1
Q
Inflammation
A
- reaction to injurious agents that limits damage and promotes repair
- mediated by blood vessels and blood cells
- tightly regulated chain of molecular and cellular events
- categorized as acute or chronic by the duration of the response and the type of cells involved
2
Q
neutrophils
A
- most common WBC in peripheral blood
- segmented nucleus w/ 3-5 lobes and numerous cytoplasmic granules
- motile phagocytes-move by pseudopods and digest foreign material via acid hyrolases from w/in granules
- *Primary responder in acute inflammation
3
Q
lymphocytes
A
- single nucleus, scant cytoplasm
- B-cells, T-cells, and NK cells
- Primarily in chronic inflammation and acquired immunity
- produce cytokines and help eliminate foreign material through production of antibodies and toxic granules
- specialized lymphocytes can elaborate antibodies when stimulated
4
Q
Monocytes
A
-produced in bone marrow, in circulation for ~1 day
5
Q
Macrophages
A
- monocytes in tissues
- motile phagocytes, cytoplasmic granules containing toxic substances
- acute and chronic inflammation: phagocytose foreign material, digest it, and present antigens via Class II MHC receptors
- integral in transition from acute to chronic
6
Q
Eosinophils
A
- bi/tri lobed nucleus, cytoplasm full of pink (eosinophilic) granules that contain numerous chemical mediators of inflammation-histamine, proteolytic enzymes, major basic protein
- primarily in rxns to allergens and parasites
7
Q
Basophils
A
- bilobed nucleus, cytoplasm filled w/ deep blue/purple (basophilic) granules-contain histamine, proteoglycans, proteolytic enzymes, and lipid mediators of inflammation (eg slow reacting substance of anaphylaxis)
- allergic and hypersensitivity rxns
8
Q
Mast cells
A
in tissues, identical to basophils
located near bv and along mucosa and dermis-interface between host and environment
9
Q
Platelets
A
- Small, anuclear discoid fragments of megakaryocyte cytoplasm, contains some cell machinery and numerous granules
- primarily involved in hemostasis (blood clot formation)
- granules contain numerous chemical mediators of inflammation (eg platelet activating factor-affects all cardinal features of inflammation)
10
Q
Inflammatory changes in vascular flow
A
- histamine mediates dilation of precapillary arterioles-increase vascular flow to capillary bed
- postcapillary venule dilation -> stasis -> increased hydrostatic pressure in capillary bed
11
Q
inflammatory changes in vascular permeability
A
- gaps form between endothelial cells -> fluids, electrolytes, and/or blood can leak out of vessels into surrounding tissues
- caused by: direct toxic injury to cells; constriction of endothelial cells and release of tight jxns due to vasoactive mediators of inflammation and cytokines
12
Q
Leukocyte adhesion
A
- stasis-blood flow slows
- margination-anionic surface charge of endothelial cells decreases-leukocytes no longer repulsed-altered blood flow pushes leukocytes to periphery
- adherence-leukocytes roll along endothelium and stick to it; mediated by expression of molecules and ligands on endothelial and leukocyte surfaces
13
Q
Roll of macrophages in leukocyte adhesion
A
produce cytokines->
- induce selectin transport to cell surfaces-bind Sialyl Lewis X-modified glycoprotein on leukocyte surfaces-slow leukocyte
- induce expression of integrin ligands and proteoglycans -> induce leukocyte integrins to switch to high affinity state and bind integrin ligands
14
Q
Transmigration
A
diapedesis-leukocytes extend pseudopods and squeeze through vessel wall-PECAM mediated
migration-leukocytes travel through extravascular space to site of injury along chemotactic gradient
15
Q
Chemotaxis; 4 strong attractants of chemotaxis
A
- movement of leukocytes along a chemical gradient-(LFB bacterial product, C5a complement protein, LTB4 arachadonic acid metabolite, IL-8 cytokine)
- chemotactic agents bind g-protein coupled receptor -> polymerization of actin filaments and extension of filopodia
16
Q
Leukocyte activation
A
-modulate leukocyte adhesion molecules
-ingest and degrade foreign substances scavenged from tissue
-degranulate
-secrete cytokines that amplify and regulate inflammation
-produce arachidonic acid metabolites
-aggregate platelets
(activators include antibodies, thrombin, bacterial products, etc)
17
Q
Phagocytosis-recognition and attachment
A
- macrophage mannose receptor recognizes terminal mannose and fucose residues of glycoproteins and glycolipids on microbial cell walls
- recognition and attachment enhanced if foreign object opsonized
18
Q
Phagocytosis-engulfment
A
- cytoplasm extends around foreign complex and forms intracellular phagosome
- phagosome fuses w/ lysosome
- contents mix and enzymes activate
19
Q
Phagocytosis-killing and degradation
A
- oxygen dependent mechanism-H2O2 and HOCl destroy microbes by halogenation or lipid peroxidation
- oxygen independent mechanism-acid hydrolases in leukocyte granules toxic to phagolysosome contents
20
Q
Leukocyte product leak
A
- regurgitation during feeding
- frustrated phagocytosis (complex fixed on tissue)
- cytotoxic release (damage own cell membrane eg gout crystals)
- active exocytosis
21
Q
Chemical mediators of inflammation
A
Histamine
bradykinin
substance P
cytokines-IL-1, TNF, IFN-gamma
22
Q
Integrin Ligands
A
- ICAM-1 and VCAM-1
- cytokines from macrophages induce their expression on endothelial cells
- bind integrins on leukocyte cell surface for leukocyte adherence
23
Q
PECAM-1
A
Integrin ligand on endothelial cell surface that mediates leukocyte diapedesis
24
Q
Defects in leukocyte adhesion
A
- genetic deficiency in leukocyte adhesion molecules (LAD 1 and 2)
- susceptible to recurrent bacterial infections and have impaired wound healing
25
defects in phagolysosome function
- Chediak-Higashi syndrome: autosomal recessive, neutropenia, defective granulation, defective ROS microbicides; albinism, nerve defects, bleeding disorders
- Chronic granulomatous disease-defect in genes encoding NADPH oxidase
26
Bone Marrow suppression
->decreased leukocyte activity due to primary or secondary ds of bone marrow
27
aberrant release of leukocyte products
underlies many severe and chronic inflammatory diseases, such as arthritis, asthma, atherosclerosis.
28
Serous inflammation
thin watery fluid (transudate) exuded at site of injury eg burn blister
29
fibrinous inflammation
clear fluid and fibrinogen escape vessel; fibrinogen polymerizes to form thick fibrin coat of tan-pink, stringy material; lining of body cavities
30
suppurative/purulent inflammation
production of large amounts of pus (neutrophils, necrotic cells, edema fluid); characteristic of pyogenic bacteria infection; eg acute appendicitis, abscess, empyema
31
pseudomembranous inflammation
overgrowth of colonic mucosa by C. dif or fungi, secondary to broad spectrum antibiotic use or immunosuppression; film of inflammatory cells, necrotic epithelium, fibrin and mucus cover mucosa
32
ulcerative inflammation
destruction of epithelial lining due to ischemic damage or infection
33
Gangrenous inflammation
tissue necrosis secondary to interruption of blood supply
- dry-w/o superinfection
- wet-leads to liquefactive necrosis
- gas-superinfection with gas forming organisms
- necrotizing fasciitis-deep tissues
- Fournier's-scrotum
34
Resolution
- replacement of dead cells by cells that were normally there before inflammatory process took place
- effects of inflammation completely reversed-resume normal tissue
- can only occur in tissues w/ regenerative capacity
35
Scar formation
- replacement of damaged tissue by fibrous tissue
| - tissue injury is extensive or involves cells that have limited regenerative capacity
36
Chronic inflammation
- injurious agent persist/cannot be removed by neutrophils alone
- acquired immune system activated
- primary response to things like autoimmune ds, some viral infections, some malignancies (TB, syphilis, DM foot ulcers, HepC)
- Macrophages present digested material or antigens to lymphocytes
37
Non-specific chronic inflammation
- mononuclear cell infiltration (macrophages, lymphocytes, and plasma cells) dominate
- cause tissue destruction and lead to scar (fibrosis)
- often w/ reparative process (granulation tissue)
38
Granulomatous inflammation
- granuloma formation-collection of activated (plump epithelioid) macrophages surrounded by a collar of chronic inflammatory cells, w/ or w/o central necrosis (caseation) and/or giant cells
- caused by certain infectious agents (TB, leprosy, brucellosis, cat-scratch, fungi), insoluble foreign objects, or sarcoidosis
- seal off injurious agent
39
chemical mediators of inflammation
- activated or released in response to particular stimuli
- rapidly released and rapidly cleared
- mediate effects through specific receptors on target cells
40
Plasma derived chemical mediators of inflammation
- produced in liver and circulate in serum as precursor forms
- factor XII (Hageman factor)
- complement proteins
- kinins
- clotting proteins
41
Cell derived chemical mediators of inflammation
- sequestered in cell organelles of produced by effector cells upon stimulation
- vasoactive amines (histamine, serotonin)
- Arachidonic acid metabolites (prostaglandins, leukotrienes, lipoxins)
- cytokines and chemokines (IL-1, TNF)
- nitric oxide
- lysosomal contents
- O2 derived free radicals
42
Vasoactive amines
- histamine and serotonin
- primarily affect altered flow and permeability of vessels
- stored in intracellular granules and rapidly released in response to injurious stimuli
- 1st mediators released
43
histamine
- in mast cells, basophils, and platelets
- dilation of arterioles and increased permeability of postcapillary venules
- principle mediator of immediate transient response
44
serotonin
- in platelets
| - released when platelets aggregate and causes vessel permeability
45
C5a
- plasma protein
- complement system
- potent chemotactic agent-attract leukocytes; also adhesion and activation
- anaphyltoxin->vascular dilation by stimulating histamine response
46
C3a
- plasma protein
- complement system
- anaphyltoxin->vascular dilation by stimulating histamine release; also vascular leakage
47
C3b
- complement system
| - opsonin-target bacteria for phagocytosis
48
Complement system
activation leads to inflammation, phagocytosis, and lysis of microbes
49
Factor XII (Hageman factor)
- plasma protein
- activated at site of tissue injury by exposed collagen, BM, and activated platelets
- activates prekallikrein-> kallikrein; kallikrein is enzyme to make bradykinin
- also initiates clotting cascade -> thrombin
- fibrinolytic system -> plasmin activation
- complement system
50
bradykinin
- plasma protein
- increases vascular permeability and pain
- rapidly cleared by kinases such as ACE in lung
51
Thrombin
- plasma protein
- activated by clotting cascade
- links clotting cascade to inflammation by activating platelets, endothelial cells, and smooth muscle cells
52
Thrombin activates:
- mobilization of selectins to endothelial cell surfaces
- change in endothelial shape-gap jxns open
- induction of metabolism of arachidonic acid
- production of cytokines, platelet activating factor, and nitric oxide
53
Fibrinolytic system
- component of clotting system
- antagonizes clotting cascade by breaking up fibrin clots once formed
- plasminogen incorporated into blood clots as they form -> gets converted to plasmin by tissue plasminogen factor, kallikrein, and factor 12 -> catalyze breakdown of fibrin
54
Plasmin
- plasma protein
- directly cleaves C3 to form anaphylatoxin C3a
- activates factor XII-> promotes activation of kinin and clotting cascades
- products of action on fibrin (fibrin split products) augment vascular permeability
55
most important plasma protein mediators of inflammation in vivo
- bradykinin
- C3a
- C5a
- thrombin
56
Kallikrein
- plasma protein
- convert C5 to C5a
- amplify inflammatory response by activating factor XII
- convert plasminogen -> plasmin
- activate bradykinin
57
Arachidonic acid metabolites
- arachidonic acid esterified in cell membrane -> metabolites synthesized in response to external stimuli -> eicosanoids
- bind G-protein coupled receptors
- chemotaxis, vasoconstriction, bronchospasm, increase permeability, vasodilation, inhibit neutrophil chemotaxis, stimulate monocyte adhesion, inhibit platelet aggregation, promote platelet aggregation, potentiate edema
58
leukotrienes
- more potent in promoting vascular permeability than histamine
- act on bronchial tree to cause bronchospasm
- C4, D4, and E4 -> slow reacting substances of anaphylaxis
- inflammatory mediators in allergic reactions
59
cyclooxygenase pathway
```
make prostaglandins (mast cells, vascular epithelium) and thromboxane (platelets)
-inhibited by acetaminophen, NSAIDs, and COX inhibitors
```
60
lipoxygenase pathway
make leukotrienes and lipoxins (neutrophils)
61
steroids
inhibit phospholipases -> can't metabolize arachidonic acid
62
Platelet activating factor
- platelet aggregation and degranulation
- increased leukocyte adhesion
- chemotaxis
- oxidative burst
- changes in vascular permeability
- augmentation of arachidonic acid metabolism in phagocytes
- bronchoconstriction
- boosts synthesis of other chemical mediators of inflammation
- produced from membrane phospholipids of many cell types
- G-protein coupled receptors
63
cytokine
- protein that modulates the fxn of other cell types (ie messenger)
- interleukins, growth factors, tumor necrosis factors
- integral to cell growth and differentiation, inflammation, immunity and repair
64
chemokine
- proteins that stimulate recruitment and migration of leukocytes
- produced by leukocytes
65
TNF-a
- one of most important cytokines for inflammation
- from macrophages
- hemodynamic effects of septic shock
- cachexia in chronic illnesses
- elicit acute phase reactions, activate endothelial cells, recruit and activate lymphocytes
- vascular leakage, chemotaxi
66
IL-1
- one of most impt cytokines in inflammation
- from macrophages
- elicit acute phase reaction, activate endothelial cells, recruit and activate lymphocytes
- vascular leakage, chemotaxis
67
Nitric oxide
- produced by endothelial cells and macrophages in response to an increase in cytosolic calcium or stimulation by cytokines
- vasodilation, vascular leakage, chemotaxis
- microbicidal via production of reactive O2 intermediates
68
Lysosomal enzymes
- present in phagocytes
- primary/azurophil granules-myeloperoxidase, defensins, elastase, lysozyme, acid hydrolases, collagenases
- secondary/specific granules-lysozyme, gelatinase, histaminase, alkaline phosphatase, collagenase, lactoferrin, plasminogen activator
69
Oxygen derived free radicals
- produced by NADPH system in leukocytes in response to microbes, chemokines, or immune complexes
- superoxide anion, H2O2, hydroxyl radical, reactive nitrogen intermediates
70
antioxidants
ceruloplasmin, superoxide dismutase, and catalase-neutralize oxygen derived free radicals
71
neuropeptides
- stress activates release of neuropeptides from small, unmyelinated sensory fibers
- substance P and calcitonin gene-related peptide
- mediate degranulation of macrophages and mast cells -> increase local cytokine [ ] and induce vascular permeability and dilation
- migraine, asthma, fibromyalgia, derm, pancreatitis, chronic pelvic pain
72
fever
- pyrogens (IL-1 and TNF-a) produced by macrophages induce prostaglandin release by hypothalamus -> reset temp set point
- may help clear infection
73
Acute phase reactants
- non-specific markers of inflammation
| - IL-6 from activated macrophages -> synthesis, primarily in liver
74
C-reactive protein
- acute phase reactant
| - marker for acute MI and and other causes of inflammation
75
Fibrinogen
- acute phase reactant
- makes erythrocytes stick together -> form stacks, fall to bottom of test tube
- erythrocyte sedimentation rate - increase ESR= more fibrinogen= more inflammation
76
Serum amyloid protein
- acute phase reactant
| - brings HDL to macrphages for metabolism (if high, then high macrophage activity)
77
leukocytosis
- elevated WBC (primarily leukocytes) in peripheral blood due to increased release from bone marrow
- if inflammation severe, may get left shift- presence of immature WBC in circulation
- mediated by IL-1 and TNF-a from macrophages
- occasionally see leukopenia
78
Acute phase reaction
- increased pulse, increased BP, sweating, rigor, chills, fever, anorexia, somnolence, and malaise
- accompany acute inflammatory response and increased acute phase reactants in blood
79
sepsis
- clinical syndrome w/ overwhelming bacterial infection or release of bacterial toxins into blood
- mediated by certain cytokines (TNF, IL-1)
- characterized by tachycardia, fever or hypothermia, hyperventilation, and leukocytosis or leukopenia
80
anaphylaxis
- type 1 hypersensitivity allergic reaction to foods, insect, stings, drugs, latex, etc
- IgE receptor cross linking on mast cells -> degranulation -> increased histamine -> vasodilation (rash, redness, edema) and bronchoconstriction (respiratory distress)
- medical emergency-epinephrine to bronchodilate and regulate heartbeat
81
Complement deficiencies
- C3-> increased susceptibility to infection
| - defective MAC formation -> unable to clear Neisseria infection
82
paroxysmal nocturnal hemoglobinuria
- complement inhibitor deficiency
- gene mutation controlling complement activation
- recurrent complement mediate intravascular hemolysis -> chronic hemolytic anemia
83
hereditary angioneurotic edema
- complement inhibitor deficiency
- C1 inhibitor deficiency
- skin edema, edema of mucosa of larynx and GI tract
- provoked by emotional stress or trauma
84
-a1-antitrypsin deficiency
- complement inhibitor deficiency
- antiprotease in tissues-major inhibitor of neutrophil elastase and others
- proteases damage tissues-lung-panacinar emphysema- and liver-cholestatic hepatitis-cirrhosis
- genetic, autosomal recessive mutation in protease inhibitor gene
85
block histamine
- allergic diseases-asthma, allergic rhinitis
- cromolyn sodium-block histamine release
- loratadine-block histamine receptor
86
Block arachidonic acid metabolism
- steroids-autoimmune ds, transplantation, asthma
- acetaminophen, NSAIDs-lots
- COX-2 inhibitors (Vioxx, celebrex, bextra)-arthritis
87
Block effect of TNF
infliximab, etanercept-autoimmune disease (crohns, rheumatoid arthritis)
88
block angiogenesis (VEG-F)
bevacizumab-solid tumors (metastatic colorectal cancer, lung cancer)
89
block effect of leukotrienes
zafirlukast, montelucast-asthma
90
prostaglandins
- from membrane phospholipids
- vasodilation, pain, fever
- potentiate other mediators
91
leukotriene B4
- from leukocytes
| - chemotaxis, leukocyte adhesion, activation
92
Leukotriene C4, D4, E4
- from leukocytes, mast cells
- vascular leakage
- bronchoconstriction
