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1. Inflamm process in higher vertebrates- characterized by:

2. Inflamm response closely intertwined with: the process of repair. Occurs at beginning of inflamm by regeneration of parenchymal cells, filling of defect with fibrous tissue (scarring), and/or a combo of these two.

3. Dif b/w regeneration and scarring: Regeneration is replacing the cells that were injured; Scarring is formation of fibrous tissue to “fill” the space where the defect was and can be hazardous (arthritis)

4. Time course of inflamm: Acute – seconds to minutes, Chronic – weeks to months

5. 4 cardinal signs of inflamm: Rubor (red), Tumor (swelling), Calor (heat), Dolor (pain)

All of the above = function laesa (loss of function)

6. 5th clinical sign added later: functio laesa (see above)

7. 3 major components of acute inflamm:

1. Vasodilation and increased blood flow

2. Increased vascular permeability = exudation of fluid to produce edema

3. Migration of inflamm cells – usually neutrophils and monocytes (fig2-6)

8. Exudate: an inflamm extravasc fluid that has high protein concentration, cellular debris, and sp. Gravity > 1.020 (means increased permeability of small BV’s)

Transudate: fluid with low protein content, mostly albumin, with a sp. Gravity < 1.012 (an ultrafiltrate of blood plasma form osmotic or hydrostatic imbalance across vessel wall without an increase in vascular permeability)

Edema: excess of fluid in the interstitial or serous cavities – can be exudates or transudate

Pus: purulent exudates rich in leukocytes (mostly neutrophils), debris of dead cells, and microbes

9. 2 major mechanisms of host defense carried in the bloodstream: antibodies and leukocytes

- Slowing of circulation is important because: allows RBC’s to accumulate and the blood to become more viscous. Slowing (stasis) allows neutrophils to accumulate along the vasc endothelial wall and eventually migrate through the wall to the site of injury

10. Leukocyte Margination: because of the slow moving blood, the wall shear stress decreases and more white cells assume a peripheral position along the endothelial surface = leukocyte accumulation

11. Hallmark of acute inflammation: increased vasc permeability

Edema results because: escape of protein-rich fluid into extravasc tissue = loss of protein from plasma reduces intravascular osmotic pressure and increases osmotic pressure of interstitial fluid. With the increased hydrostatic pressure from the increased blood flow = outflow of fluid and its accumulation in the interstitial tissue = net =increase of extravascular fluid = edema

12. Delayed Prolonged Leakage: increased permeability that begins after a delay of 2-12 hours, lasts hours to days, and involves venules and capillaries. Caused by thermal injury (UV, x-rays) Late appearing sunburn is a good example.

13. Angiogenesis: during repair, endothelial cells proliferate and form new vessels. These new vessels remain leaky until the endothelial mature and form intercellular junctions. Also VGEF increases vasc permeability, and endothelial cells in foci of angiogenesis have increased density of receptors for vasoactive mediators (hist, subs P, VGEF)

14. Neutrophil Extravasion: (movement of leukocytes from vessel lumen to interstitial tissue):

1. Margination, rolling, and adhesion to endothelium in lumen

2. Transmigration across the endothelium (diapedesis)

3. Migration in interstitial tissues toward a chemotactic stimulus

15. 4 categories of adhesion receptors:

1. Selectins: have an extracellular N-terminal domain related to sugar-binding mammalian lectins; consist of E-selectin (confined to endothelium), P-selectin (in endo and platelets), L-selectin(expressed on most leukocyte types)

a. They bind through their lectin domains to sialylated forms of oligosaccharides which themselves are covalently bound to mucin-like glycoproteins

2. Immunoglobulins: 2 endothelial adhesion molecules: ICAM-1 (intercell) and VCAM-1 (vasc adhesion) – serve as ligands for integrins found on leukocytes

3. Integrins: transmem heterodimeric glycoproteins made of alpha and beta chains which bind to ligands on endo cells, other leukocytes and ECM

16. 4 functional responses of leukocytes induced by leukocyte activation:

1. Production of arachidonic acid metabolites from phospholipids – as a result of activation of PLA2 by increased intracellular Ca and other signals

2. Degranulation and secretion of lysosomal enzymes and activation of the oxidative burst

3. Secretion of cytokines – which amplify and regulate inflamm rxns; macrophages are chief source, mast cell contribute

4. Modulation of leukocyte adhesion molecules – dif cytokines cause increased indo expression of adhesion molecules and increased avidity of leukocyte integrins

17. Neutrophils predominate in the inflamm infiltrate during the first 6-24 hours, then monocytes take over form 24-48 hours

18. Chemotaxis: after extravasation, the leukocytes emigrate in tissues toward the site of injury – locomotion oriented along a chemical gradient. Exogenous chemoattractants include bacterial products. Endogenous chemoattractants include: complement system(C5a), products of lipoxygenase pathway (leuko B4) and cytokines

Actin involvement: chemotactic agents bind to G protein-coupled receptors and activate GTPase which polymerizes actin at leading edge of the cell. The Leukocytes move by extending filopodia that pull the back of the cell in the dir of the extension

19. 3 steps in phagocytosis:

1. Recognition and attachment: leukocytes express mannose and scavenger receptors that bind to ingest microbes. Mannose receptors bind to fucose and mannose residues of glycoproteins on microbes (mammalian glycoproteins have a terminal sialic acid and are therefore not recognized by mannose receptors). Scavenger receptors can bind to oxidized LDL particles and Mac-1

a. Efficiency of phagocytosis is enhanced when microbes are opsonized by specific proteins (opsonins) for which the phagocytes express high-affinity. Major opsonins are: IgG antibodies, C3b breakdown product of complement, and plasma lectins (MBL)

2. Engulfment: extensions of cytoplasm flow around particle and eventually result in complete enclosure of particle within a phagosome. The phagosome then fuses with a lysosome = phagolysosome. Phagocytosis is dependent upon polymerization of actin filaments; therefore signals are similar to chemotaxis

3. Killing and Degradation: microbial killing is accomplished largely by oxygen-dependent mechanisms. Phagocytosis stims a burst in oxygen consumption, glycogenolysis, increased glucose oxidation and production of ROS (H2O2 generated by NADPH oxidase system)

a. Granules of neutrophils contain myeloperoxidased (MPO) which in the presence of Cl converts H2O2 to hypochlorite (HOCl) which destroys microbes by halogenation

20. 3 major opsonins: opsonins coat microbes and target them for phagocytosis

Include: antibodies(IgG) , complement proteins (C3 protein), lectins (mannose binding lectin)

21. A membrane bound opsonized particle fuses with a lysosome and forms a phagolysosome

22. Bacterial killing by neutrophils is mainly accomplished by: oxygen dependent mechanisms

23. The major species of oxygen-derived free radicals are: superoxide anion(O2-), hydrogen peroxide (H2O2), and hydroxyl radical (OH) formed from activation of NADPH oxidative system

- they increase the expression of chemokines, cytokines, and endothelial leukocytes adhesion molecules, amplifying the cascade that elicits the inflamm response.

- The major physiologic function is to destroy phagocytosed microbes

24. Superoxide is reduced oxygen. It is converted into H2O2 mainly by spontaneous dismution

25. The most efficient bactericidal system in neutrophils are bactericidal permeability increasing protein (BPI) – a highly cationic granule-assoc protein that causes phospholipase activation, phospholipid degradation and increased permeability in the outer membrane of the microorganisms (lysozyme, lactoferrin, major basic protein, defensins)

26. Some acute and chronic forms of leukocyte injury:

Acute: acute resp distress syndrome, acute transplant rejection, asthma,

glomerulonephritis, reperfusion injury, septic shock, vasculitis

Chronic: Arthritis, asthma, ahterosclerosis, chronic lung disease, chronic rejection

27. After phagocytosis, neutrophils rapidly undergo apoptotic cell death and are ingested by macrophages

28. Disease characterized by congenital dysfunction in bacterial killing, which renders the patient susceptible to recurrent bacterial infection: Chronic Granulomatous Disease.

- from inherited defects in the genes coding for NADPH oxidase, which generates superoxide

29. Histamine: richest source is mast cells normally present in CT adjacent to BV’s, also found in blood basophils and platelets

- performed histamine is in mast cells granules and is released by mast cell degranulation is response to: physical injury such as trauma, cold or heat; immune reactions involving binding of antibodies to mast cells; fragments of complement called anaphylatoxins; histamine-releasing proteins derived from leukocytes; neuropeptides; and cytokines

- *histamine causes dilation of the arterioles and increases the permeability of venules. It is the principle mediator the immediate transient phase of increased vascular permeability, causing venular gaps. Acts on microcirculation via bonding to H1 receptors on endothelial cells

30. Endogenous chemoattractants:

1. components of the complement system, C5a

2. products of the lipoxygenase pathway, leukotriene B4

3. cytokines, chemokine family like IL-8

31. Bradykinin: responsible for increased vascular permeability and pain

32. 2 specific components of the coagulation system that act as links b/w coagulation and inflamm: 1. Activated Hageman factor (factor XIIa): initiates four systems involved in the inflamm response: 1. the kinin system, 2. the clotting system which induces fibrinopeptides and factor X which have inflamm properties, 3. the fibrinolytic system which produces plasmin and degrades fibrin, and 4. the complement system which produces anaphylatoxins – a product of initiation (kallikrein) and feedback activate Hageman factor

33. Function of plasmin: plasmin is a multifunctional protease. It is important in lysing fibrin clots but also cleaves C3 to produce C3 fragments, and it degrades fibrin to form fibrin split products which may have permeability-inducing properties. Plasmin can also activate Hageman factor which can trigger multiple cascades and thereby amplify the response

34. Clinical manifestations of inflammation resulting from prostaglandins:

- from the cyclooxygenase pathway from arachidonic acid – involved in pain and fever

- PGE2 is hyperalgesic and makes skin hypersensitive to painful stimuli

- PGD2 is major metabolite of CO pathway in mast cells (and PGE2 and PGF2) and cause vasodilation and increase permeability of postcapillary venules = edema

35. Aspirin and NSAIDs inhibit the phospholipase activity of the AA metabolism so that the phospholipids are not liberated from the cell membrane and do not form arachidonic acid

36. Cytokines: are proteins produced by many cells; principally activated lymphocytes and macrophages. Also endothelium, epi, and CT cells

37. 2 major cytokines that mediate inflammation:

- TNF (tumor necrosis factor) and IL-1 (interleukin-1) produced by activated macrophages

- They are responsible for the systemic acute-phase response

38. The systemic acute-phase responses include: fever, increased sleep, decreased appetite, increase in acute-phase proteins, hemodynamic effects(shock), and neutrophilia

- the cytokines responsible are IL-1 and TNF

39. TNF also regulates body mass by promoting lipid and protein mobilization and by suppressing appetite

- sustained production of TNF contributes to cachexia, a pathological state characterized by weight loss and anorexia that accompanies some infections and neoplastic diseases

40. NO is synthesized form L-arginine by the enzyme nitric oxide synthase

- it is a potent vasodilator because it relaxes sm muscle

- also reduces platelet aggregation and adhesion, and inhibits several features of mast cell-induced inflamm, and serves as an endogenous regulator of leukocyte recruitment

- production of NO is an endogenous compensatory mechanism that reduces inflammatory responses

- Blocking NO production under normal conditions promotes leukocyte rolling and adhesion in postcap venules

41. Alpha1-antitrypsin is the major inhibitor of neutrophil elastase. Neutrophil elastase can degrade virulence factors of bacteria and thus combat bacterial infection

42. Extracellular release of low levels of oxygen-derived free radicals can amplify the cascade of the inflamm response by increasing the expression of chemokines, cytokines, and endothelial leukocyte adhesion molecules

43. The 3 major responses to oxygen derived free radical mediators are:

a. Endothelial cell damage with resultant increased vascular permeability – adherent neutrophils produce xanthine oxidase in endo cell and therefore elicit more superoxide

b. Inactivation of antiproteases – such as alpha-antitrypsin – leads to unopposed protease activity with increased destruction of EC matrix

c. Injury to other cell types

44. 5 antioxidants that protect against the harmful effects of oxygen-derived free radicals:

1. Ceruloplasmin – copper containing serum protein

2. Transferrin – iron-free fraction of serum

3. Superoxide dismutase – found in a variety of cell types

4. Catalase – detoxifies H2O2

5. Glutathione peroxidase – H2O2 detoxifier

45. Main mediators of acute inflammation and their mode of action:

Bradykinin (plasma substrate) – Pain

C3a (plasma protein in liver) – opsonic fragment C3b

C5a (macrophages) – leukocyte adhesion, activation

Prostaglandins (mast cells, mem phospholipids) – vasodilation, pain, fever

Leukotriene B4 (leukocytes) – Leukocyte adhesion, activation

Leukotriene C,DandE4 (leukocytes,mast cells) – bronchoconstriction, vasoconstriction

Oxygen metabolites (leukocytes) – Endo damage, tissue damage

PAF (leukocytes, mast cells) – bronchoconstriction, leukocyte priming

IL-1, TNF (macrophages, other) – acute-phase reactions, endo activation

Chemokines (leukocytes, other) – leukocyte activation

NO (macrophages, endo) – vasodilation, cytotoxicity

46. 3 general outcomes of acute inflammation:

1. Complete resolution: neutralized and eliminating injurious stimuli and restoration of the site to normal

a. Usually occurs when injury is limited or short-lived

b. Return to normal vasc permeability, cessation of leukocyte infiltration, death of neutrophils, and removal of edema

2. Healing by CT replacement (fibrosis)

a. Occurs after substantial tissue destruction when tissue is incapable of regeneration or there is abundant fibrin exudation – CT grows into the area of exudates and converts it into a mass of fibrous tissue (process is called organization)

3. Progression of the tissue response to chronic inflammation. Failure to resolve leads to extensive tissue destruction and formation of a cavity in which inflamm continues to smolder (can form an abscess)


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