Lec2-3 Acute and Chronic Inflammation Flashcards Preview

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Flashcards in Lec2-3 Acute and Chronic Inflammation Deck (113):
1

Inflammation basics

- ubiquitous, fast, non-specific rxn of vascularized tissue to local injury
- functions:
--- defend and stop aggression
--- clean up [phagocytosis]
--- repair

2

Characteristics of acute inflammation

- interstitial edema
- accumulation neutrophils

3

3 major steps of acute inflammation

- alteration vascular caliber to increase blood flow

- structural change in microvasculature so plasma proteins and neutrophils can leave circulation

- emigration of neutrophils from microcirculation and accumulation in injury site

4

5 Classic signs of inflammation

Present in acute inflammation
- heat [calor]
- redness [rubor]
- edema [tumor
- pain [dolor]
- loss of function

5

Characteristics of chronic inflammation

- presence of mononuclear cells
--- lymphocytes, plasma cells, macrophages

- admixed with granulation tissue

6

Cause of acute inflammation

- microbial infection
- physical agents
- chemicals
- necrotic tissue
- immunologic reactions

7

4 Vascular events in acute inflammation

- brief vasoconstriction then vasodilation --> increase blood flow
- increased vascular permeability
- interstitial edema
- vascular stasis and congestion

8

vascular permeability in acute inflammation

endothelial cells become leaky from direct cell injury or via chemical mediators
- get escape protein rich fluid into interstitium
- inflammation associated edema

9

Endothelial cell contraction

- gap between cells due to endothelial contraction
- common in venules
- fast process, short-lived
- due to vasoactive mediators [histamine, leukotrienes]

10

Vasodilation or vasoconstriction in acute inflammation

immediately vasoconstriction then vasodilation which leads to greater blood flow to area
- leads to redness [rubor] and heat [calor]

11

Exudation

fluid, proteins, RBCs and WBCs leave intravascular space because of high extravascular - due to osmotic P (∏i) or high hydrostatic P intravascularly [Pc]

12

Vascular stasis

slowing of blood in bloodstream, along with vasodilation and fluid exudation allows chemical mediators and inflammatory cells to collect and respond to stimulus

13

Endothelial cell retraction

- delayed response, long lived
- cytoskeletal and junctional reorganization
- due to cytokine mediators: IL-1, TNF

14

4 Mech of increase endothelial permeability

- endothelial cell contraction
- endothelial cell retraction
- direct endothelial injury
- neutrophil-mediated endothelial injury

15

Direct endothelial injury

- endothelial cell necrosis and detachment
- occurs in severe necrotizing injuries [toxins, burns, chemicals]
- occurs in venules, capillaries, arterioles
- causes immediate and long term leakage

16

Neutrophil-mediated endothelial injury

- mostly in venules, pulmonary capillaries
- due to neutrophil aggregation, adhesion, and emigration across endothelium
--- release ROS and proteolytic enzymes
--- endothelial injury / detachment --> more permeability
- late response, long-lived

17

3 Steps extravasation

extravasation = leukocytes going to site of injury
1. rolling and adhesion of leukoctyes in lumen
2. transmigration across endothelium
3. Migration through interstitial tissue toward chemotactic stimulus

18

Selectins

- surface molecules that share similar carbohydrate binding domain
- bind sialyl Lewis-X glycoprotein on cells
- allow attachment and rolling of neutrophils
- stimulated by histamine + cytokine to present on cell surface

19

3 Types of selectins

P-selectin: platelets, endothelial cells

E-selectin: endothelial cells

L-selectin: leukocytes

20

Integrins

- expressed in cytokine stimulated endothelial cells
- affinity of integrins increased by chemokines
--- allows firm adhesion of neutrophil to endothelial surface

21

PECAM

Platelet endothelial cell adhesion molecule
- involved in migration

22

Diapedesis

Movement of neutrophils through intracellular junctions into interstitium

23

Neutrophil chemotaxis

- neutrophils migrate along gradient of chemotactic agents in interstitial space
- chemotactic agents bind receptors on neutrophils and produce secondary messengers
---leads to assembly of contractile elements that allows the cell to move via extension of pseudopods

24

4 Neutrophil chemotactic agents

- bacterial products
- complement fragments [C5a]
- arachidonic acid metabolites [leukotriene B4]
- chemokines [IL-8]

25

What does neutrophil do once it reaches site?

- phagocytosis of offending agent
- release lysosomal contents and free radicals to interstitium --> chemical tissue destruction

26

Steps of phagocytosis

- recognition and attachment
---opsonins coat antigens and enhance recognition
------ Fc of IgG and C3b of complement

- engulf phagocytosed particule
--- form phagosome
--- lysosome fuses with phagosome, form phagolysosome

27

Neutrophil oxygen dependent bactericidal mech

- triggered by activation nicotinamine-adenine dinucleotide phosphatase
--- reduces O2 --> O2- --> H2O2
- myeloperoxidase [MPO] from lysosomal granule converts H2O2 --> HOCL- which kills bacteria

28

Neutrophil oxygen independent bactericidal mech

- kill bacteria directly by releasing bactericidal permeability-increasesing-proteins, lysozyme, lactoferrin, major basic protein [MBP], eosinophils, argenine-rich defensins
- killed organisms degraded by hydrolases + other lysosomal enzymes

29

myeloperoxidase

MPO
- from lysosomal granules
- converts H2O2 + Cl- --> HOCL- which is very bactericidal
- part of oxygen dependent mech

30

Neutrophil induced tissue injury

during phagocytosis neutrophils release products into phagolysosomes but also into extracellular space
- lysosomal enzymes
- free radicals
- products of arachidonic metabolism [prostaglandins and leukotrienes]

amplifies effects of initial inflammatory stimulus

31

Macrophages in inflammation

clean up everything, migrate away, restore normality of area

32

Purulent

exudate with prominent neutrophils

33

suppurative

purulent exudate plus tissue necrosis

34

abscess

localized collection of pus [tissue necrosis]

35

fibrinous

exudate that has fibrin due to proteins leaking from vessels with increased permeability and activation of coagulation cascade

36

ulcer

defect on surface of organ or tissue secondary to sloughing off of inflamed necrotic tissue

37

4 Possible outcomes of acute inflammation

- complete resolution: restoration to normal
- abscess formation: particularly in infections
- healing by fibrosis [connective tissue replacement] and scarring
- progression to chronic inflammation

38

Histamine

- mostly from mast cells plus basophils + platelets
- prefomed
- one of first mediators of inflammatory response
- causes vasodilation and increased vascular permeability

39

Cell derived mediators of inflammation [2 main types]

preformed mediators secreted in granules
-- vasoactive amines [histamine, serotonin]
-- lysosomal enzymes

newly synthesized mediators
-- arachidonic acid metabolites
------ cyclooxygenases [prostaglandins + thromboxanes]
------lipoxygenases [leukotrienes + lipoxins]
-- platelet activating factor
-- activated oxygen species
-- nitric oxide
-- cytokines

40

Serotonin

Preformed, in platelets

41

What causes mast cells to release histamine

- physical agents [trauma/heat]
- immunologic rxns of binding IgE Ab to mast cell
- complement fragments C3a, C5a [anaphylatoxin]
- neuropeptide [substance P]
- cytokines [IL1-8, IL8]
- histamine releasing factors from leukocytes

42

Functions of Prostaglandin I2?

Prostacyclin
- vasodilates, inhibits platelet aggregation

43

Functions of Prostaglandin E2?

Hyperalgesic [makes skin hypersensitive to pain] , vasodilates

44

Functions of Thromboxane A2?

vasoconstrictor, promotes platelet aggregation

45

Functions of Leukotrienes C4, D4, E4?

Increase vascular permeability, vasoconstrictor

46

Functions of leukotriene B4?

powerful chemotactic agent
by leukocytes

47

Functions of Lipoxin?

Endogenous negative regulators of leukotrienes, inhibit neutrophil chemotaxis, cause vasodilation

48

Inhibitors of cyclooxygenase?

aspirin

49

What are cyclooxygenases?

prostaglandins + thromboxanes

50

Platelet activating factor

- phospholipid-derived
- from mast cells [and other leukocytes + EC]
- Stimulated by IgE mediated rxns
- function: platelet aggregation, broncoconstriction, vasodilation, increase vascular permeability, leukocyte adhesion, chemotaxis

51

5 Major categories of cytokines

1. Regulators of lymphocyte function
2. inflammatory cytokines = involved in immunity
3. Activate inflammatory cells
4. Chemokines
5. Cytokines that stimulate hepatopoiesis

52

What are cytokines?

- proteins that modulate function of other cell types
- Can act on multiple cell types
- Can be multifunctional with opposing actions
- Bind specific receptors on target cells

53

3 [2 do the same thing] Cytokines that regulate lymphocyte function

IL2 and IL4: favor lymphocyte growth and differentiation

IL1 and transforming growth factor: neg regulation of immune

54

Inflammatory cytokines

TNF-alpha, IL-beta
Type 1 interferons [IFN-a and b]
IL6

55

Cytokines that activate inflammatory cells

IFN-gamma, TFN-a, IL-5, IL10, IL12

56

Chemokines

chemotactic activity for leukocytes
IL-8

57

Cytokines that stimulate hematopoiesis

mediate immature leukoctye growth and differentiation
- Il3, Il7, GM-CSF, macrophage-CSF, granulocyte-CSP, stem cell factor

58

IL-1 and TNF

- major inflammatory cytokines
- act on: endothelium, leukocytes, induction of systemic rxns to acute inflammation
- produced in macrophages

59

What stimulates secretion of IL-F and TNF

Macrophages secrete them when:
- endotoxin, immune complexes, toxins, physical injury

60

Cachexia

wasting syndrome
- due to overproduction TNF-alpha
- characterized by weight loss and anorexia

61

Endothelial cell activation by ILF-1/TNF

stimulate:
- Induction adhesion molec and chemical mediators
- production of enzymes associated with matrix remodeling

62

Hemodynamic effects of septic shock produced by IL-1 and TNF

hypotension
decreased vascular resistance
high HR
low blood pH

63

Acute inflammation responses by IL-1 and TNF

- fever, loss of appetite, production sleep
- release neutrophils into circulation, release adrenocorticotropic hormone + corticosteroids

64

3 systems of plasma derived mediators of inflammation

3 interrelated systems
- complement system
- kinin system
- clotting factor [Hageman factor] system

65

Hageman Factor

Hageman factor = clotting factor XII
- activated by: neg charge substances on cell surface, bacterial lipopolysaccharides
- initiates kinin, clotting, fibrinolytic and complement cascades
- Has chemotactic activity
- Causes neutrophil aggregation

66

Complement components with inflammatory activity

- C3a and C5a: increase vascular permeability
- C3b/C3bi: opsonin
- C5b-9: membrane attack complex

67

Functon of C3a in inflammation?

an anaphylatoxin, increase vascular permeability

68

Function of C5a in inflammation?

An anaphylatoxin, increase vascular permeability, highly chemotactic to most leukocytes

69

Function of C3b and C3bi in inflammation?

opsonin - aid phagocytosis

70

Function of C5b-9 in inflammation?

- Form membrane attack complex
- lyse cells, stimulate arachidonic acid metabolism, produce ROS by leukocytes

71

Kinin system

- generates bradykinin = vasoactive protein
- regulates BP, smooth muscle relaxation/contraction, cell migration, inflammatory cell activation

72

Bradykinin

- vasoactive protein of kinin system
- formed from plasma kininogens via enzyme kallikrein
- blood vessel dilator, increases vascular permeability, causes pain

73

What does Kallikrein do?

- enzyme in kinin system
- forms bradykinin from plasma kininogens
- part of autocatalytic loop = activator of hagemen factor so amplifies the effect

74

Intrinsic clotting pathway

- series of plasma proenzymes that can be activated by hageman factor
- activation of thrombin
- cleavage of fibrin, generation of fibrin clot
- forms fibrinopeptides

75

Thrombin

- Activated from prothrombin by factor Xa
- Increases leukocyte adhesion to endothelium

76

Fibrinopeptides

- Formed in rxn fibrinogen --> fibrin activated by thrombin
- induce vascular permeability
- Chemotactic for leukocytes

77

Chronic inflammation

inflammation of wks or months, active inflammation, tissue destruction and attempts at healing all proceeding simultaneously

78

3 main causes of chronic inflammation

- progression of acute inflammation
- repeated bouts of acute inflammation
- low grade response does not follow classic acute inflammation [most common]

79

How does acute inflammation lead to chronic inflammation?

- persistent stimulus
- abnormality in healing

80

3 Major cause of chronic inflammation?

- low-grade response does not follow classic acute inflammation
--- persistent infection by intracellular microbes of low toxicity [TB, viral]

-- prolonged exposure to toxic endogeneous or exogenous substances [ silica and silicosis, plasma lipid and atherosclerosis]

-- immune rxns against own tissue [autoimmune]

81

3 Characteristics chronic inflammation

- tissue infiltration by mononuclear cells
--- macrophages, lymphocytes, plasma cells
- tissue destruction
--- induced by inflammatory cells
- attempts at repair
--- connective tissue replacement, angiogenesis, fibrosis

82

Lymphocyte

- Single nucleus fills most of cell, looks like stand-alone nucleus

83

Plasma cell

- Produces Abs against foreign Ag or altered tissue component
- Clock face nucleus with adjacent halo pale area from large golgi

84

Macrophage

Synonyms: histiocyte, kupffer cell
- from peripheral blood monocytes
- activated by cytokines [interferon gamma, T cells], endotoxins
- secrete toxic substances [ex ROS]
- cause influx other cells [macro + lymphocytes]
- cause fibroblast proliferation + colllagen deposition
- phagocytosis

85

Mast cell

- found in connective tissue
- express receptors that bind Fc portion of IgE
- in acute response: Ag recognition --> histamine release
--- part of anaphylactic rxn to allergens
- some parasite infections also increase IgE and mast cell activation

86

Eosinophil

- immune rxn mediated by IgE and parasites
- recruitment of eotaxin [a chemokine]
- granules contain major basic protein [MBP] that is toxic to parasites and epithelial cells

87

Factors secreted by macrophages

- neutral proteases
- chemotactic factors
- arachidonic acid metabolites
- ROS
- complement components
- coagulatin factors
- growth factors
- cytokines [IL-1 and TNF]
- others [PAF and alpha-IFN]

88

Granulomatous inflammation

characterized by
- collections of epithelioid macrophages surrounded by collar of mononuclear leukocytes [mostly lymphocyte, some plasma]
- central necrosis may be present

2 types: foregin body, immune

Occurs in TB, sarcoid, leprosy

89

Epithelioid macrophage

activated macrophage that has epithelial like appearance

90

Immune Granuloma

Formed by T-cell mediated rxn to Ag that are hard to degrade
- prototype = TB

May have central necrosis [necrotizing granuloma]
- caseous necrosis

91

Foreign body granuloma

Caused by inert foreign bodies
ex. suture granulomas

92

3 Outcomes of chronic inflammation

- resolution/regeneration to normal
--- requires removal toxic agent, cells able to regenerate, intact stromal frame
- reapire/organization/healing by connective tissue/fibrosis/scarring
- idenfinitely occuring [ex. rheumatoid arthritis]

93

Requirements for chronic inflammation to resolve to normal

- removal toxic agent
- cells able to regenerate
- intact stromal framework

94

How to tell acute vs chronic inflammation [time frame, cell types, pathogenesis, cause, outcomes, treatments]

time frame: acute = short, chronic = long

components: acute = neutrophils, chronic = lymphocytes + macrophages

pathogenesis: acute = vasodilation + vascular permeability, chronic = cytokines/chemokines attract lymphocytes + neovascularization

cause: acute = infection or burn, chronic = prolonged exposure to toxic agent

outcomes: acute = resolution or abscess or scarring or become chronic, chronic = regeneration or scar formation or resolution

95

What should you look for in histology of tissue undergoing repair?

- granulation tissue
- brining in fibroblasts to form scar

96

What should you look for in histology of tissue undergoing regeneration?

- mitotic figures
- hyperplasia

97

Granulation tissue is a sign of what?

repair
- composed of proliferating capillaries + cells [fibroblasts, macrophages, etc] within loose connective tissue

98

What is etiology of rheumatoid arthritis?

AA amyloids from precursor SAA protein

99

What histologically shows you there is cirrhosis of the liver?

presence of fibrous septa that subdivide parenchyma into disorganized regenerating nodules

100

If you see liver nodules, think what condition?

cirrhosis!

101

predominant cell type in acute inflammation

neutrophils

102

3 chemotactic agents for neutrophils

- leukotriene B4
- C5a/C3a
- cytokines [IL-8]

103

2 chemical mediators of systemic acute phase response

TNF-alpha
IL-1

104

What stimulates selectins?

histamine and cytokines

105

What 2 cytokine mediators induce endothelial cell retraction?

IL-1
TNF

106

Is endothelial cell contraction or retraction longer liver? Which happens first?

endothelial cell contract is first
endothelial cell retract lasts longer

107

Among the 4 mechanisms of increased vascular permeability, which are short/long lived and which are immediate/delayed?

neutrophil mediated endothelial injury: late, long lived
direct endothelial injury: immediate, long term
endothelial cell contraction: immediate, short lived
endothelial cell retraction: late, long liveed

108

What are the functions of IL-1 and TNF

- systemic acute phase response

109

Where does endothelial contraction usually occur?

venules

110

What produces leukotrienes?

lots of cells?

111

Where does neutrophil mediated endothelial injury occur?

mostly in venules, pulmonary capillaries

112

What is a function of IL-2 and IL-4?

favor lymphocyte growth and differentiation

113

What cytokine is associated with cachexia?

TNF-alpha