Week 1 Inflammation Flashcards Preview

Pathophysiology > Week 1 Inflammation > Flashcards

Flashcards in Week 1 Inflammation Deck (42):
1

Blood cells involved in inflammation

Neutrophils, Eosinophils, Basophils, Monocytes, Lymphocytes, Platelets,

ENDOTHELIAL cells, basement membrane, and Smooth Muscle cells.

2

Connective tissue cells involved in inflammation

Mast cells, Fibroblasts, Macrophages, Lymphocytes

3

Plasma proteins involved in inflammation

Coagulation proteins, Kinins, Fibrinolytic enzymes

4

Duration and main characteristics of Acute Inflammation

1 week max.
Edema fro increased blood flow and vascular permeability, exudate.
Leukocyte emigration to site of inflammation

Rubor, Tumor, Calor, Dolor
Redness, Swelling, Heat, Pain
Loss of function

5

What are the advantages of exudation to a wound site?

Dilution of toxins
Increased protein content --> Increased Immunoglobulin

6

What are the advantages of exudation to a wound site?

Dilution of toxins

Increased protein content -->
-Increased Immunoglobulin
-Fibrin nets, fixing bacteria and wound healing
-Acute phase proteins

7

What are 4 methods of vascular leakage

Endothelial cell contraction in small venules - histamine, bradykinin, leucotrienes.
Occurs rapidly and is short lived.

Junctional retraction - IL-1, TNFa, IFNy
-delayed effect after 4-6 hours.

Leokocyte-dependent leakage
- leukocyte-produced proteolytic enzymes and free radical increase permeability

Leakage from regenerating/damaged capillaries
-increased leakage as angiogenesis occurs and vessels aren't sealed tightly.

8

Stages and mediators of extravasation

1) Rolling. P-selectins bind endothelial glycoproteins
P-Selectin on leukocytes --- P-selectin glycoprotein ligand-1 on Endothelial cells

VLA-4 also

2) Slow rolling. Shorter, higher affinity E-selectins bind glycoproteins
E-Selectins

3) Slow rolling allows for chemokine signaling to increase as they move through the inflamed region

4) Firm Adhesion. Leukocyte Integrins bind endothelial GAGs on endothelial Cell Adhesion Molecules (glycoproteins).
VLA1 ---- VCAM1
(Very Late Antigen 1)
LFA1 ---- ICAM1
(Leukocyte Function-associated Antigen 1)

5) Extravasaion/Diapdesis
Also involves cell adhesion molecules and integrins: LFA1, VCAM1, ICAM1, ICAM2

9

Exogenous substrates (from pathogens) that activate leukocytes

PAMPs and DAMPs, bound by C-type lectins, and TLRs TLR1, 2, 4, 5, 6, which can be Endosomal or Cell Surface receptors



Pathogenic associated molecular patternsm, PAMPs:

From GrPos bact: G+ cell wall peptidoglycan, lipoteichoic acid

From GrNeg bact: LPS

From either: Flagellin, N-formylmethionine, hypometheylated CpG-DNA, free single or double stranded DNA or RNA



Damage associated molecular patterns, DAMPs:

Components of cells that should be intracellular but are encountered by the macrophages in the environment (from lysed/dead cells)

Nuclear proteins

Mitochondrial DNA

Oxygen radicals

Heat shock proteins

10

What are endogenous substrates that activate leukocytes?

IL-8

Lipoxygenase productes LTB4

Complement proteins C5a, C3a

11

What is the receptor expressed on phagocytes that binds opsonized microbes and induces phagocytosis?

What is its ligand?

Receptor: Fc-gamma receptors FcyRs

Ligand: C3b and Fc-fragment of IgG in complex

12

What are the two pathways of that can initiate phagocytosis?

Opsonin mediated pathway: binding opsonized, antibody bound microbes

Nonspecific pathway: PAMPs

13

What are the stages of phagocytosis?

What are the two major pathways used to kill target microbes?

1) Recognition and binding
binding PAMPS or opsonized antibody complexes

2) Englufment
Surrounding, Fusion of phaocytic and lysosomal granules onto the target microbe membrane

3) Killing
Oxygen dependent:
NAPDH oxidase --> Superoxide ion --> H2O2
MPO --> H2O2 + Cl- --> HOCl
NO synthase --> Peroxinitrite

Oxygen indepdendent
lysozymes
lactoferrin
MBP, Major basic protein
Defensins - pore forming proteins
Acid hydrolase

14

What are some types of Acquired Defects in leukocyte functions? ie, what can disrupt chemotaxis, phagocytosis, microbe killing ability

Burns, Malignancy, Sepsis, AIDS --> disrupt chemotaxis

Hemodialysis --> disrupts leukocyte adhesion

Leukemia, Anemia, Sepsis, Malnutrition, and Neonatal period --> disrupts phagocytosis and microbiocidal ability

Diabetes --> disrupts chemotaxis, adhesion, phagocytosis and killing ability

15

What major inflammatory cytokines initiate the Acute Phase Reaction?

What other major event do these cytokines initiate?

IL-1
IL-6
TNFa

Stimulate Fever, by activating the hypothalamic regions responsible for inducing fever.

16

What is the Acute Phase Response? (APR)

What can stimulate it?

The changes in protein expression primarily caused by altered expression in the liver, induced by inflammatory cytokines that are released from innate immune cells.

Stimulated by:
Trauma/Injury, Infection, Stress, Neoplasia, or Inflammation

17

What are the Acute Phase Proteins? (APPs)

CRP: 100-1000x
C1 inhibitor: 6-8x
Antitrypsin: 2-4x
Fibrinogen: 2-4x
Complement protein C3 and Factor B: 1.5-2x
MBL: Mannose Binding Lectin, activates Lectin pathway of complement system along with MASP
Protease inhibitors
Ceruloplasmin - Scavenges ROS radicals


Negative acute phase protein:
Transferrin: decreases to limit available iron, which is used by bacteria
Albumin
Antithrombin

18

What is the function of CRP?

It binds to lysophosphatidylcholine (a phosphatidy-choline with one of its FA tails hydrolyzed off)

This is found on dead/dying cells and on some bacteria

CRP binds the lysophosphatidylcholine, and also binds and activates the C1 complement protein complex, allowing it to activate the classical pathway of the complement system (active C1 generates C4bC2b C3-convertase)

19

What are the 3 major Plasma Protease systems?

Kinin system

Thrombotic/Fibrinolytic system

Complement system

20

What are the functions of 1) Bradykinin and 2) Kallinkrein?

Bradykinin:
Arteriole Dilation
Increases Venule permeability
Causes pain in nociceptors

Kallinkrein:
Activates plasminogen --> plasmin
Activates C1q

21

What are the effects of fever?
What is the beneficial range and pathologic range?
What is the major factor that induces fever?

38-38.5 beneficial

>39 needs to be brought down.

Bacteria have a narrow temperature optimum, fever may disrupt this
Fever also increases reaction rates, increases immune reactions

IL-6 predominantly generates fever (IL-1 and TNFa to a lesser degree)

22

What are the effects of fever?

What is the beneficial range and pathologic range?

What is the major factor that induces fever?

38-38.5 beneficial

>39 needs to be brought down.

Bacteria have a narrow temperature optimum, fever may disrupt this
Fever also increases reaction rates, increases immune reactions.

Each 1 degree C increases Heart rate by 10 bpm.

High temperatures also disrupt body protein function, major organ functions.

IL-6 predominantly generates fever (IL-1 and TNFa to a lesser degree)

23

What is Hageman Factor?

Coagulation factor XII (12)

Activates Intrinsic Pathway of coagulation (contact of blood with foreign object in blood, other pathway is the TF pathway/extrinsic pathway)

XIIa --> activates XI,
XIa --> activates IX
IXa, VIIa, plus X generates IXa, VIIa, Xa ten-ase complex.



1) Activates Intrinsic Coagulation pathway

2) Activates Kallikrein, which also activates Bradykinin

3) Converts Plasminogen to Plasmin

4) Plasmin can also activate complement proteins C3 and C5 to C3b and C5b.

24

What are major effects of Plasmin?

Digests fibrin, and causes vasodilation by generating FDP (fibrin degradation products)
Activates complement system C3 -> C3b

25

Activators of plasminogen?

tPA
uPA

Streptokinase
Trypsin
Macrophage plasminogen activator
Hageman factor (Factor XII)

26

What results from complement C3 deficiency?

Recurring life threatening infections with encapsulated microbes.

27

What results from C1-Inhibitor deficiency?

What are the targets of C1-inhibitor

HANO, Hereditary Angioneurotic Oedema
aka, HAE. Physical signs of HAE include overt, noninflammatory swelling of the skin and mucous membranes

C1-inhibitor blocks:
C1 activation
Kallekrien activation --> Bradykinin activation and vasodilation

28

What results from C1, C2, C4 deficiency?

SLE autoimmune disease
Systemic lupus erythematosus

29

DAF deficiency

DAF = Decay accellerating factor (paradoxycally named), protects red blood cells from degradation by the complement system.
Paroxysmal nocturnal hemoglobinuria
RBC hemolysis

DAF is an inhibitor of C2->C2a conversion and C3 convertase: inhibits membrane attack complex formation

30

Factors that cause vasodilation:

Factors that increase vascular permeability:

Vasodilation:
Histamine, Prostaglandins

Permeability:
C3a, C5a
Bradykinin
Leukotrienes,
PAF (platelet activating factor)
Vasoactive Amines

31

Chemotactic mediators

IL-8, C5a, Leukotriene B4, Lipids, Bacterial products

32

Fever inducers

IL-6,
IL-1, TNFa, Prostaglandin E2

33

Pain mediators

Prostaglandins, Bradykinin

34

Mediators of tissue injury during inflamation

Macrophage lysosomal enymes
ROS

35

Anti-inflammatory mediators

IL-4, IL-10, TGF-beta

36

Hypothalamic factors involved in inflammation

CRH,
Vassopressin

37

Factors that induce granulocyte apoptosis

TNFa, IL-10, Prostaglandins

38

What simultaneous processes are occuring during chronic inflammation?

What are some characteristics of chronically inflammed tissue?

Tissue destruction from inflammatory processes, and simultanous tissue regeneration and healing processes.

Results in:
Infiltration with mononuclear cells, lymphocytes and macrophages
Granuloma accumulation
Tissue destruction
Fibrosis
Angiogensis
Epethlioid cell formation - activated macrophages that resemble epithelial cells
Giant cell formation

39

Causes of chronic inflammation?

Chronic infection
Prolonged exposure to toxin
Autoimmune reactions

40

Phases of wound healing (4)

Coagulation
Inflammation
Fibroplasia/ epethelisation, fibrous ECM re-deposited, angiogenesis, epethilial regrowth over top.
Remodeling - wound retraction fibroblast deposition, equilibrium is reached between ECM synthesis and degradation

41

2 Types of abnormal wound healing

Excessive wound healing:
Hypertrophic scar - excessive dermal collagen, doesn't extend beyond wound borders into unwounded skin. Will often gradually subside.
Keloid scar - Unknown etiology. Overgrows the original wound and produces collagen in a pseudotumour fasion. Normal fibrobglast numbers but drastically excesses collagen production, exceeding collagenase ability.

Inadequate wound healing
Larger than normal scar, chronic unstable wound

42

Factors that affect wound healing

Anatomic location and amount of blood supply. - Fastest in face and neck

Weight
- Adipose tissue heals slowly due to poor blood supply

Age
-Slows with age

Oxygen
-Wound PO2 affects it, hyperbaric O2 chambers can accelerate it

Infections
-Local or systemic infections slow it.

Medications
-Chemo, Steroids slow it.

Nutritional status

Type of wound,
Contusion, abrasion, lacerations, clean or jagged, etc.

Chronic diseases,
Diabetes or cirrhosis slow it.

Smoking causes vasoconstriction
slows it

Radiation therapy
Causes stasis and vessel occlusion

Hydration
- Moist wounds heal faster

Growth factors
endogenous or exogenous can accelerate it