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USC BISC 307L - Blood Figs and Innate Immune
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BISC 307L 2nd Edition Lecture 30 Current LectureHematopoiesisBlood cells come from the bone marrow. Red bone marrow, in fetal life, create red blood cells. After birth, however, most red bone marrow converts to yellow bone marrow, except for a few of the long bones(pelvis, etc.), which retain the ability to make red blood cells. The rest of the bonemarrow is yellow bonemarrow, which is usedin fat storage.You have various levelsof commitment of stemcells(top left):pluripotenthematopoietic stemcells, which proliferateand becomeuncommitted stemcells, which becomecommitted to give rise to certain mature blood types but remain stem cells, and continue to proliferate. One of the daughter cells then becomes fully committed, becoming a progenitor of a full cell – these are NOT stem cells, they mature into mature cell types. Neutrophils are shown, as are RBC’s and a megakaryocyte, which stays in the bone marrow and buds off platelets. Can see a monocyte, which will give rise to a macrophage. The hematopoiesisof these different cell types is controlled by hematopoietic cytokines (hormones of the immune system). One example is erythropoietin, which stimulates the production of erythrocytes. Another is thrombopoietin, which stimulates the megakaryocytes and therefore the platelets to develop, and then there are a variety of cytokines called colony stimulating factors, or interleukines, and they stimulate all the blood cell types in different ratios. They are produced in prestigious numbers – the most abundant blood cells are the erythrocytes(have a life span of 90-120 days, after which they are destroyed, so there is a substantialproduction of RBC’s all the time). The cell type being produced at the highest rate are the neutrophils. They have a life span of a few hours, so they must be produced rapidly. HemostasisThe viscosity of the blood can’t be too high, or it can’t flow freely. And it definitely should not clot – if it clots incorrectly then resistance would go up greatly and problems would ensue. But it also has to be able to clot to stop leaks. Hemostasis, the cessation of bleeding, is a five step process:1.) Vasoconstriction2.) Platelet plug formation3.) Coagulation4.) Tissue repair5.) ThrombolysisThe process begins with damage to the wallof the blood vessel. The damage to anysmooth muscle cells that happen to be inthe vessel is going to causevasoconstriction, which will minimize bloodloss in that area. (left hand path)Blood is normally only in contact with theendothelium, except when the vessel isdamaged. Two abundant proteins in thelayers of the blood vessel wall outside thelumen are collagen and tissue factor. Theexposure of collagen and tissue factor toplatelets is going to trigger clotting. Tissuefactor is also known as coagulation orclotting factor three, or thromboplastin.When platelets contact collagen, they bind to them by means of integrins, which are membrane proteins that bind to certain 3 amino acid sequences in extracellular matrices on the outside of the cell. There are also some changes inside the cell that cause the platelets to become sticky and adhere to each other. These sticky mutually adhering platelets form a platelet plug, which increases the resistance to the blood flowing out, decreasing the flow and pressure. In particular, stuff oozing out initially is blood, but then becomes serum (plasma – clotting factors) that are being filtered through the spaces of the porous platelet plug. Platelets do not aggregate in a healthy endothelium. The intact endothelial cellssecretes nitrous oxide, which inhibits platelet adhesion, and it converts some of the membrane lipids into an eicosanoid called prostacyclin. Secretion of prostacyclin and N.O. inhibit platelet adhesion. So no clots should form on a healthy endothelium.Platelets also release platelet factors – platelets are full of vesicles and they burst open, releasing the contents, which are three things: 1. Platelet activating factor and 2. Serotonin and 3. ADP.These platelet factors bind to receptors on other platelets, activating them. Platelet activating factor additionally causes the synthesis of an eicosanoid named thromboxane A-2.TA2 and serotonin are vasoconstrictors. Release of platelet factors also enhancing vasoconstriction, that’s due to platelet activating factor activating synthesis of thromboxane A2 and serotonin being the vasoconstrictive agent that add to the vasoconstriction of vascular smooth muscle in the neighborhood. Coagulation CascadeAt the very bottom of the cascade we will end up with cross-linked fibrin, which will reinforce the platelet plug. Fibrin fibrils are sticky and strong, so that they stick to the wound and they adhere to each other and form a mesh that greatly reduces blood loss. Once they’ve polymerized from their subunits, they began contracting or getting shorter, pulling the edges of the torn vessel together, sealing the vessel for good. On the right is the extrinsic pathway, involving mechanisms that are external to the blood itself. Start with damage exposing tissue factor III which converts clotting factor VII to active VII. ActiveVII is also an enzyme, and along with tissue factor III they both activate IX to make it active IX. There is also the intrinsicpathway on the left. Itincludes tissue factor XII,which is activated by bindingto collagen and othersubstances. XII is inactive, andwhen it gets activated, itcatalyzes inactive XI to activeXI. Active XI catalyzes inactiveIX to active IX. At this point,the pathways converge. Active IX catalyzes conversionof X to active X, whichrequires factor VIII as a cofactor, along with calcium, membrane phospholipids, tissue factor III and active VII both stimulate it. So everything converges again on formation of active X. Active factor X is going to convert prothrombin to thrombin. This is a Ca dependent step that also requires clotting factor V and PL(phospholipids). Where do all these inactive proteins(prothrombin, fibrinogen, etc.) in the plasma come from? They are all made by the liver.Thrombin catalyzes the conversion of inactive fibrinogen to fibrin, a structural protein. And thrombin also feeds back positively and converts XI to active XI, as does active X for VII. Fibrin polymerizes to form long fibrils, as well as catalyzing the conversion of XIII to active XIII, which crosslinks fibrin to make the cross-linked fibrin mesh. Active VII and X promote tissue repair. Notice the importance of Ca in


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