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Blood Physiology 2 September 2004

Blood Physiology 2 September 2004. Andres Soosaar http://biomedicum.ut.ee/~andress. Migration of WBCs. Unlike RBCs leukocytes can penetrate blood vessel wall without injury of it. This process is sometimes called the leukodiapedesis .

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Blood Physiology 2 September 2004

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  1. Blood Physiology 2September 2004 Andres Soosaar http://biomedicum.ut.ee/~andress

  2. Migration of WBCs Unlike RBCs leukocytes can penetrate blood vessel wall without injury of it. This process is sometimes called the leukodiapedesis. Leukocyte migration is important in both hematopoiesis and reactions of immunological defence. Positive chemotaxis is a process where cell moves towards higher content of certain chemotactic substance (e.g. Some factors of the complement system). Leukocyte migration is driven by chemokines and adhesion molecules.

  3. Chemokines A big family of proteins which contain 67-127 amino acids. Chemically CXC and CC subfamilies are differentiated. There are several types of chemokine receptors. Functionally are there inflammatory chemokines, homeostatic chemokines and dual-function chemokines. The inflammatory chemokines control recruitment of WBCs into inflammation, tissue injury and tumors, e.g. CX3CL1 or fractalkine. The homeostatic chemokines control migration of cells through hematopoiesis, e.g. CXCL12 (SDF-1).

  4. Chemokines -- biological actions Chemokines act over G-protein coupled surface receptors after what several important intracellular become activated, among them are phospholipase C (PLCbeeta), phosphoinositid 3-kinases (Ptdlns3-Ks), and tyrosin kinases of C-Src family. The Ptdlns3-Ks are crucially important to switch on cellular contractile machinery. In hematopoiesis different hematopoietic cells have different sensitivity to chemokines and as a final result only mature cells can reach circulation.

  5. Hematopoiesis

  6. In adult organism main place for hematopoiesis is red bone marrow, only some lymphocytes (T type) are coming from lymphatic Before birth erythropoiesis is going in yolk sac (I trimester), liver, spleen, lymphatic tissue (II trimester) and red bone marrow (III trimester).

  7. Main principles of hematopoiesis All mature cells are originated from the pluripotent hematopoietic stem cells (HSCs) Maturation of cells is going through several intermediate steps. Capacity to differentiate is increasing and capacity to divide and sel-production is decreasing during maturation. Mature blood cells are not able to divide. Usually only mature cells can reach blood Hematopoiesis must and is very carefully regulated to hold stable number of cells in the blood

  8. Hematopoiesis in the red bone marrow http://cwx.prenhall.com/bookbind/pubbooks/silverthorn2/

  9. Intensity of hematopoiesis RBCs: 3,5x1011 cells per day Neutrophils: 1011 cells per day Monocytes: 8,4x109 cells per day Platelets: 1011 cells per day

  10. http://www.oup.com/uk/booksites/content/0198585276/

  11. Mazur E, Cohen JL, Clin Pharmacol Ther, 1989, 46, 250-256

  12. HSCs – Hematopoietic Stem Cells HCSs have been discovered some 50 years ago. These cells are able to self-reproduce and differentiate in a unlimited way.There are findings that in certain circumstances HCSs can produce other cell types, eg hepatocytes, renal cells, myocytes etc. An adult person has ~50 million HPCs A HCS is able to produce altogether ~1013 mature blood cells

  13. Main features of HPSs They are pluripotent, i.e. they may change through several steps of development to different cell types. They have high level of proliferation and self reproduction. They are able to leave bone marrow and exist and function in other tissues.

  14. Regulation of hematopoiesis There is big number regulatory substances, hematopoietic factors, which may influence almost all phases of hemaotpoiesis. Hematopoietic factors are members cytokine family. Hematopoietic factors are released from hematopoietic, stromal and other cells and can interact through specific receptors with different types of cells and change their functional activity. Better understanding of hematopoiesis would improve treatment of hematological diseases

  15. http://www.copewithcytokines.de/cope.cgi?004470

  16. Chemical intercellular signalling http://cwx.prenhall.com/bookbind/pubbooks/silverthorn2

  17. HEMATOPOIETIC FACTORS n, neutrophils; m, monocytes; e, eosinophils; b, basophils; meg, megakaryocytes; rbc, red blood cells IL – interleukin , CSF – colony stimulating factor

  18. Mazur Em, Cohen JL, Clin Pharmacol Ther, 1989, 46, 250-256

  19. Mazur Em, Cohen JL, Clin Pharmacol Ther, 1989, 46, 250-256

  20. Mazur Em, Cohen JL, Clin Pharmacol Ther, 1989, 46, 250-256

  21. Some important trancription factors in hematopoiesis GATA-2, TAL-1/SCL, and HOXB4 are important in early phases of hematopoiesis and stem cells functioning GATA-1 is important in differentiation and development RBCs and other myeloid blood cells. Data about hematopoietic gene regulation are rapidly increasing.

  22. Basic regulatory mechanisms of hematopoiesis I • Programmed cell death (apoptosis) is a normal physiological form of cell death that plays a key role both in the maintenance of adult tissues and in embryonic development. In adults, programmed cell death is responsible for balancing cell proliferation and maintaining constant cell numbers in tissues undergoing cell turnover. For example, about 5 × 1011 blood cells are eliminated by programmed cell death daily in humans, balancing their continual production in the bone marrow. http://www.ncbi.nlm.nih.gov/books/bv.fcgi?tool=bookshelf&call=bv.View..ShowSection&searchterm=cell&rid=cooper.section.2281 • Apoptosis is a powerful regulatory process which is influenced by different pathways of cell signalling. See respective chapters on cell biology.

  23. Basic regulatory mechanisms of hematopoiesis II • Cross-antagonism of transcription factors There is cross-antagonism between GATA-1 and PU.1 in different cell lines which is important in development of RBCs and other myeloid cells • The negative feedback mechanisms The classical example is EPO role in RBC development

  24. Erythropoietin (EPO) • Glycoprotein with 165 amino acids, produced mainly in kidneys and only small amount in liver. The name comes from the Bonsdorff and Jalavisto’s paper (1948). • History of the issue is much longer, already in 1906 Paul Carnot possibility of humoral regulation of erythropoiesis.

  25. EPO 2 In 1985 recombinant EPO (rHuEPO) was get and new perspectives for scientific study and clinical use were open. The EPO receptors (EPO-R) were firstly described in 1989/1990. Currently EPO is widely used in therapy of different anemias, especially those have renal or cancerous origin. EPO is a tempting but dangerous doping substance in sport

  26. EPO 2 EPO release into blood is increased 1-2 h after kidney hypoxia and is disrupted when hypoxia is removed. It is an example of typical negative feedback loop regulation Activation of EPO gene in response to hypoxia goes through special transcription factor HIF-1alpha (hypoxia induced factor) which amount goes up by hypoxia.

  27. Negative feedback model by Erslev and Gabuzda (1985) O2 detection in kidneys RBCs in blood EPO Erythropoiesis in bone marrow

  28. EPO 3 EPO receptors are located on BFU-E, CFU-E, and normoblasts’ cell membranes, also on other cells (neurons, myocytes, endotheliocytes etc) Signalling in EPO receptors goes over JAK2 tyrosin kinases and later on via pathways of Jak/STAT and Ras/MAP kinases.

  29. EPO 4 EPO’s influence on erythropoiesis in based on its antiapoptotic effect in respective cell types (CFU-E, normoblasts) According to new data EPO wide spectrum of other biological effects outside of hematopoiesis. EPO is able to stimulate angiogenesis ja neurogenesis, also proliferation different cell types (e.g. myosytes) and antihypoxic effects in several experimental conditions.

  30. References Horst Ibelgaufts'C O P ECytokines Online Pathfinder Encyclopaedia: http://www.copewithcytokines.de/cope.cgi Barreda D.R, Hanington P.C, Belosevic M. Regulation of myeloid development and function by colony stimulating factors. Developmental and Comparative Immunology, 2004, 28, 509-554. Fisher JW. Erythropoietin: physiology and pharmacology update. Experimental Biology and Medicine, 2003, 228, 1-14. Shivdasani RA, Orkin SH. The transcriptional control of hematopoiesis. Blood, 1996, 87, 4025-4039. Szilvassy SJ. The biology of hematopoietic stem cells. Archives of Medical Research, 2003, 34, 446-460.

  31. Hemostasis A good overview and illustrations: http://ntri.tamuk.edu/homepage-ntri/lectures/clotting.html

  32. Main processes of hemostasis • 1. Platelets adhesion and aggregation, formation of the platelet plug • 2. Vasoconstriction • 3. Blood clotting • 4. Final repair by connective tissue NB! The phases are not separated but rather manyfold interconnected

  33. Hemostasis http://cwx.prenhall.com/bookbind/pubbooks/silverthorn2

  34. Classics of blood clotting • Alexander Schmidt and Paul Morawitz They discovered the enzymatic cascade nature of blood clotting 1st phase – activation (of thrombokinase which converts prothrombin to thrombin) 2nd phase -- coagulation (fibrinogen is converted to soluble fibrin) 3rd phase – retraction (production of stable fibrin)

  35. Adhesion of platelets, white thrombus http://cwx.prenhall.com/bookbind/pubbooks/silverthorn2

  36. Thrombocytes Production from megakaryocytes, 1,5-3,0 x 1011 in 1L blood Reservoirs of bioactive substances Serotonin (5-HT) and thromboxan A2 potent vasoconstrictors

  37. Factors influencing platelets adhesion Collageen and plasma von Willebrand faktor (vWf) iniate adhesion. Adhesion is blocked by negative surface charge of platelets, certain biochemical regulators (e.g. NO, prostacyclin etc), and endothelial barrier between collagen and blood.

  38. Platelets in “normal” state http://ntri.tamuk.edu/homepage-ntri/lectures/clotting.html

  39. The activated platelets http://ntri.tamuk.edu/homepage-ntri/lectures/clotting.html

  40. http://ntri.tamuk.edu/homepage-ntri/lectures/clotting.html

  41. http://ntri.tamuk.edu/homepage-ntri/lectures/clotting.html

  42. Blood clot s. “red thrombus” http://ntri.tamuk.edu/homepage-ntri/lectures/clotting.html

  43. http://ntri.tamuk.edu/homepage-ntri/lectures/clotting.html

  44. Conversion of prothrombin to thrombin http://ntri.tamuk.edu/homepage-ntri/lectures/clotting.html

  45. Fibrinogen http://ntri.tamuk.edu/homepage-ntri/lectures/clotting.html

  46. Conversion of fibrin from fibrinogen http://ntri.tamuk.edu/homepage-ntri/lectures/clotting.html

  47. Fibrinogen structure http://ntri.tamuk.edu/homepage-ntri/lectures/clotting.html

  48. Fibrin network http://ntri.tamuk.edu/homepage-ntri/lectures/clotting.html

  49. Initiation of coagulation • The extrinsic pathway is critical in initiating of blood clotting. • The intrinsic pathway plays an important role in maintenance of coagulation. There is no bleeding disorders in case of lack XII

  50. Regulation of coagulation Serine protease inhibitors (antithrombin III) The protein C system activated by thrombin The regulatory influences of intact endothelial and blood cells The fibrinolytic system

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