MUDr. Dana Maňasková


Vyhledávání na medicinman.cz
 

Lymfatické cévy

Early lymphatic endothelial cell markers

  • Prospero homeobox protein 1 (PROX1)
  • Lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1) [37]

Endothelial cells of collecting lymphatics

  • Joined by continuous zippers
  • Similar to those in adjacent blood vessels
  • Endothelial cells of lymphatics were appreciably larger than those in blood vessels
  • Occludin and claudin-5 were continuously distributed at zippers in collecting lymphatics
    • Partially colocalized with VE-cadherin [47]
  • Buttons and zippers have the same repertoire of junctional proteins, including
    • Occludin,
    • Claudin-5,
    • ZO-1,
    • ESAM,
    • JAM-A [47]
  • Principal difference between these junctions is their organization rather than their composition [47]

Endothelial cells of initial lymphatics

  • Were joined by discontinuous buttons [47]
  • Buttons consisted of roughly parallel linear segments of VE-cadherin
  • Length of button-rich regions varied from vessel to vessel
  • Scattered endothelial cells of some lymphatics had zippers
  • Transition from buttons to zippers was typically abrupt in individual vessels [47]
  • VE-cadherin at buttons colocalized with the tight junction protein occludin
  • Largely matched the distributions of the classical tight junction protein claudin-5
    • Intracellular tight junction protein zonula occludens – 1
  • Associated Ig-like transmembrane proteins endothelial cell – selective adhesion molecule (ESAM )
  • Two types of junctions contained the same proteins [47]
  • PECAM-1 and VE-cadherin partially colocalized at buttons at the borders of oak leaf – shaped endothelial cells
    • Of initial lymphatics [47]
    • At zippers of collecting lymphatics [47]
  • VE-cadherin and tight junction –associated proteins were present in buttons [47]

Model of sustained inflammation

  • Robust lymphangiogenesis
  • Growing tips of lymphatic sprouts had zippers, not buttons
  • Zippers at the tip of lymphatic
    • Continuous junctions can form rapidly
  • Buttons are not a feature of the most dynamic, immature region of lymphatic sprouts
  • Over time all but the tips of new lymphatics had buttons [47]
  • DCs predominately gain access to the lymphatic lumen where the basement membraneis sparse.
    • These areas are referred to as portals [51]

Lymphatic endothelial cells (LECs)

  • Migrate away from the cardinal vein v době emryogeneze
  • Assemble into vessels to form a de novo collecting vascular system
  • This blood-lymphatic vessel separation is regulated by a SYK-SLP-76 signalling pathway in blood cells
    • Platelets as the cell type in which SLP-76 signalling is essential to regulate lymphatic vessel development

-transcription factor Prox1

    • As the master of LEC specification [35]
  • Majority of LECs are produced by transdiferentiation from venous endothelium
  • Subpopulation of venous ECs expressing Prox1 is specialized into LECs (Escobedo and Oliver, 2016; Venero Galanternik et al., 2016) [35]


Lymphatic endothelial cells (LECs)

  • Migrate away from the cardinal vein v době emryogeneze
  • Assemble into vessels to form a de novo collecting vascular system
  • This blood-lymphatic vessel separation is regulated by a SYK-SLP-76 signalling pathway in blood cells
    • Platelets as the cell type in which SLP-76 signalling is essential to regulate lymphatic vessel development
  • Transcription factor Prox1
    • As the master of LEC specification [35]
  • Majority of LECs are produced by transdiferentiation from venous endothelium
  • Subpopulation of venous ECs expressing Prox1 is specialized into LECs (Escobedo and Oliver, 2016; Venero Galanternik et al., 2016) [35]


Lymphangiogenesis

  • New lymphatic vessels grow out of pre-existing vessels
    • Enables lymphatic endothelial cells (LECs) to proliferate and migrate through lymphatic vessels surrounding the tumors
  • Lymphangiogenic factors
    • Vascular endothelial growth factor (VEGF)-C or D
      • Predominantly bind to VEGF receptor-3 (VEGFR-3)
        • Promote several downstream signaling pathways for regulating lymphangiogenesis
  • LEC survival, proliferation, migration and tube formation
    • Depends upon the activation of the VEGF-C/VEGFR-3 axis
www.researchgate.net/publication/320024243_Lymphangiogenesis_guidance_by_paracrine_and_pericellular_factors
  • Tumor-induced lymphangiogenesis correlated with
    • A high amount of lymph node metastasis
    • VEGF-C expression
    • Worse disease-free/overall survival in BC patients
www.researchgate.net/publication/320024243_Lymphangiogenesis_guidance_by_paracrine_and_pericellular_factors
  • Lymphangiogenesis
    • Lymphatic vessels grow out of pre-existing vessels
    • Enables lymphatic endothelial cells (LECs) to proliferate and migrate through lymphatic vessels surrounding the tumors [38]

Lymphangiogenesis

  • New lymphatic vessels grow out of pre-existing vessels
    • Enables lymphatic endothelial cells (LECs) to proliferate and migrate through lymphatic vessels surrounding the tumors
  • Lymphangiogenic factors
    • Vascular endothelial growth factor (VEGF)-C or D
      • Predominantly bind to VEGF receptor-3 (VEGFR-3)
        • Promote several downstream signaling pathways for regulating lymphangiogenesis
  • LEC survival, proliferation, migration and tube formation
    • Depends upon the activation of the VEGF-C/VEGFR-3 axis
www.researchgate.net/publication/320024243_Lymphangiogenesis_guidance_by_paracrine_and_pericellular_factors

  • Tumor-induced lymphangiogenesis correlated with:
    • A high amount of lymph node metastasis
    • VEGF-C expression
    • Worse disease-free/overall survival in BC patients
www.researchgate.net/publication/320024243_Lymphangiogenesis_guidance_by_paracrine_and_pericellular_factors

Collagen 1

  • Abundance of collagen I in the trunk is the key regulator:
    • It determines the dominant transport phenomenon and the extent of VEGFC-collagen I binding
    • Thus affecting the distribution of VEGFC
  • The abundance of collagen I is in turn regulated by the matrix metalloproteinase 2 (MMP2)
www.researchgate.net/publication/333650501_Mathematical_modelling_of_Lymphangiogenesis

Collagen 1

  • Abundance of collagen I in the trunk is the key regulator:
    • It determines the dominant transport phenomenon and the extent of VEGFC-collagen I binding
    • Thus affecting the distribution of VEGFC
  • The abundance of collagen I
    • Is in turn regulated by the matrix metalloproteinase 2 (MMP2)
www.researchgate.net/publication/333650501_Mathematical_modelling_of_Lymphangiogenesis

Earliest committed lymphoid progenitor (CLP) cell

  • May require osteoblasts for survival, proliferation, or differentiation

Stem cell niche

  • Close relationship between CLP and the stem cell niche expression of the:
    • Notch-1 ligand
    • Jagged-1 in the osteoblastic niche [12]


Earliest committed lymphoid progenitor (CLP) cell

  • May require osteoblasts
    • For survival, proliferation, or differentiation

Stem cell niche

  • Close relationship between CLP and the stem cell niche expression of the:
    • Notch-1 ligand
    • Jagged-1 in the osteoblastic niche [12]


Ductus thoracicus cysticus

  • Lze retrográdně zadrénovat a zobrazit
  • Neprovádí se v ČR

Lymphatic endothelial cells (LEC)


Expressed the hepatocyte growth factor (HGF) receptor MET

  • Treatment of LEC with recombinant HGF promoted
    • Proliferation
    • Migration
    • Tube formation of LEC [1]
  • Subcutaneous or transgenic delivery of HGF
    • Promoted lymphatic vessel formation in the mouse !!
      • HGF/MET as viable candidate genes for hereditary lymphedema [1]
  • Expression of HGF by plasmid transfer
    • Promotes lymphangiogenesis
    • Ameliorates secondary lymphedema in the rat tail injury model [1]
  • Mouse corneal lymphangiogenesis model
    • HGF could be lymphangiogenic [1]
  • HGF/MET signaling affects
    • Morphogenic differentiation
    • Cell motility
    • Growth
    • Intercellular junctions
    • Survival [1]

HGF

  • Independently identified for its potent effects
    • On cell motility in epithelial cells (scatter factor )
    • Cell proliferation in hepatocytes (hepatocyte growth factor/hepatopoietin A22–24) [1]
  • Large multidomain polypeptide
  • Similarities to plasminogen
  • Synthesized as a single long polypeptide
  • Requires proteolytic conversion to its active form as a heterodimer
  • Biologic activity is dependent on its binding to the MET receptor [1]

MET receptor

  • Predominantly in cells of mesenchymal and epithelial origin [1]
  • Prototypical receptor tyrosine kinase
  • First recognized as a protein product of an oncogene, TPR-MET
  • MET signals are channeled by an unconventional multi-docking site
    • That consists of two tyrosines that
    • When phosphorylated, recruit a wide spectrum of transducers and adaptors
      • PI3K, Src, Grb2, Shp2 Gab1, and STAT3
        • Whether mutations in any of these downstream genes acting in the HGF/MET signaling pathway are responsible for lymphatic phenotypes has not been studied.
  • Extracellular Sema domain
    • Necessary for MET receptor dimerization and activation in vitro using several human cell lines [1]

MET receptorové mutace a klinika

  • Rs3458946
    • Lymphedema and protein losing enteropathy secondary to intestinal lymphangiectasia [1]


Embryonic veins

  • Lymphatic EC (LEC) progenitors are initially specified.
  • The differentiation and maturation of these progenitors continues as
    • Bud from the veins
    • Produce scattered primitive lymph sacs
      • From which most of the lymphatic vasculature is derived
  • Some extra LEC progenitors are provided directly by the veins(Chen et al., 2014)
  • Only a subpopulation of the LEC progenitors in the veins exit and sprout out
  • Progenitors that do sprout out
    • Take on distinct spindle morphologies
    • Up-regulate their rate of proliferation
    • Express LEC markers such as
      • Podoplanin (PDPN)
      • NRP2 (Yang and Oliver, 2014a;Koltowska et al., 2013;Chen et al., 2014)
      • Tyrosine kinase activity of VEGFR3 is necessary for LEC progenitor sprouting (Yang and Oliver, 2014a)
  • Progenitors that remain in the veins
    • Develop into the lymphovenous valves - junction of the
      • Jugular veins
      • Subclavian veins(Yang and Oliver, 2014b)
  • www.researchgate.net/publication/260485353_Development_of_the_mammalian_lymphatic_vasculature

Lymphangiogenesis

  • Growth of lymphatics from pre-existing vessels [41]

Lymphvasculogenesis

  • Differentiation and assembly from non-venous precursor cells
  • Used in different organs and by different organisms to various degrees
    • In mice, the lymphvascularization of the heart (Klotz et al., 2015)
    • The mesentery (Stanczuk et al., 2015)
    • Skin (Martinez-Corral et al., 2015) involves lymphvasculogenesis
  • Molecular process is under investigation, and similar to lymphangiogenesis
  • VEGF-C appears to be required [41]

Embryonic veins

  • Lymphatic EC (LEC) progenitors are initially specified.
  • The differentiation and maturation of these progenitors continues as
    • Bud from the veins
    • Produce scattered primitive lymph sacs
      • From which most of the lymphatic vasculature is derived
  • Some extra LEC progenitors are provided directly by the veins(Chen et al., 2014)
  • Only a subpopulation of the LEC progenitors in the veins exit and sprout out
  • Progenitors that do sprout out
    • Take on distinct spindle morphologies
    • Up-regulate their rate of proliferation
    • Express LEC markers such as
      • Podoplanin (PDPN)
      • NRP2 (Yang and Oliver, 2014a;Koltowska et al., 2013;Chen et al., 2014)
      • Tyrosine kinase activity of VEGFR3 is necessary for LEC progenitor sprouting (Yang and Oliver, 2014a)
  • Progenitors that remain in the veins
    • Develop into the lymphovenous valves - junction of the
      • Jugular veins
      • Subclavian veins(Yang and Oliver, 2014b)
  • www.researchgate.net/publication/260485353_Development_of_the_mammalian_lymphatic_vasculature

Hlavní endotelové receptory

  • VEGFR-3
  • Hyalouronový receptor - CD44 - homologní k LVIE-1 a
    • často expr. na nádorových buněkách
    • Klíčové pro adhezi

Exprese v lymfatických cévách

  • Highly expressed by lymphatic endothelial cells and macrophages
    • LYVE-1
    • TLR-4
  • Largest producer of IL-7
    • To maintain T cell homeostasis in lymph nodes
  • Macrophage-sustaining cytokines
    • CSF-1 in tumors depend substantially upon the presence of lymphatic vessels [51]

Funkce lymfatického systému

  • Drenáž
  • Transport porteinu, lipidu, vitaminu, hormonu žláz s vnitřní sekrecí, iontů
  • Imunostimulace
  • Metabolické funkce

Kapiláry

  • V celkové délce přibližně 96 000 km
  • Ploše 500 až 1 000 m2
  • široké přesně tak, aby se do nich vešel jeden erytrocyt
    • Jedna krevní buňka za druhou
  • Tlak se v kapilárách mění podle Starlingova zákona filtrace a resorpce
  • Na tepenném konci kapiláry je krevní tlak vždy vyšší
  • Směrem k venóznímu konci se postupně snižuje přechodem živin a krevních plynů do tkání
  • V krvi obsažené plazmatické bílkoviny se za normálních okolností přes póry nedostanou
    • Udržení stabilního onkotického tlaku
      • Díky němuž jsou na venózním konci kapiláry nasávány odpadní látky metabolismu zpět do žilního systému
  • Krev je filtrována z 90 procent krevními
    • Z 10% procent lymfatickými kapilárami
  • Jakákoli dysbalance v této soustavě vyvolá patologický stav a vznik otoku.

Kapiláry

  • V celkové délce přibližně 96 000 km
  • Ploše 500 až 1 000 m2
  • široké přesně tak, aby se do nich vešel jeden erytrocyt
    • Jedna krevní buňka za druhou
  • Tlak se v kapilárách mění podle Starlingova zákona filtrace a resorpce
  • Na tepenném konci kapiláry je krevní tlak vždy vyšší
  • Směrem k venóznímu konci se postupně snižuje přechodem živin a krevních plynů do tkání
  • V krvi obsažené plazmatické bílkoviny se za normálních okolností přes póry nedostanou
    • Udržení stabilního onkotického tlaku
      • Díky němuž jsou na venózním konci kapiláry nasávány odpadní látky metabolismu zpět do žilního systému
  • Krev je filtrována z 90 % krevními kapilárami zpět
    • Z 10% procent lymfatickými kapilárami
  • Jakákoli dysbalance v této soustavě vyvolá patologický stav a vznik otoku.

Lymfatické cévy

  • štÄ›rbiny na molekulárnĂ­ Ăşrovni v endotelu kapilár a lymfatik

Prelymfatika - 10 aĹľ 100 mikrometrĹŻ


Lymfatické cévy

  • Otvroy jako chlopnÄ› na vláknech - otevĂ­ránĂ­ pĹ™i otoku tkánÄ›
    • Vázáno na proteoglykany aj.

Lymfagnion

  • LymfatickĂ˝ syst. má "tisĂ­ce srdcĂ­" - lymfangiony
    • Ăşsek mezi lymfatickĂ˝mi chlopnÄ›mi
    • Lymfangiom má svalovinu

Vasa afferentia

  • Z uzliny

Vasa efferentia

  • Do uzliny
    • MajĂ­ párovĂ© chlopnÄ›

PravostrannĂ˝ lymfatickĂ˝ ductus

  • částeÄŤnÄ› zaniklĂ˝ (levostrannĂ˝ plnÄ› vyvinutĂ˝)
  • Do pravĂ©ho ductus angulus...
  • Velká variabilita
  • Lymfatika z jater teÄŤou do cisterna chyli



Veno-lymfatické chlopně

Initiation of valve development

  • Appearance of clusters of cells
    • Often near vessel branchpoints with high levels of the transcription factors
      • PROX1, FOXC2, and GATA2
  • Valve-forming cells reorient themselves
    • With respect to the longitudinal axis of the vessel
    • Extend into the vessel lumen
    • Form elongated valve leaflets composed of a bilayer of endothelial cells sandwiching an extracellular matrix core composed largely of
      • Fibronectin-EIIIA (FN-EIIIA)
      • Laminin-alpha5
      • EMILIN1 [34]
  • Genes identified to be important for lymphatic vessel valve development
    • FOXC2
    • NFATC1
    • The transmembrane ligand ephrinB2
    • Integrin-alpha 9
      • Its ligands FN-EIIIA
      • Emilin1
      • Gap junction proteins connexin37 (CX37)
      • Connexin43 (CX43)
      • NOTCH1
      • SEMA3A
      • Receptor components
        • NRP1
        • PLEXINA1
      • Angiopoietin2
      • TIE1
      • BMP9
  • location of valves predominantly in regions of disturbed flow
    • Mechanical stimuli including shear stress might be important valve-initiating stimuli [34]

Human lymphatic endothelial cells (hLECs)

Oscillatory shear stress (OSS)

  • In vitro exhibit elevated
    • Levels of FOXC2
    • Connexin37 (CX37)
    • Activation of NFATC1
    • Change in their morphology from an elongated to cuboidal shape [34]
  • Observed in lymphatic endothelial cells within valve territories in vivo
  • Venous valves share expression of lymphatic valve markers including
    • PROX1
    • EphrinB2
    • Integrin-alpha9
  • Together with a dependence on
    • EphrinB2
    • Integrin-alpha9 [34]
  • Common genetic pathways direct valve development in both lymphatic vessels and veins [34]

Lymphovenous valves (LVVs)

  • At the junction of the jugular and subclavian veins
    • Thoracic
    • Right lymphatic ducts
  • Together with platelets to partition the lymphatic vasculature from the blood vasculature
  • Endothelial cells of the LVVs express
    • PROX1
    • FOXC2
    • Integrin-alpha 9
    • Integrin-alpha5
  • Valve development in distinct vascular compartments relies on common pathways
  • One leaflet derived from venous endothelial cells
  • One derived from lymphatic endothelial cells
  • Valves are exquisitely sensitive to changes in Prox1 dosage for their development
    • Lymphatic vessel valves form in Prox1 heterozygous mice
    • But LVVs do not !
  • Lymphovenous valve + platelet thrombus at this junction
    • Crucial to preventing blood at a higher pressure in veins than the pressure in the thoracic duct
    • Patency of the lymphovenous valve is dependent upon platelet-expressed CLEC-2
      • Ligand for podoplanin that is rich in lymphatic endothelium [51]

Veno-lymfatické chlopně

Initiation of valve development

  • Appearance of clusters of cells
    • Often near vessel branchpoints with high levels of the transcription factors
      • PROX1, FOXC2, and GATA2
  • Valve-forming cells reorient themselves
    • With respect to the longitudinal axis of the vessel
    • Extend into the vessel lumen
    • Form elongated valve leaflets composed of a bilayer of endothelial cells sandwiching an extracellular matrix core composed largely of
      • Fibronectin-EIIIA (FN-EIIIA)
      • Laminin-alpha5
      • EMILIN1 [34]
  • Genes identified to be important for lymphatic vessel valve development
    • FOXC2
    • NFATC1
    • The transmembrane ligand ephrinB2
    • Integrin-alpha 9
      • Its ligands FN-EIIIA
      • Emilin1
      • Gap junction proteins connexin37 (CX37)
      • Connexin43 (CX43)
      • NOTCH1
      • SEMA3A
      • Receptor components
        • NRP1
        • PLEXINA1
      • Angiopoietin2
      • TIE1
      • BMP9
  • location of valves predominantly in regions of disturbed flow
    • Mechanical stimuli including shear stress might be important valve-initiating stimuli [34]

Human lymphatic endothelial cells (hLECs)

Oscillatory shear stress (OSS)

  • In vitro exhibit elevated
    • Levels of FOXC2
    • Connexin37 (CX37)
    • Activation of NFATC1
    • Change in their morphology from an elongated to cuboidal shape [34]
  • Observed in lymphatic endothelial cells within valve territories in vivo
  • Venous valves share expression of lymphatic valve markers including
    • PROX1
    • EphrinB2
    • Integrin-alpha9
  • Together with a dependence on
    • EphrinB2
    • Integrin-alpha9 [34]
  • Common genetic pathways direct valve development in both lymphatic vessels and veins [34]

Lymphovenous valves (LVVs)

  • At the junction of the jugular and subclavian veins
    • Thoracic
    • Right lymphatic ducts
  • Together with platelets to partition the lymphatic vasculature from the blood vasculature
  • Endothelial cells of the LVVs express
    • PROX1
    • FOXC2
    • Integrin-alpha 9
    • Integrin-alpha5
  • Valve development in distinct vascular compartments relies on common pathways
  • One leaflet derived from venous endothelial cells
  • One derived from lymphatic endothelial cells
  • Valves are exquisitely sensitive to changes in Prox1 dosage for their development
    • Lymphatic vessel valves form in Prox1 heterozygous mice
    • But LVVs do not !

Lymfatické uzliny

  • Lymph node typically substantially concentrates lymph
    • So that the protein concentration of efferent lymph is similar to that of plasma
    • Afferent lymph typically has a protein concentration less than half that of plasma
    • Absorption of water into the high endothelial venules within the lymph node [51]

Lymphangiogenic regulators

  • Obligate molecular components that define LEC fate and LV expansion in all organs:
    • Prox1
    • VEGF-C/VEG FR3/ADAM metallopeptidase
    • Thrombospondin type 1
    • Motif 3/collagen
    • calcium-binding EGF domains 1 [35]


Lymphangiogenic regulators

  • Obligate molecular components that define LEC fate and LV expansion in all organs:
    • Prox1
    • VEGF-C/VEG FR3/ADAM metallopeptidase
    • Thrombospondin type 1
    • Motif 3/collagen
    • calcium-binding EGF domains 1 [35]


Růstové faktory

  • VEGF-C, D (nadprodukce u nádorů)
    • I pro cévy
  • VEGFR3
  • V3GFR2
  • I cévy, krevní tlak a nervy
  • Růstový faktor do místa transplantace
    • Riziko vzniku nádorů
  • Funkce může být i jen v určité fázi vývoje
  • Bylo zkoušeno s kmenovými buňkami, ale význa pro regeneraci nebyl tak významný

Separace lymfytických cév o krevních

Krevní destičky

  • Platelets as the critical cell type mediating blood-lymphatic vascular separation
  • Podoplanin, a transmembrane protein expressed on lymphatic endothelial cells
    • Engages the platelet C-type lectin-like receptor 2 (CLEC-2) when exposed to blood
    • Leading to SYK-SLP-76-dependent platelet activation
  • When components of this pathway are disrupted, aberrant vascular connections form, resulting in blood-lymphatic mixing.
  • Platelet-null embryos manifest identical blood-lymphatic mixing
  • Platelets mediate blood and lymphatic separation by activation of the CLEC-2 receptor
    • Following interaction with the podoplanin ligand found on the surface of LECs
  • Platelet CLEC-2 and podoplanin on lymphatic endothelial cells as the receptor–ligand pair required to trigger platelet activation in this setting
    • During
      • Embryonic development
      • Tumor metastasis (Bertozzi et al., 2010)
  • www.researchgate.net/publication/47755648_Platelets_Covert_Regulators_of_Lymphatic_Development

Podoplanin

  • Membrane glycoprotein
  • Activates platelet receptor, C-type lectinlike receptor (CLEC)-2 of platelet
    • Essential role in blood – lymphatic separation during lymphatic development (Fu et al. 2008; Kato et al. 2008; Bertozzi et al. 2010a,b; Suzuki-Inoue et al. 2007, 2010; Uhrin et al. 2010; Suzuki- Inoue 2011)

Podoplanin-deficient mice

  • Fail to develop a functional lymphatic system with a severe lymphedema in the extremities (Schacht et al. 2003)
  • Podoplanin or CLEC-2 knockout mice
    • Blood – lymphatic mixing phenotype of mice
      • Lacking SYK, SLP-76, or PLCg-2 (Bertozzi et al. 2010a,b; Suzuki-Inoue et al. 2010; Uhrin et al. 2010)
    • Mice deficient for CLEC2 display a similar phenotype as mice deficient for podoplanin
      • Bleeding and defects in vascular connections
      • Bloodlymphatic shunts at mid-gestation and are embryonic lethal
      • Combination of lymphatic-venous connections and retrograde flow through the thoracic duct
  • www.researchgate.net/publication/47755648_Platelets_Covert_Regulators_of_Lymphatic_Development
  • Mutant mice with defects in podoplanin-induced platelet activation
    • Fail to separate their lymphatic vessels from the blood circulation
    • Develop blood-filled lymphatics ( Bertozzi et al., 2010)
  • www.researchgate.net/publication/47755648_Platelets_Covert_Regulators_of_Lymphatic_Development

Podpplanin expression

Endothelial cell O-glycan deficiency

Podoplanin neutralization

Separace lymfytických cév od krevních

Krevní destičky

  • Platelets
    • Critical cell type mediating blood-lymphatic vascular separation
  • Podoplanin
    • A transmembrane protein expressed on lymphatic endothelial cells
    • Engages the platelet C-type lectin-like receptor 2 (CLEC-2) when exposed to blood
    • Leading to SYK-SLP-76-dependent platelet activation
  • When components of this pathway are disrupted
    • Aberrant vascular connections form
      • Blood-lymphatic mixing.
  • Platelet-null embryos
    • Manifest identical blood-lymphatic mixing
  • Platelets
    • Mediate blood and lymphatic separation
      • By activation of the CLEC-2 receptor
      • Following interaction with the podoplanin ligand found on the surface of LECs
  • Platelet CLEC-2 and podoplanin on lymphatic endothelial cells
    • As the receptor–ligand pair required to trigger platelet activation during
      • Embryonic development
      • Tumor metastasis (Bertozzi et al., 2010)
  • www.researchgate.net/publication/47755648_Platelets_Covert_Regulators_of_Lymphatic_Development

Podoplanin

  • Membrane glycoprotein
  • Activates platelet receptor, C-type lectinlike receptor (CLEC)-2 of platelet
    • Essential role in blood – lymphatic separation during lymphatic development (Fu et al. 2008; Kato et al. 2008; Bertozzi et al. 2010a,b; Suzuki-Inoue et al. 2007, 2010; Uhrin et al. 2010; Suzuki- Inoue 2011)

Podoplanin-deficient mice

  • Fail to develop a functional lymphatic system with a severe lymphedema in the extremities (Schacht et al. 2003)
  • Podoplanin or CLEC-2 knockout mice
    • Blood – lymphatic mixing phenotype of mice
      • Lacking SYK, SLP-76, or PLCg-2 (Bertozzi et al. 2010a,b; Suzuki-Inoue et al. 2010; Uhrin et al. 2010)
    • Mice deficient for CLEC2 display a similar phenotype as mice deficient for podoplanin
      • Bleeding and defects in vascular connections
      • Bloodlymphatic shunts at mid-gestation and are embryonic lethal
      • Combination of lymphatic-venous connections and retrograde flow through the thoracic duct
  • www.researchgate.net/publication/47755648_Platelets_Covert_Regulators_of_Lymphatic_Development
  • Mutant mice with defects in podoplanin-induced platelet activation
    • Fail to separate their lymphatic vessels from the blood circulation
    • Develop blood-filled lymphatics ( Bertozzi et al., 2010)
  • www.researchgate.net/publication/47755648_Platelets_Covert_Regulators_of_Lymphatic_Development

Podpplanin expression

Endothelial cell O-glycan deficiency

Podoplanin neutralization

Mesenteric lymphatic system to the general circulation

  • Obchází játra

Hypovolemic shock

  • Leads to systemic inflammatory response syndrome
  • Principally through the entry of digestive enzymes into the intestinal interstitial space and the subsequent progression of enzymes and inflammatory agents through the mesenteric lymphatic system to the general circulation.
  • Primary factor leading to inflammatory edema formation
    • Decrease in interstitial hydrostatic pressure that dramatically increases microvascular filtration

Transkripční faktory

  • Velmi důležité - genet. poruchy - závaž. důsledky gent. mutací

Transport

Objem

  • Lower limb lymphatics allow the transport of 20 to 250 mL of lymph in a 70-kg man, daily [54]

Leukocyty

  • Leukocyte count in the thoracic duct in healthy men
    • From 2 to 20 x 10 na 9
  • Almost totally of lymphocytes
    • Nearly 2 to 10 times the number of lymphocytes that can be found in the peripheral blood [54]

Erythrocytes

  • Negligible under physiological conditions
  • Might increase remarkably in certain disorders
    • Characterized by marked capillary damage and extravasation [54]
O úroveň výše

Poslední aktualizace: 6. 10. 2024 23:18:48