Chapter 25.docx

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University of Manitoba
Biochem. and Medical Genetics
BGEN 3020
Jason Leboe- Mcgowan

Chapter 25 Acute Inflammation Cardinal signs of inflammation In the scenario with a bee sting: you will see redness (Tubor). The king of vasodilators is histamine and it vasodilates the arterioles. Therefore, histamine is responsible for the redness of acute inflammation (ie bee sting), and is working on arterioles. Now if we felt the area, it will be warm (Calor = heat), this is due to vasodilating the arterioles, which is caused by histamine. For example in endotoxic and septic shock, the skin is warm b/c you are vasodilated. Tumor is a raised structure caused by histamine. Histamine can lead to increased vessel permeability in the venules; is arterial thicker than venules? Yes. The venules are very thin; they basically have an endothelial cell with a basement membrane, all you have to is drill a hole through the BM and you are out. Therefore, increased vessel permeability occurs at the venule level, not the arterial level. Histamine contracts the endothelial cells, and leaves the BM bare, leading to increased vessel permeability, producing an exudate, and swelling of tissue, hence tumor of acute inflammation. The area may hurt (Dolor = pain) but hitamine does not have anything to do with this. Bradykinin is part of the kininogen system between factor 11 and Hageman factor 12. So when you activate the intrinsic pathway, you automatically activate the kininogen system. When you activate factor 12 (Hageman factor), it will activate 11 and the whole kininogen system. The end product is bradykinin. ACE degrades bradykinin. Complication of ACE inhibitor is angioedema. Also inhibit metabolism of bradykinin, which increases vessel permeability, producing the angioedema (swelling of the tissues). How bradykinin produces cough is not really understood. Bradykinin and PGE2 cause pain (dolor) and is the only one out of the four Latin terms of acute inflammation that is not due to histamine release. Steps involved in Acute inflammation (this the normal sequence in acute inflammation): 1. Emigration: includes margination, paveenting, rolling, adhesion, and transmigration Neutrophils in circulation start to become sticky b/c of adhesion molecule synthesis. Endothelial cells begin to synthesize adhesion molecules. Eventatually, neutrophils will stick to endothelial cells, these steps are called pavmenting or margination. Then neutrophils look for bare basement membrane on the venules and then they drill a hole through it via type 4 collagenase. Cancer cells also have type 4 collagenase, that’s how they metastasize. Cancer cells attach to endothelial via adhesion molecules, usually against laminin in BM, and they have collagensae to get through the BM, therefore, cancer cells are pretty much like a neutrophil when invading tissue. Chemotaxis: When they pass BM of small venules, they emigrate but they have to know what direction to go. They get directions in a process called directed chemotaxis. C5a and LT-B4 (leukotriene B4) are the chemotactic agents. These chemotactic agents are also involved in making adhesion molecules on neutrophils). Therefore, they make adhesion molecules AND give direction by acting like chemotactic agents. 3. Phagocytosis via opsonization: a) Example: in an acute inflammation with staph aureus, the bacteria are being processed by opsonins, which immobilize the particles on the surface of the phagocyte. The two main opsonins are IgG and C3b. They help with phagocytosis. b) Example of an opsonization defect: Brutons agammaglobinemia: an x-linked recessive dz, where all the immunoglobulins are missing, including IgG. Therefore, MCC death in these pts is due to infection b/c cannot opsonize things. It produces hypogamma-globinemia, but the mechanism of infection is due to not having IgG to opsonize bacteria, therefore cannot phagocytose it. Bacteria are opsonized by IgG and C3b, which means that neutrophils must have receptors for those. In acute inflammation the main cell is neutrophil and in chronic inflammation the main cell is macrophage/monocyte (monocytes become macrophages). These cells have to have receptors for these opsonins (IgG and C3b). Then they become phagocytosed or become phagolysomes. When they are phagocytosed, the lysosomes go to microtubules and empty their enzyme into this. c) Example: In I-cell disease: in this dz, mannose residues cannot be phosphorylate in golgi apparatus therefore the enzymes are not marked with phosphorus, and the lysosome are empty. 4. Intracellular microbial killing: a) Examples: (1) Staph aureus in hottub surrounded by enzymes (2)Chlamydia can get out of phagolysosome, mechanism unknown, but sometimes they have mucous and all kinds of things around them. b) O 2ependent myeloperoxidase system is the boards!! Molecular O i2 converted by NADPH oxidase, which is in the cell membrane of neutrophils and monocytes, but not mac
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