF- Endothelin-1 PGE 1 PGE 2 GM-CSF Tissue Factor Soluble adhesion molecules Angiogenic markers CD40L LIGHT NT-proBNP Anti-inflammatory Proteins IL-10 HO-1 Lanaro et al., 2009; Lampoumeroulie et al., 2005; Conran et al., 2004
82 Targeting Vascular Inflammation: Plasma Inflammatory Proteins in SCD IL-8 TNF- IL-6 PGE 2 PGE 1 GM-CSF C-reactive protein Endothelin-1 TF NT-proBNP Soluble adhesion molecules Angiogenic markers CD40L LIGHT Anti-inflammatory Proteins HO-1 Lanaro et al., 2009; Brittain et al., 2007; Lee et al., 2006; Makis et la., 2006; Mohan et al., 2005; Rybicki 1998; Graido Gonzalez et al., 1998
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