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Angiogenesis Associated Mechanisms in Airway Inflammation and Remodelling

Angiogenesis Associated Mechanisms in Airway Inflammation and Remodelling. Cengiz KIRMAZ MD. Associated Professor of Internal Medicine Celal Bayar University Department of Immunology and Allergy. Angiogenesis (angio'gen'esis). The growth of new blood vessels…

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Angiogenesis Associated Mechanisms in Airway Inflammation and Remodelling

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  1. Angiogenesis Associated Mechanisms in Airway Inflammation and Remodelling Cengiz KIRMAZ MD. Associated Professor of Internal Medicine Celal Bayar University Department of Immunology and Allergy

  2. Angiogenesis (angio'gen'esis) • The growth of new blood vessels… • It is an important natural process occurring in the body, • in health and • in disease…

  3. Control of Angiogenesis • Angiogenesis occurs in the healthy body for healing wounds and for restoring blood flow to tissues after injury… • The healthy body controls angiogenesis through a series of “" and “" switches: • The main "ON" switches are known as angiogenesis-stimulating growth factors • The main "OFF” switches are known as angiogenesis inhibitors… ON OFF

  4. List of Known Angiogenic Growth Factors ON OFF • Angiogenin • Angiopoietin-1 • Del-1 • Fibroblast growth factors: acidic (aFGF) and basic (bFGF) • Follistatin • Granulocyte colony-stimulating factor (G-CSF) • Hepatocyte growth factor (HGF) /scatter factor (SF) • Interleukin-8 (IL-8) • Leptin • Midkine • Placental growth factor • Platelet-derived endothelial cell growth factor (PD-ECGF) • Platelet-derived growth factor-BB (PDGF-BB) • Pleiotrophin (PTN) • Progranulin • Proliferin • Transforming growth factor-alpha (TGF-alpha) • Transforming growth factor-beta (TGF-beta) • Tumor necrosis factor-alpha (TNF-alpha) • Vascular endothelial growth factor (VEGF)/vascular permeability factor (VPF)

  5. List of Known Angiogenesis Inhibitors ON OFF • Angioarrestin • Angiostatin (plasminogen fragment) • Antiangiogenic antithrombin III • Cartilage-derived inhibitor (CDI) • CD59 complement fragment • Endostatin (collagen XVIII fragment) • Fibronectin fragment • Gro-beta • Heparinases • Heparin hexasaccharide fragment • Human chorionic gonadotropin (hCG) • Interferon alpha/beta/gamma • Interferon inducible protein (IP-10) • Interleukin-12 • Kringle 5 (plasminogen fragment) • Metalloproteinase inhibitors (TIMPs) • 2-Methoxyestradiol • Placental ribonuclease inhibitor • Plasminogen activator inhibitor • Platelet factor-4 (PF4) • Prolactin 16kD fragment • Proliferin-related protein (PRP) • Retinoids • Tetrahydrocortisol-S • Thrombospondin-1 (TSP-1) • Transforming growth factor-beta (TGF-ß) • Vasculostatin • Vasostatin (calreticulin fragment)

  6. Diseased or injured tissues produce and release angiogenic growth factors (proteins) that diffuse into the nearby tissues The angiogenic growth factors bind to specific receptors located on the endothelial cells (EC) of nearby preexisting blood vessels Once growth factors bind to their receptors, the endothelial cells become activated. Signals are sent from the cell's surface to the nucleus. The endothelial cell's machinery begins to produce new molecules including enzymes Enzymes dissolve tiny holes in the sheath-like covering (basement membrane) surrounding all existing blood vessels The endothelial cells begin to divide (proliferate), and they migrate out through the dissolved holes of the existing vessel towards the diseased tissue Specialized molecules called adhesion molecules, or integrins (avb3, avb5) serve as grappling hooks to help pull the sprouting new blood vessel sprout forward Additional enzymes (matrix metalloproteinases, or MMP) are produced to dissolve the tissue in front of the sprouting vessel tip in order to accommodate it. As the vessel extends, the tissue is remolded around the vessel Sprouting endothelial cells roll up to form a blood vessel tube Individual blood vessel tubes connect to form blood vessel loops that can circulate blood Finally, newly formed blood vessel tubes are stabilized by specialized muscle cells (smooth muscle cells, pericytes) that provide structural support. Blood flow then begins. The Angiogenesis Process: How Do New Blood Vessels Grow?

  7. Angiogenesis and Remodelling • Angiogenesis and microvascular remodelling are elements of the tissue remodelling in and tumors. • Both types of change in the microvasculature result from endothelial cell proliferation and often occur together, but they represent different phenomena and responses to different stimuli. • Angiogenesis is the growth of new blood vessels • Microvascular remodelling involves structural alterations—usually enlargement—of arterioles, capillaries or venules, without the formation of new vessels. chronic inflammatory disorders

  8. Background of angiogenesis and microvascular remodelling in airway disease • There are clues that changes in the airway microvascul-ature have long been recognized as a feature of asthma… • it was recognized many years ago that the airway mucosa in fatal asthma is edematous and contains dilated, congested blood vessels… Unger L. South Med J 1945;38:513–523. Walzer I, Frost TT. J Allergy 1952;23:204–214. Dunnill MS. J Clin Pathol 1960;13:27–33.

  9. Background of angiogenesis and microvascular remodelling in airway disease • Early studies also showed that the airway wall of subjects with asthma is abnormally thick… • The increased wall thickness would necessitate an expansion of the microvasculature to accommodate the extra tissue mass, and the abundant, enlarged, and congested mucosal blood vessels contribute to the wall thickness… Macdonald IG. Ann Intern Med 1932;6:253–277. James AL, et al. Am Rev Respir Dis 1989;139:242–246. Carroll N, et al. Am Rev Respir Dis 1993;147: 405–410.

  10. WHAT IS ASTHMA ???

  11. Definition of Asthma* • A chronic inflammatory disorder of the airways • Many cells and cellular elements play a role • Chronic inflammation is associated with airway hyperresponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing • Widespread, variable, and often reversible airflow limitation *Captureddirectly fromGINA 2006 slide set…

  12. Captured directly from GINA 2006 slide set…

  13. Superimposed acute inflammation Chronic inflammation Airway remodeling Structural changes Time Inflammation in asthma

  14. Remodeling A critical aspect of wound repair in all organs representing a dynamic process that associates • matrix production and degradation in reaction to an inflammatory insult, • leading to a normal reconstruction process or a pathologic process.

  15. Remodelling in Airway • Several years ago, Bousquet et al. proposed as definition of remodelling 'model again or differently, reconstruct‘… Bousquet J, Chanez P, Lacoste JY, White R, Vic P, Godard P . Asthma: a disease remodelling the airways? Allergy 1992;47:3–11.

  16. Processes in Airway Remodelling Angiogenesis

  17. The histologic hallmarks of remodeling are as follows • infiltration by macrophages and lymphocytes; • proliferation of fibroblasts that may take the form of myofibroblasts; • angiogenesis; • increased connective tissue (fibrosis); • tissue destruction.

  18. Prototype Angiogenics • VEGF • Anjiyopoetin-1 (Ang-1) • CXC Kemokinler…

  19. VEGF • VEGF is an interesting inducer of angio- genesis and lymphangiogenesis, because it is a highly specific mitogen for endothel- ial cells. • Signal transduction involves binding to tyrosine kinase receptors and results in endothelial cell proliferation, migration, and new vessel formation. • The VEGF family currently comprises seven members: • VEGF-A, • VEGF-B, • VEGF-C, • VEGF-D, • VEGF-E, • VEGF-F, • PlGF. • All members have a common VEGF homology domain. found in lung

  20. VEGF Receptors • Three VEGF tyrosine kinase receptors have been identified: • The fms-like tyrosine kinase Flt-1 (VEGFR-1/Flt-1), • The kinase domain region, also referred to as fetal liver kinase (VEGFR-2/KDR/Flk-1), • Flt-4 (VEGFR-3). • Each receptor has • seven immunoglobulin like domains in the extracellular domain, • a single transmembrane region, • a consensus tyrosine kinase sequence interrupted by a kinase insert domain Most important receptor in lung

  21. VEGF and Receptors in Airway

  22. Signal Transduction

  23. Regulation of VEGF Gene Expression • Hipoxia • Cytokines and growth factors • TNF-, • TGF-, • EGF, PDGF-BB, • IGF-1, • COX-2 • PGE2 • Hormons • Estrogen • Testosterone

  24. VEGF and Angiopoietins in Angiogenesis • The endothelial cell-specific growth factors, VEGF and angiopoietin 1 (Ang1), have potent and clinically relevant actions on the microvasculature. Yancopoulos GD. Nature 2000;407:242–248. • Both of these growth factors play essential but separate roles in vascular development in the embryo. Ferrara N, et al. Nature 1996;380:439–442.

  25. VEGF and Angiopoietins in Angiogenesis • VEGF is key to the formation of the initial vascular plexus in early development. • VEGF expression increases in the airways of subjects with asthma and correlates with mucosal vascularity… Hoshino M, et al. J Allergy Clin Immunol 2001;107:295–301. Hoshino M, et al. J Allergy Clin Immunol 2001;107:1034-1038. • Ang1 appears to be essential for maturation of the vasculature from primitive tubes into a hierarchical network of vessels composed of endothelial cells and pericytes or smooth muscle cells. Suri C, et al. Cell 1996;87:1171–1180.

  26. VEGF and Angiopoietins in Angiogenesis

  27. VEGF and Angiopoietins in Angiogenesis • Ang2 antagonizes the effects of Ang1 on Tie2 receptors and in some contexts acts as a natural inhibitor of Ang1. • Whereas Ang1 is widely expressed in normal adult tissues, Ang2 is expressed mainly at sites of vascular remodeling such as the ovary, placenta, uterus, and tumors. • Ang2 expression in the presence of VEGF is accompanied by angiogenesis, but Ang2 expression in the absence of VEGF is associated with vascular regression. Maisonpierre PC, et al. Science 1997;277:55–60. Holash J,et al. Science 1999;284:1994–1998. Zagzag D, et al. Lab Invest 2000;80:837–849.

  28. CXC Chemokines and Angiogenesis • Chemo-attractive cyto-kines • On a structural level, they have four highly conserved cysteine amino acid residues. • The NH2 terminus of the majority of the CXC chemokines contain a three-amino-acid motif (Glu-Leu-Arg: the ELR motif). • The family members that contain the ELR motif (ELR+) are potent promoters of angiogenesis, • ELR- members are potent inhibitors of angiogenesis…

  29. Angiogenic and Angiostatic CXC Chemokines Angiogenic CXC chemokines containing the ELR motif (ELR+) Interleukin-8 (IL-8) Epithelial neutrophil activating protein-78 (ENA-78) Growth-related gene alpha (GRO-) Growth-related gene beta (GRO-) Growth-related gene gamma (GRO-) Granulocyte chemotactic protein-2 (GCP-2) Platelet basic protein (PBP) Connective tissue activating protein-III (CTAP-III) Beta-thromboglobulin ( -TG) Neutrophil activating protein-2 (NAP-2) Angiostatic CXC chemokines that lack the ELR motif (ELR-) Platelet factor-4 (PF4) Interferon-  -inducible protein (IP-10) Monokine induced by interferon-  (MIG)

  30. CXCR1 CXCR2 CXC Chemokine Receptors Interleukin-8 (IL-8) Granulocyte chemotactic protein-2 (GCP-2) Epithelial neutrophil activating protein-78 (ENA-78) Growth-related gene alpha (GRO-) Growth-related gene beta (GRO-) Growth-related gene gamma (GRO-) Platelet basic protein (PBP) Connective tissue activating protein-III (CTAP-III) Beta-thromboglobulin ( -TG) Neutrophil activating protein-2 (NAP-2) Endothelial Cell Angiogenic activation

  31. Angiogenesis and Treatment (Inhaled Steroide) • Chetta A, et al. Vascular endothelial growth factor up-regulation and bronchial wall remodelling in asthma. Clin Exp Allergy 2005;35:1437-42. • They showed that • The counts of VEGF(+) cells, mast cells and EG2(+) cells were higher in asthmatics than in controls. • The number of vessels, the vascular area in the lamina propria, and the basement membrane thickness were significantly higher in asthmatics than in healthy volunteers. • In asthmatic patients, the number of VEGF(+) cells was significantly related to the number of vessels, to mast cells and to basement membrane thickness. • High doses of inhaled fluticasone propionate significantly reduced VEGF(+) cells, vessel number, vascular area and basement membrane thickness in a subgroup of asthmatic patients

  32. Angiogenesis and Treatment(Inhaled 2-agonist) • Bernadette E, et al. Effect of a long-acting 2-agonist over three months on airway wall vascular remodeling in asthma. Am J Respir Crit Care Med 2001;164:117-121. • They showed that • airways of subjects with asthma had a significant increase in the number of vessels/mm2 of lamina propria compared with airways of normal subjects • a decrease in the density of vessels of lamina propria after treatment only in the salmeterol group compared with baseline…

  33. Angiogenesis and Treatment (Leukotriene antagonists) • Lee KS, et al. Cysteinyl leukotriene receptor antagonist regulates vascular permeability by reducing vascular endothelial growth factor expression.J Allergy Clin Immunol 2004, 114:1093-1099. • They showed that • asthmatic lungs have increased numbers of inflammatory cells of the airways, airway hyperresponsiveness, increased vascular permeability, and increased levels of VEGF. • Administration of cysLT receptor antagonists markedly reduced plasma extravasation and VEGF levels in allergen-induced asthmatic lungs.

  34. Angiogenesis and Treatment (VEGFR antagonists) • Lee YC, et al. Contribution of vascular endothelial growth factor to airway hyperresponsiveness and inflammation in a murine model of toluene diisocyanate-induced asthma. J Immunol 2002;168:3595-600. • They used • Inhibitors of VEGFR tyrosine kinase, SU5614 and SU1498 for treatment of toluene diisocyanate (TDI) sensitized and challenged mice…

  35. Angiogenesis and Treatment (VEGFR antagonists) H&E-stained sections of the lungs VEGF-positive cells in the bronchioles VEGF-positive cells in the BAL fluids Placebo TDI TDI + VEGFR inhibitors Lee YC, et al. J Immunol 2002;168:3595-600.

  36. What about us???

  37. Increased expression of angiogenic markersin patients with seasonal allergic rhinitis • We aimed to investigate the presence of increased angiogenesis and its relation to angiogenic molecules, • VEGF, • CD34, • FvW, in endothelial cells of nasal mucosa in patients with seasonal allergic rhinitis (SAR) • Twenty patients with symptomatic SAR, who were not under treatment, were enrolled in the study. • Ten patients with nasal septal deviation NSD, who needed surgical therapy, served as the non-allergic control group. • Three different immunohistochemical analysis methods, • HSCORE, • microvessel density (MVD), • vascular surface density (VSD) were used.

  38. Results of Our Study • Especially; • HSCORE showed statistically significant differences among the two groups; • p=0.002 for VEGF; • p=0.045 for CD34; • p=0.016 for FvW...

  39. Conclusion • Although we have not evaluated other markers of remodelling; • Our observation suggests that • The presence of angiogenesis and related remodelling cannot be denied in patients with SAR despite a certain amount of controversy. • Proving the presence of increased angiogenesis, an important part of remodelling and other chronic inflammatory changes in the nasal mucosa, may improve treatment choices, and follow-up in subjects with SAR.

  40. Our Another Research • Icreased expression of tissue VEGF and Flk-1 receptor in seasonal allergic rhinitis and relevance to asthma component (Yuksel H, Kose C, Yilmaz O, Ozbilgin K, Kirmaz C)… • Final revised form underreview in Clinical and Experimental Allergy

  41. Aim of this study • Compare VEGF and its receptor Flk-1 expression • between SAR patients and non-allergic controls and • between SAR patients with and without asthma.

  42. Results • Mean HSCORE and VSD for VEGF was significantly higher in the patient group, • Mean HSCORE and VSD for Flk-1 in the patient group was significantly higher than those in the control group, • The difference between mean VEGF HSCORE and VSD scores in patients with pure AR and AR with asthma was insignificant , • Mean HSCORE and VSD scores for Flk-1 in patients with pure AR were significantly lower than those in AR patients with asthma… Flk-1

  43. Conclusion • Angiogenic factor VEGF and its receptor Flk-1 is increased in AR patients when compared to the non-allergic controls, • VEGF is increased similarly in AR patients with and without asthma. • However, Flk-1 that is the main receptor of VEGF is significantly lower in pure AR patients than that in patients with AR and asthma. • This may be a possible explanation to the excessive presence of angiogenesis in airway wall in patients with asthma but not in the ones with AR not associated with asthma.

  44. Imagination is better than knowledge… Einstein

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