1. Inflammation is a process carried out in response to either physical or immunological tissue insult. It consists of a destructive process to remove the inflammatory trigger and damaged tissue, followed by repair and replacement. The main actors in the destructive phase are neutrophils and macrophages. Inflammation is signaled by heat, pain, redness, and swelling (calor, dolor, rubor, tumor). Inflammatory conditions are named with the suffix itis. Chapter 10 Inflammation

2. Macrophages are highly complex cells engaged in normal tissue maintenance and turnover. Among their varied functions, they are sentinels against infection, both through the use of receptors for common molecules carried by pathogens, and through opsonization. Macrophages exist in various levels of activation, wherein they become more aggressive at destroying macromolecules, and sending distress signals to recruit other components of the inflammatory response. The most aggressively activated macrophages are derived from blood monocytes in response to inflammatory signals. These are called “infiltrating macrophages”.

3. Names of Macrophages According to Tissue Locations Location Connective tissue Serous cavity Liver Bone tissue Lung Nervous system Spleen Skin Inflamed tissue Name Histiocyte Peritoneal macrophage Kupffer cell Osteoclast Alveolar macrophage (dust cell) Microglial cell Sinusoidal lining cell Langerhans cell Infiltrating macrophage

4. Macrophage activation: Toll-like receptors (TLR1-10) & C-type lectin receptors: Moieties found in cell walls of Gram positive and Gram negative bacteria, Mycobacteria, Trypanosomes, Treponema, Neisseria; bacterial flagellin; viral glycoproteins; dsRNA; virus single stranded RNA; unmethylated CpG DNA; malarial pigment haemozoin; Toxoplasma gondi profilin-like protein; HIVgp120; fungus  -glucans; zymosan. Opsonization: Immune complexes with IgG, IgA, activated complement on bacterial cell wall. T lymphocyte signaling Interferon 

5. Homing lymphocyte selectin binds endothelial addressin cellular integrins bind endothelial ICAM/VCAM

6. Cells involved in inflammatory response Neutrophils Monocytes -> Infiltrating Macrophages T lymphocytes Resolution phase: Epithelial cells Fibroblasts

7. Leukocytes and % of Each Type in Blood Granular Neutrophils Eosinophils Basophils % 59.0 2.7 0.3 Nongranular Monocytes Lymphocytes % 4.0 34.0

9. Some cytokines involved in inflammatory responses IL1Macrophage distress signal; recruits and activates CD4 and CD8 T cells; systematically causes fever. INF , IL2 Drives T H 1 response. IL4,5Drives T H 2 response; suppresses T H 1 response. TGF  Deactivate macrophages; stimulate resolution; promote matrix synthesis; switch B cells from IgG to IgA. IL3 Stimulates production of more blood cells. IL8Chemotactic factor for neutrophils. INF ,  Shuts down translation; initiates virus-resistant state.

10. Mediators of inflammatory responses Histamine Kinins Serotonin Kinins are produced from kininogens during the coagulation cascade. Serotonin is released from platelets during platelet activation.

11. Neutrophil/ macrophage interaction Activated neutrophils secrete oxygen radicals, antimicrobial peptides, lysosomal granule contents, and signals to attract monocytes. Monocytes differentiate to macrophages which will remove dead neutrophils and their secreted products.

12. Kinin (bradykinin) receptors Acute inflammationChronic inflammation B 2 receptorB 1 receptor Constitutively expressedInduced by chronic stimulation Rapidly desensitizedNot desensitized

13. When phagocytes fail to remove the inflammatory trigger: Purulent exudate (pus) formation in an abscess – typically means that a bacterial pathogen is resisting killing by macrophages. Fibrosis – formation of abnormal scar tissue because repair cells can not properly access the still-inflamed area. Chronic inflammation – a long term state of inflammation in which there will be loss of tissue.

14. Deepening Periodontal Pocket

15. Periodontal probe used to measure depth of periodontal pocket

16. Steps and inhibitors of hemostasis 1. Vascular spasm 2. Platelet plugging aspirin (acetylsalicylic acid), plavix (colpidogrel) 3. Coagulation coumadin (warfarin), dicoumerol (active form of coumarin)

17. Vascular Spasm Contraction of smooth muscle cells surrounding the injured vessel. Upstream constriction reduces blood loss. Can last 30 minutes. Signaled by: Thromboxane A2 Thrombin

18. Platelet activation Receptors: Glycoprotein Ib/V/IX --> von Willebrand Factor Glycoprotein Ia --> collagen Glycoprotein VI --> collagen Glycoprotein IIb/IIIa --> fibronectin, other platelets Signals: Thromboxane A 2 (COX pathway) [inhibited by aspirin] ADP [inhibited by plavix] (Other N.S.A.I.D.s inhibit COX, but are reversible inhibitors).

19. True or False? http://biochem.uthscsa.edu/hardies-bin/survey.pl The glycoproteins of this kind are generically called “adhesion proteins” Three of the proteins are of a class called “integrins”. Integrins exhibit “inside out” signaling. That means: a) When activated, the cell turns inside out. b) When it binds its ligand, a signal is passed into the cell. c) When the cell is activated, it shifts the integrin from an inactive to an active binding conformation. d) They cause platelets to become “sticky”.

20. NSAIDs (non steroidal anti inflammatory drugs) include: True or False? http://biochem.uthscsa.edu/hardies-bin/survey.pl a)aspirin b)ibuprofin c)tylenol d)naproxin e)prednisone

21. Coagulation Pathways

22.  -carboxy glutamic acid modification in liver

23. coumadin (warfarin) vitamin K vitamin K epoxide vitamin K epoxide reductase dicoumerol carboxylase inactive factorgamma carboxylated factor O

24. Membrane binding domain of prothrombin

25. Coagulation Complexes neg. surface XII HMW kininogen preKallikrein Kallikrein kinin XIIa platelet surface VIIIa IXa X Ca +2 Xa tissue cell TF X Ca +2 VIIa platelet surface Va XaII Ca +2 IIa Ca +2

26. Coagulation Pathways vWF + PTT + PT/INR + Coumadin platelets aspirin plavix hemophilia A hemophilia B kininogen kinin Inflammation Tissue cell collagen fibers + + + + (platelet count; platelet function assay) ristocetin +vWF aggregation

27. True or False? http://biochem.uthscsa.edu/hardies-bin/survey.pl a)The lab test for coagulation integrity in a patient taking coumadin is PTT. b)von Willebrand Disease can look like a mild factor VIII deficiency. c)A lab test for adequate compensation for classic hemophilia is INR. d)A specific test for von Willebrand Disease is the ristocetin agglutination assay.

28. Regulation of coagulation heparin: chopped up glycosaminoglycan released from mast cells, or administered clinically. Stimulates antithrombin III, which inhibits factors IIa, IXa, Xa, XIa, and XIIa. Reversed by protamine sulfate. heparan sulfate: on surface of endothelial cells acts like heparin. thrombomodulin: on surface of endothelial cells; activates Protein C & S; Protein C cleaves and inactivates factors VIIIa and Va. prostaglandin I 2 (PGI 2 ): secreted by endothelial cells inhibits platelet activation.

29. Fibrinogen fibrin Thrombin removes N ter. propeptides half staggered array

31. Fibronectin crosslinked to fibrin

32. Fibrinolysis plasminogenplasmin tissue plasminogen activator

33. TPA resolving a clot in a coronary artery

34. Causes of abnormal bleeding Genetic hemophilia. A (F-VIII), B (F-IX).X-linked von Willebrand Disease up to 1%, men or women Drugs coumadin, plavix, aspirin, Vascular fragility vitamin C deficiency, connective tissue disorders Diseases affecting platelets leukemia, AIDS Diseases affecting the liver cirrhosis chemotherapy, alcohol, broad spectrum antibiotics

35. Laboratory Tests Platelet count Prothrombin time (PT/INR) plasma from patient plus thromboplastin (contains triggers of extrinsic pathway) Measures 3 Vit K dependent factors. VII has shortest half life of vitamin K-dependent factors. Time to clot normalized by normal controls and adjusted for the potency of the thromboplastin is called INR (0.8 – 1.2 is normal). Partial thromboplastin time (PTT) plasma from patient plus thromboplastin (without TF) plus trigger of intrinsic pathway.

36. Functions of the clot Stop bleeding Seal against infection Scaffold for epithelial cells, and for deposition of granulation tissue