Inflammation - patho 4

What does inflammation do?

1. neutralize or destroy offending agents

2. restrict tissue damage to the smallest possible area

3. alerts body to threat or tissue

4. prepares injured area for healing

trauma, surgery, infection, caustic chemicals, extremes of heat or cold, immune responses, ischemic damage

all can cause what?

INFLAMATION

inflammation was read as “shement” which means what?

hot thing

what cells are involved in inflammation?

1. fibroblasts

2. macrophages

3. neutrophils

4. mast cells

5. platelets

which type of inflammation involves

• hemodynamic changes (change in blood flow)

• exudate formation (mass of cells seeping out of blood vessels)

• presence of granular leukocytes (mast cells, neutrophils)

acute inflammation

which type of inflammation involves

• presence of nongranular leukocytes (t cell, b cell, monocytes)

• extensive scarring

chronic inflammation

first responder in tissues?

first responder in blood?

tissue = resident macrophages

blood = neutrophils (PMN)

SEQ: phases of inflamation

1. innate (macrophages, neutrophils, mast cells) and adaptive (th cells, b cells) immunity cells

2. release of inflammatory mediators (histamines, chemokines, complement proteins)

3. chemotaxis — immune cells migrate towards signals of mediators

4. wound repair (remove cell debris+ release of growth factors—stimulate cell migration and proliferation with tissue repair and formation of new blood cells )

Different pathways to inflammation:

1. direct stimulation of monocyte/macrophages, neutrophils, mast cells or complement by components of microorganisms (_____________) or cell debris ( __________)

2. Synthesis of ______

   • activates mast cells and basophils

3. direct activation (degranulation) of __________ cells

4. synthesis of _____ and/or ______ (complement activation)

5. recognition of Ag/MHC complexes by ______ cells which release cytokines

1. PAMPS (pathogen-associated molecular patterns)

2. DAMPS (damage-associated molecular patterns)

3. mast

4. IgM and IgG

5. helper t cells

what are mast cells in relation to basophils?

mast cell - in tissue

basophil- in blood

MHC 1 is recognized by which t cell?

what about MHC 2?

MHC 1 = cytotoxic T = CD8

MHC 2 = helper T cells = CD4

which MHC is presented on a cell with internal damage?

which MHC is presented on cells with damage caused by its surroundings?

• MHC 1 = self

• MHC 2 = non-self

what do Th1 cells signal? what about Th2 cells?

Th1 — cytotoxic t

Th2 —b cells

these types of receptors bind microbial components such as double stranded RNA (viral) and bacterial liposaccarides using monocytes and other cells to release inflammatory cytokines

Toll like receptors

bind bacterial peptidoglycan fragments and activate NF-kB signaling causing cytokine release

NOD like receptors

what activates the blood clotting and/or complement cascade?

Lipopolysaccharide (LPS) and Teichoic Acids

what are the main characteristics of acute inflammation?

• exudation of fluid and plasma proteins (cells spewing out of blood)

• emigration of leukocytes (mostly neutrophils)

what are the five CARDINAL signs of acute inflammation

1. heat

2. redness

3. swelling

4. pain

5. loss of function

heat is caused by which physiological response(s)?

• increased blood flow

• elevated cellular metabolism

redness is caused by which physiological response(s)?

• vasodilation

• increased blood flow

swelling is caused by which physiological response(s)?

• vasodilation

• extravasation of fluid (permeability)

• cellular influx (chemotaxis)

• elevated cellular metabolism

pain is caused by which physiological response(s)?

• release of inflamation mediators

• cellular influx (chemotaxis)

• elevated cellular metabolism)

match term with symptom

• calor

• rubor

• tumor

• dolor

• heat

• redness

• swelling

• pain

Triple response:

• 3-50 seconds: a thin red line appears due to what?

• 30-60 seconds: flush — what happens?

• 1-5 minutes: wheal — what happens?

• thin red line = vasodilation of CAPILARIES

• flush = vasodilation of ARTEOLIES

• increased vascular permeability, edema

SEQ cellular response:

1. Margination and pavement of white blood cells (white blood cells move towards blood vessel walls)

2. Rolling: white blood cells roll alongside the cell wall

3. Adhesion: white blood cells adhere to adhesion molecules on the cell wall

4. Diapedeis: white blood cells leave blood vessels and come into tissues

5. Chemotaxis: neutrophils attack chemotaxis signals sent by resident macrophages

6. Phagocytosis: neutrophils engulf microbes

How do nuetrophil extracellular traps (NETs) work?

neutrophils spill their guts and trap microbe

what are the 5 types of exudates (what can seep out of cell due to inflammation)?

1. serous (plasma)

2. fibrinous (fibrin)

3. purulent (puss)

4. hemorrhagic (blood)

5. catarrhal (mucus)

what helps to shut down the inflammatory response?

interleukins (IL-10, 6, 35, lipids, proteins

what is an abscess?

enclosed infection (puss filled lump)

Inflammation Outcome Resolution:

• infarction, bacterial infections, toxins, and trauma can lead to acute inflammation. what occurs during acute inflammation?

• when acute inflammation progresses angiogenesis, mononuclear cells infiltrate, and fibrosis (scarring) occurs due to ____________________

• what happens during the resolution of acute inflammation?

• what happens during the healing process of chronic inflammation or abscess (pus formation)?

• vascular changes, neutrophil recruitment, mediators

• chronic inflamation

• clearance of injurious stimulus, mediators, and acute inflammatory cells. injured cells are replaced.

• fibrosis

SEQ: first responders of inflammation

1. mast cells in tissues degranulate

2. resident macrophages eat microbes

3. neutrophils in blood respond through chemotaxis to histamines released by mast cells

4. neutrophils and complements get out of the blood through (migration, rolling, adhesion, diapedesis, chemotaxis, phagocytosis)

5. wound repair (M1 macrophage to M2, anti-inflammatory complements)

what is opsonization?

coating of foreign material to identify what to attack

what are compliment proteins capable of?

where do they come from?

how are they activated?

• opsonization (mark for macrophage to eat)

• microbe lysis (form pores)

• enhance inflammation

compliment proteins come from the liver and travel through the bloodstream

compliment proteins activated through CASCADES by interacting with each other

what are the three different compliment pathways? whcih was the first to be discovered?

1. classical (innate) FIRST DISCOVERED

2. lectin

3. alternative

persistent antigen, accumulation of antigen-processing cells and tissue destruction are all major features of…

CHRONIC inflammation

Acute Inflammation:

• initiators: _________ surfaces and fragments. _________ tissue and tissue fragments. (EASY TO DIGEST)

• mediators: _______ cell products (histamine), Bradykinin, ROI, ____________ lysosomal components, lipid mediators, _______________

• cell populations: ___________ and ______________

• time course:

• outcome: resolution, ________ formation, ____________ inflammation

• microbial

• mast, complement, cytokines

• macrophages and neutrophils

• seconds - days

• abscess, chronic

Chronic Inflammation:

• Initiators: _____-________ organisms and foreign matter and autoimmune reactions

• Mediators: ____- cell and macrophage products: __________, ______ ________, proteases, ROI, _________, lipid mediators

• Cell Populations (4) :

• time course:

• outcome:

• non-digestible

• t, cytokines, growth factors, complements

• t-cells, plasma cells, macrophages, fibroblasts

• weeks - years

• tissue destruction + fibrosis

when macrophages are activated in the tissues they can either cause tissue injury to foreign materials (inflammatory) or fibrosis (anti-inflammatory)

what does the macrophage secrete that causes TISSUE INJURY?

1. toxic oxygen metabolites

2. proteases

3. neutrophil chemotactic factor

4. coagulation factors

5. AA metabolites

6. Nitric oxide (apoptosis/ activate t cell)

when macrophages are activated in the tissues they can either cause tissue injury to foreign materials (inflammatory) or fibrosis (anti-inflammatory)

what does the macrophage secrete that causes FIBROSIS?

1. growth factors

2. fibrogenic cytokines

3. angiogenesis factors

4. remodeling collagenisis

what are the two types of chronic inflammation?

1. nonspecific chronic inflammation

2. Granulomatous

Nonspecific chronic Inflammation: Diffuse accumulation of macrophages and lymphocytes at iinjury site.

What are the 3 sources of these macrophages?

1. recruitment (chemokines)

2. local proliferation

3. prolonged survival (from embryo)

how are granulomas formed?

Granulomas are a deposition of antigenic material, what type of hypersensitivity are they?

mass macrophages and leukocytes surrounding foreign bodies

4

what are the preformed mediators in secretory granules?

where are they sourced?

histamines and steroids

mast cells, basophils, platelets

where can prostaglandins be found?

all leukocytes + mast cells

where can leukotrienes be found?

all leukocytes + mast cells

where can platelet activating factors be found?

all leukocytes AND epithelial cells

where can reactive oxygen species be found?

all leukocytes

where can nitric oxide be found?

macrophages AND endothelial cells

where can cytokines be found?

• macrophages, lymphocytes, mast cells, endothelial cells

where can neuropeptides be found?

leukocytes and nerve fibers

Where do the complement activation factors and factor XII activation originate?

liver

which complements are involved in complement activation?

C3a and C5a (anaphylatoxins)

C3b

C5b-9 (membrane attack complex)

mediators of factor XII (Hageman factor) activation include:

Kirin system (bradykinin)

coagulation/ fibrinolysis system

what are the early compliment proteins involved in the CLASSICAL pathway ?

• C1q

• C1r

• C1s

• C4

• C2

what are the early compliment proteins involved in the ALTERNATIVE pathway ?

C3

B

D

Properdin

what are the early compliment proteins involved in the LECTIN pathway ?

• MBL/ficolin

• MASP-2

• C4

• C2

All of the early compliment proteins have the shared goal to do what? (MAIN EXPANSION POINT on surface of the cell)

C3 —> C3a and C3b

the main expansion point is the conversion of C3 to C3a and C3b. what is the difference between the two?

C3a: enhance inflammation

C3b: lysis of cell / membrane attack complex

how are compliments activated? give an example?

compliments are activated when they are CLEAVED

ex. C3 activated once its cleaved into C3a and C3b

which activated compliments act as peptide mediators of inflammation and recruit phagocytes?

C3a and C5a

which activated compliment binds to complement receptors on phagocytes and opsonizes pathogens and removes immune complexes?

C3b

what are the terminal complement components and what do they do?

C5b, C6, C7, C8, C9

lysis of pathogens and cells using the membrane- attack complex

what do neutrophils secrete (7)

1. LTs

2. proteases

3. Thromboxane A2

4. Prostaglandin E2

5. Reactive Oxygen Species

6. hydrolases

7. myeloperoxidase

what do monocytes secrete? (15)

1. Reactive Oxygen Species

2. Reactive Nitrogen Intermediates

3. Leukocytes

4. IL1

5. IL4

6. IL10

7. IL6

8. TNF-a (tumor necrosis factor)

9. CSFs (colony stimulating factor)

10. a-interferon

11. g-interferon

12. complement components

13. coagulation factor X

14. Prostaglandin E2

15. Chemokines

What to T-helper cells secrete? (4)

1. interleukins (depending on if its Th1, 2, 17 or reg)

2. g-interferon

3. colony stimulating factor

4. lymphotoxin

what do cytotoxic t cells secrete (6)?

• lymphotoxin

• perforins

• granzymes

• interferon gama

• IL2

• IL12

what do b cells secrete?

Interleukins

immunoglobulins

interferon-gamma

what is the role of eosinophils?

control mediators released by mast cells

what do mast cells secrete? (what are on their granules when they are created)

1. histamine

2. seretonin — vasoconstriction

3. serine protease

thromboxane

prostaglandin D2

leukotriene

C4

platelet-activating factor

are all __________________

newly formed lipid mediators

___________ are inflamatory mediators released by mast cells which cause

• airway constriction

• dilation of small blood cells

• increased permeability of post-capilary venules

• secretion of mucus by nasal mucosa

histamines

are the following anti or pro inflammatory mediators?

• lipotoxins

• prostoglandins

• resolvins, protectins, maresins

• IL1ra, IL4, IL6, IL10, IL13, Transforming growth factor b

antiinflammatory

Tissue healing can be done by first or second intentions.

what occurs during first intention healing?

• minimal tissue loss

• no or minimal granulation tissue formation

Tissue healing can be done by first or second intentions.

what occurs during second intention healing?

• significant tissue loss

• granulation tissue

• slow healing

• scar tissue

SEQ scar formation

1. fibroblast and vascular endothelial cell migration

2. proliferation of fibroblasts and small blood vessels— granulation tissue (fibroblasts divide rapidly)

3. Maturation of collagen fibers

what are the major PRO inflammatory cytokines?

which cells are most likely to produce them?

• IL1

• IL6

• TNFa (tumor necrosis factor alpha)

produced by macrophages and Th cells

what are pyrogens?

fever producing substances

what is the differece between the endogenous and exogenous pyrogens?

exogenous = bacterial products (endotoxin)

endogenous = leukocyte products (TNFa, IL1, PGE2)