ABSITE ch 13 cytokines and inflammation

1. Factors released by platelets that lead to PMN and macrophage recruitment after
injury

TGFbeta, PDGF

2. Cell type instrumental in wound healing that release TGFbeta and PDGF, IL-1 and
TNFalpha

Macrophages

3. Factors released by endothelium after injury

Platelet-activating factor, tissue factor

4. Growth factor that is chemotactic, activating for macrophages, PMNs and

fibroblasts. Overproduction can cause fibrosis

TGF beta

5. Growth factor that is chemotactic for PMNs, macrophages and fibroblasts. Has
been shown to accelerate wound healing

PDGF

6. Growth factors that are chemotactic for fibroblasts, though less potent than TGF
beta (2)

EGF, FGF

7. Chemotactic factors for inflammatory cells (7)

TGF beta, PDGF, IL-8, LTB-4, C5a and C3a, PAF

8. Chemotactic factors for fibroblasts (4)

TGF beta, PDGF, EGF, FGF

9. Angiogenic factors (6)

TGF beta, EGF, FGF, TGF alpha, IL-8, hypoxia

10. Epithelialization factors (5)

TGF beta, PDGF, EGF, FGF, TGF alpha

11. Length of time PMNs last in tissues

1-2d

12. length of time platelets last in tissues

7-10d

13. primary cell type in Type I hypersensitivity reactions

eosinophils

14. factor released by eosinophils, causing basophils and mast cells to release
histamine

major basic protein

15. functions of histamine (3)

vasodilation, tissue edema, postcapillary leakage

16. functions of bradykinin (4)

vasodilation, increased permeability, pain, contraction of pulmonary arterioles

17. molecule that activates guanylate cyclase and increases cGMP, resulting in
vascular smooth muscle dilation

NO

18. Hormone that causes vascular smooth muscle constriction

Endothelin

19. Cytokine produced largely by macrophages, a procoagulant, and causes cachexia

in cancer patients

TNF alpha
20. Cytokine that activates PMNs and macrophages, causes fever, hypothermia,
tachycardia

TNF alpha

21. Cytokine produced largely by macrophages, responsible for fever, increases IL-6

IL-1

22. Cytokine that increases hepatic acute phase proteins

IL-6

23. Cytokines released by lymphocytes in response to viral infection; activate

macrophages, NK cells and cytotoxic T cells to inhibit viral replication

Interferons

24. Cell adhesion molecules on leukocytes that bind ICAMs

Beta-2 integrins

25. Cytokines that mediate early loos adhesion, or cell "rolling" for PMN activation

Selectins

26. Complement pathway activated by antigen-antibody complexes

Classic pathway

27. Complement factors found only in the classic pathway (3)

C1, C2, C4

28. Complement pathway activated by endotoxin, bacteria

Alternative pathway

29. Complement factors found only in alternative pathway

B, D, and P

30. Complement factor common to both classic and alternative pathway, and is the
convergence for the two
 C3

31. Anaphylatoxins that increase vascular permeability and activate mast cells and
basophils

C3a, C4a, C5a

32. Membrane attack complex components

C5b-C9

33. Complement factor that is important for opsonization

C3b

34. Complement factor important for chemotaxis

C3a, C5a

35. Prostaglandins for vasodilation, bronchodilation, increased permeability, and

platelet inhibition

PGI2, PGE2

36. Prostaglandin for vasodilation, bronchoconstriction, and increased permeability

PGD2

37. Drugs that inhibit cyclooxygenases reversibly

NSAIDS

38. Drug that inhibits cyclooxygenases irreversibly, and inhibit platelet adhesion by
decreasing TXA2

aspirin

39. drugs that inhibit phospholipase, which convert phospholipids to arachadonic acid

steroids

40. slow reacting substances of anaphylaxis that cause bronchoconstriction,

vasoconstriction followed by increased permeability
 leukotrienes LTC4, LTD4, LTE4

41. chemotactic leukotriene

LTB4

42. Peak catecholamine response after injury

24-48 hours

43. neural response to injury

epi and norepi release

44. origin of norepinephrine release after injury

sympathetic postganglionic neurons

45. origin of epinephrine release after injury

adrenal medulla

46. factors released as neuroendocrine response to injury

CRF, ACTH, ADH, Growth hormone

47. Role of CXC chemokines (3)

Chemotaxis, angiogenesis, wound healing

48. Oxidants generated in inflammation (5)

Superoxide anion, hydrogen peroxide, hydroxyl radical, hypochlorous acid,

chloramines

49. Primary mediator of reperfusion injury

PMNs

50. Defect in PMN NADPH-oxidase system resulting in decreased superoxide radical

formation

Chronic granulomatous disease

1. Inflammation phases:
o Injury-
o leads to exposed collagen, platelet-activating factor release, tissue factor
release from endothelium.

o Platelets bind-
o release important growth factors (platelet-derived growth factor PDGF)
and cytokines (IL-1 and TNF-alpha)

o Macrophages-
o dominant role in wound healing, release important growth factors
(PDGF) and cytokines (IL-1 and TNF-alpha)
2. See image on pg 60 (and commentary below)

Establishment of a provisional wound matrix:

o 1) platelets bind to the exposed wound matrix through interaction of

beta-1 and beta-3 integrins and collagen, laminin, and fibronectin
receptors
o 2) after wounding, the coagulation cascade is activated, generating
thrombin, which activates platelet glycoprotein gpIIb/IIIa and increases
platelet aggregation.
o 3) A provisional wound matrix is formed, made up of platelets, fibrin,
fibrinogen, and fibronectin. The activated platelets in the wound
generate transforming growth factor beta (TGF-beta), PDGF, and
thrombin.
o 4) TGF-beta is strongly chemotactic for neutrophils, macrophages, and
fibrobrasts, recruiting these cells into the provisional wound matrix,
where they are also subsequently activated by TGF-beta.
o 5) Increasting concentrations of TGF-beta results in macrophage
activation, producing increased amounts of tumor necrosis factor-alpha
(TGF-alpha) and interleukin-1 (IL-1). TGF-beta also stimulates
fibroblast production of extracellular matrix proteins. These reactions
further enhance migration of macrophages and fibroblasts into the
wound, facilitating repair.
3. Growth and Activating Factors (on following slides)
4. PDGF
o 1) similar effects as TGF-beta
 o 2) chemotactic and activates inflammatory cells (PMN and
macrophages)
o 3) chemotactic and activates fibroblasts --> collagen and ECM proteins
o 4) angiogenesis
o 5) epithelialization
o 6) chemotactic for smooth muscle cells
o 7) has been shown to accelerate wound healing
5. EGF (epidermal growth factor)
o 1) acts on similar receptors as TGF-beta
o 2) less potent
o 3) chemotactic and activates fibroblasts --> collagen and ECM proteins
o 4) angiogenesis- V-EGF stimulates angiogenesis and is involved in
tumor metastasis
o 5) epithelialization
6. FGF (fibroblast growth factor)
o 1) chemotactic and activates fibroblasts --> collagen and ECM proteins
o 2) angiogenesis
o 3) epithelialization
7. PAF (platelet-activating factor)
o 1) not stored
o 2) generated by phospholipase in endothelium and other cells
o 3) stimulates many types of inflammatory cells chemotactic; increases
adhesion molecules
8. Chemotactic factors:
For inflammatory cells:
For fibroblasts:
o For inflammatory cells:
o 1- TGF-beta
o 2- PDGF
o 3- PAF
o 4- IL-8
o 5- LTB-4
o 6- C5a and C3a

oFor Fibroblasts:
o 1- TGF-beta
o 2- PDGF
o 3- EGF
o 4- FGF
9. Angiogenesis factors:
 o 1) TGF-alpha
o 2) TGF-beta
o 3) EGF
o 4) FGF
o 5) IL-8
o 6) hypoxia
10. Epithelialization factors:
o 1) TGF-alpha
o 2) TGF-beta
o 3) EGF
o 4) FGF
o 5) PDGF
11. How long do PMNs stay in tissues? How long in blood?

last 1-2 days in tissues (7 days in blood)

12. How long do platelets last?

platelets last 7-10 days

13. Lymphocytes

1) involved in chronic inflammation (T cells) and antibody production (B-cells)

14. Cell Types in Type I hypersensitivity reactions: (following slides)

15. Eosinophils
o 1) have IgE receptors that bind to allergen
o 2) release major basic protein, which stimulates basophils and mast cells
to release histamine
o 3) eosinophils increased in parasitic infections
16. Basophils
o 1) have IgE receptor
o 2) main source of histamine in blood
o 3) not found in tissues
17. Mast cells
o 1) primary cell type in type I hypersensitivity reactions
o 2) main source of histamine in tissues other than stomach
o
18. Histamine
o 1) vasodilation
o 2) tissue edema
o 3) postcapillary leakage
 o 4) primary effectors in type I hypersensitivity reactions (allergic
reactions)
19. Bradykinin
o 1) vasodilation
o 2) increased permeability
o 3) pain
o 4) contraction of pulmonary arterioles
20. Angiotensin-converting enzyme (ACE)

inactivates bradykinin

21. Nitric Oxide

o 1) has arginine precursor
o 2) Activates guanylate cyclase and increases cGMP, resulting in vascular
smooth muscle dilation
o 3) is also called endothelium-derived relaxing factor (EDRF)
22. Endothelin

vascular smooth muscle constriction

23. Important Cytokines (to follow)

24. What are the main initial cyokines involved in injury/infection:

TNF-alpha and IL-1

25. TNF-alpha (tumor necrosis factor-alpha)

o 1) macrophages- largest producers of TNF
o 2) increases adhesion molecules
o 3) overall, a procoagulant
o 4) causes cachexia in patients with cancer
o 5) activates neutrophils and macrophages--> more cytokine production,
cell recruitment
o 6) can cause myocardial depression
o 7) fever, hypothermia, tachycardia, increased cardiac output, decreased
SVRI --> high concentration can cause circulatory collapse and
multisystem organ failure
26. IL-1
o 1) main source also macrophages
o 2) effects similar to TNF and synergizes TNF
o 3) Responsible for fever (PGE2 mediated in hypothalamus)
o 1- raises thermal set point, causing fever
o 2- NSAIDs- decrease fever, reducing PGE2 synthesis
 o 4) alveolar macrophages- cause fever with atelectasis by releasing IL-1
o 5) IL-1 also increases IL-6 production
27. IL-6
o 1) increased hepatic acute phase proteins (C-reactive protein, amyloid
A)
o 2) lymphocyte activation
28. Interferons
o 1) released by lymphocytes in response to viral infection or other
stimulants
o 2) activate macrophages, natural killer cells, and cytotoxic T cells
o 3) inhibit viral replication
29. Hepatic acute phase response proteins
o 1) IL-6 is most postent stimulus
o 2) Increased:
o 1- C-reactive protein (an opsonin, activates complement)
o 2- amyloid A and P
o 3- fibrinogen
o 4- haptoglobin
o 5- ceruloplasmin
o 6- alpha-1 antitrypsin
o 7- alpha-1 antichymotrypsin
o 8- C3 (complement)
o 3) Decreased:
o 1- albumin
o 2- transferrin
30. Cell Adhesion Molecules (upcomming slides)
31. Selectins

L-selectins, located on leukocytes, bind to E- (endothelial) and P-(platelets)

selectins; rolling adhesion

32. Beta-2 integrins -

Beta-2 integrins (CD11/18 molecules)- on leukocytes, bind ICAMS etc.

anchoring adhesion

33. ICAM, VCAM, PECAM, ELCAM

on endothelial cells, bind beta-2 integrin molecules located on leukocytes and

platelets. These are also involved in transendothelial migration

34. Image at bottom of pg 62: Leukocyte recruitement

 o 1) circulating leukocytes express integrins in a low-affinity conformation
o 2) exposure to activated endothelium leads to rolling, which is mediated
by L-selectin and P-selectin on the neutrophil and E-selectin on the
endothelium
o 3) leukocye exposure to cytokines released by macrophages
phagocytosing pathogens induces a high affinity integrin conformation.
Tight leukocyte-endothelial adhesion involves integrin engagement with
counter-ligand expressed on endothelium
o 4) subsequent exposure to chemokines leads to diapedesis, which is
further mediated by the family of beta-1 and beta-2 integrins
35. Complement:
o Classic pathway (IgG or IgM)- antigen-antibody complex activates
o 1- factors C1, C2, and C4- foudn only in the classic pathway

o Alternative pathway- endotoxin, bacteria, other stimuli activate

o 1- factors B, D, and P (properdine) found only in the alternate pathway

C3- common to and is the convergence point for both pathways

Mg- required for both pathways

o Anaphylatoxins- C3a, C4a, C5a;

o 1- increases vascular permeability
o 2- smooth muscle contraction (bronchi)
o 3- activate mast cells and basophils
36. Image on pg 63: Complement pathways:
o Alternative pathway:
o 1) C3 is cleaved to C3b
o 2) C3b binds and cleaves B to Bb to form C3 convertase (C3bBb)
o 3) another C3b binds C3 convertase to form C5 convertase (C3bBbC3b)

o Classical pathway:
o 1) C1 binds immunoglobulin
o 2) C1 binds and cleaves C4 and C2 to C4b and C2a to form C3
convertase (C4b2a)
o 3) C4b2a binds another C3b to generate C5 convertase (C4b2aC3b)
 o Late pathway:
o 1) C5 convertase cleaves C5 to form C5b, which integrates into the
plasmalemma
o 2) C6-8 are recruited forming the C5b-8 complex
o 3) C5b-8 recruits numerous C9 subunits, which form a pore in the
pathogen cell wall
37. Prostaglandins (following slides)
38. PGI2 and PGE2
o 1) vasodilation
o 2) bronchodilation
o 3) increased permeability
o 4) inhibit platelets
39. PGD2
o 1) vasocilation
o 2) bronchoconstriction
o 3) increased permeability
40. NSAIDS:

1) inhibit cyclooxygenase (reversible)

41. Aspirin
o 1) inhibits cyclooxygenase (irreversible)
o 2) inhibits platelet adhesion by decreasing TXA2
42. Steroids:

inhibit phospholipase, which converts phospholipids to arachidonic acid-->

inhibits inflammation

43. Leukotrienes:
LTC4, LTD4, LTE4-
LTB4-

LTC4, LTD4, LTE4- slow reacting substances of anaphylaxis;

bronchocontriction, vasoconstriction followed by increased permeability
(wheal and flare)

LTB4- chemotactic

44. Picture on Pg 64: Eicosanoid production

45. Catecholamines (following slides)
46. When do catecholamines peak after injury?

24-48 hours

47. Where are norepinephrine and epinephrine released from?

1) norepinephrine released from sympathetic postganglionic neurons

2) epinephrine and norepinephrine released from adrenal medulla (neural

response to injury)

48. Neuroendocrine responses to injury:

o Afferent nerves from site of injury stimulate:
o 1- CRF
o 2- ACTH
o 3- ADH
o 4- growth hormone
o 5- epinephrine
o 6- norepinephrine release
49. What role does thyroid hormone play in injury:

thyroid hormone does not play a major role in injury

50. CXC chemokines:

o 1) Chemotaxis, angiogenesis, wound healing
o 2) IL-8 and platelet factor 4 are CXC chemokines
o 3) C=cysteine X--> another amino acid
51. Pg 65 (see two figures): oxidants generated in inflammation and Cellular Defenses
against antioxidants
52. What are the RBC antioxidant properties:

RBCs have some antioxidant properties (superoxide dismutase and catalase)

53. Reperfusion injury: whats the primary mediator?

PMNs are the primary mediator

54. Chronic granulomatous disease:

o 1) NADPH-oxidase system enzyme defect in PMNs
o 2) results in decreased superoxide radical (O2-) formation