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MOD - 2 - Cells: Adaptation, Injury, and Death > Pathoma - Ch. 3 - Acute Inflammation > Flashcards

Pathoma - Ch. 3 - Acute Inflammation Flashcards

1
Q

what is the hallmark difference between acute and chronic inflammation?

A

actue - neutrophil heavy

chronic - lymphocyte heavy

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2
Q

what is acute inflammation characterized by?

A

edema and neutrophils in tissue

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3
Q

explain this picture

A

indicative of acute inflammation

note blood vessels on bottom corners; note the neutrophils; and note all the empty space in between the blood vessels and in the general area; that is edema

so edema and neutrophils : acute

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4
Q

what are the two stimuli that inflammation arises in response to?

what is the goal?

A
  • infection
  • necrosis
    goal: to eliminate pathogen or clear necrotic debris
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5
Q

know that acute inflammation is an Immediate response with limited specifity

A

* innate immunity

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6
Q

what is acute inflammation mediated by?

A

.

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7
Q

describe TLRs

A
  • present on cells of innate immune systems (macrophages and dendritic cells)
  • recognize PAMPs
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8
Q

what is an example of TLR?

A

CD14

  • present on macrophages

on macrophages that recgonizes the LPS on the outer membrane of Gram neg bacteria

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9
Q

what does activated TLR result in?

A

the upregulation of NF-kB;

this NFkB is like a switch, and it goes on to activate other immune response genes

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10
Q

describe Arachidonic Acid

A
  • released from phospholipid cell membrane by phospholipase A2
  • acted on by cyclooxygenase or 5-lipooxygenase
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11
Q

what happens when arachidonic acid is acted on by cyclooxygenase?

A

it produces PG (prostaglandins)

  • PGI2, PGD2, PGE2, (together) mediate vasodilation (at the level of arterial) AND Increased vascular permeability (specifically, at the post-capillary venule)
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12
Q

what does PGE2 also mediate?

A

fever and pain

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13
Q

what happens when arachidonic acid interacts with 5-lipooxygenase?

A

produces leukotrienes (LT)

  • LTB4

LTC4

LTD4

LTE4

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14
Q

*randomly: what 4 mediators attract and activate neutrophils?

A

-LTB4,

C5a,

IL-8,

and bacterial products

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15
Q

what do the 4 leukotrienes do?

A

LTB4: attract and activate neutrophils

LTC4, LTD4, LTE4: mediate vasoconstriction, bronchospasm, and increased vascular permeability

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16
Q

in general, what do LTs do?

A

contract smooth muscle

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17
Q

what 3 things activate mast cells?

A
  • tissue trauma
  • complement proteins: C3a and C5a
  • cross-linking of cell-surface IgE by antigen
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18
Q

what is the immediate response to mast cell activation?

A

**release of preformed histamine granules

- two primary fxs of histamine: vasodilation of arterioles and Increased vascular permeability (at the level of the post capillary venule)

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19
Q

what is the delayed response when a mast cell is activated?

A

production of arachidonic acid metabolites, particularly leukotrienes

  • this is for the maintenance of the mast-cell response
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20
Q

what is the compliment system?

A
  • proimflammatory serum proteins
  • circulate as inactive precursors
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21
Q

what are the 3 ways to activate the complement system?

A
  • classic pathway: C1 binds to IgG or IgM that is bound to the antigen
  • alternative pathway: microbial products directly activate complement
  • mannose-binding lectin pathway: MBL binds mannose on microorganisms and activates complement
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22
Q

what are the key products of complement system activation and what do they do?

A
  • C3a and C5a: trigger mast cell degranulation
  • C5a: chemotactic for neutrophils
  • C3b: opsonin for phagocytosis
  • MAC: lyses microbes by creating holes in the cell membrane
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23
Q

what is the Hagemen factor?

A
  • inactive proinflammatory protein produced in the liver
  • activated upon exposure to subendothelial or tissue collage

*plays a big role in DIC, esp. gram negative sepsis

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24
Q

what is the reaon hagemen factor plays an important role in DIC (disseminated intravascular coagulation)?

A

HF in turn activates:

  • coagulation and fribrinolytic system
  • complement
  • and kinin system: cleaves HMWK to bradykinin, which mediates vasodilation, incr vascular permeability and pain
25
Q

what is the only difference between histamine and bradykinin?

A

they both mediate vasodilation and incr vascular permeability

  • but bk mediates pain
26
Q

what mediates pain?

A

PGE2 and bradykinin

27
Q

***what are the cardinal signs of inflammation?

A

rubor (redness) and calor (warmth)

swelling (tumor)

pain (dolor)

fever

28
Q

what mediates the redness of the tissue?

what are the key mediators?

A
  • due to vasodilation, which results in incr blood flow (occurs via relaxation of arteriolar smooth m.)
  • key mediators: histamine, PGs, and bradykinin

*warmth is mediated by the exact same info*

29
Q

define swelling and its mediators

A
  • due to leakage of fluid from postcapillary venules into interstitial space
  • mediators: histamine and tissue damage
30
Q

what mediates pain and how?

A

bradykinin and PGE2 by sensitizing sensory nerve endings

31
Q

how is fever caused?

A
  • pyrogens cause macrophages to release IL-1 and TNF
  • they make their way in the blood to the perivascular cells of the hypothalamus, and increase COX (cyclooxigenase) activity
  • COX leads to incease in production of PGE2, which raises the temp set point

*high yield*

32
Q

—-VIDEO 2: NETROPHIL—-

A

three step process to inflammation (acute)

3 waves; fluid, neutrophil, macrophages

n-phase peaks at 24 hours:

m-phaseL peaks at 2-3 days

33
Q

what happens in order for margination to occur?

A

neutrophils, being bigger components within the blood stream, ride the wave in the center due to lamilar flow;

when vasodilation occurs, they are allowed to go to the edges of the blood vessel = margination

34
Q

desribe Step 1 - Margination

A
  • vasodilation slows blood flow in postcapillary venules
  • cells migrate from center to periphery of flow
35
Q

describe Step 2 - Rolling

A
  • endothelial cells begin to express Selectins (aka speed bumps), causing neutrophil to slow down
  • P-selectin is released from Weibel-Palade bodies (small bodies in the endothelial cells); mediated by histamine

- E-selectin: Induced by TNF and IL-1

36
Q

What do selectins bind?

A
  • bind sialyl Lewis X on leukocytes (specifically neutrophils, but also macrophages, wbc, etc.)
  • interaction results in rolling of leukocytes
37
Q

describe Step 3 - Adhesion

A
  • Cellular Adhesion Molecules (CAMs) are upregulated on endothelium by TNF and IL-1
  • INTEGRINS upregulated on leukocytes by C5a and LTB4
  • interaction results in firm adhesion to vessel wall
38
Q

describe Lukocyte Adhesion Deficiency

and its clinical findings/ features (v important)

A
  • AR defect of integrins (CD18 subunit)

CFs: delayed separation of the umbilical cord (this is cuz leukocytes help clean up necrotic tissue; and if there is a delay, it indicates that leukocytes never migrated)

    • Incr circulating neutrophils* (marginated pool is not present, cuz theyre circulating due to lack of integrin)
    • recurrent bacterial Infections that lack pus formation*
39
Q

why does it lack pus formation?

A

cuz pus is a pool of dead neutrophils. since they cant migrate, then no pool

40
Q

Step 4 - Transmigration and Chemotaxis

A
  • leukocytes transmigrate across endothelium of postcapillary venules
  • (Neutrophils) move towards chemical attractants: bacterial products, C5a, IL-8, LTB4
41
Q

step 5 - phagocytosis

A

consumption of pathogens or necrotic tissue

  • enhanced by IgG and C3b (opsonins)
42
Q

how does phagocytosis occur in this instance?

A
  • pseudopods from leukocytes extend to form phagosomes
  • internalize stuff and merge it with lysosomes to form phagolysosomes
43
Q

what is a defect that impairs the formation of phagolysosome?

A

Chediak-Higashi syndrome

  • protein trafficking defect (microtubules)
  • AR
  • characterized by impaired phagolysosome formation
44
Q

what are the clinical features of Chediak-Higashi syndrome?

A
  • incr risk of pyogenic infections (cuz phasgosome cant be desrtoyed)
  • neutropenia (because division cannot be pulled apart due to microtubule defect)
  • giant granules in leukocytes (cuz when the granules get made, they cant get sent nowhere, so they build up)
  • defective primary hemostasis
  • albinism (melanocyte produces melanin, then hands it off to surrounding cells; since it cant be moved along the railroad -microtubules-, it cant be distributed)
  • peripheral neuropathy
45
Q

Step 6 - destruction of phagocytosed material

A

occurs in 2 ways:

oxygen-dependent >>> oxygen-independent

46
Q

how does the oxygen dependent fashion occur?

A

O2 gets acted upon by NADPH-oxidase and turns it to SuperOxide (O2-)

then SOD (super-oxide dismutase) acts on O2- and converts it into hydrogen peroxide (H2O2)

then H2O2 is acted on by myeloperoxidase (MPO) and will be converted to bleach (HOCl)

*HOCl then destroys organism*

high yield card

47
Q

what does HOCl do?

A

destroys phagocytosed microbes in phagolysosomes

48
Q

what is chronic granulomatous disease?

A

you get poor O2-dependent killing

  • due to NADPH-oxidase defect

- X-linked or AR

pt gets granuloma diseases often

49
Q

what particular organisms cause infection and granuloma formation in these pts with a defect in NADPH-oxidase?

A

catalase-positive organisms

S Aureus

P cepacia

S marcescens

Nocardia

Aspergillus

50
Q

why is it that catalase-positive organisms cause problems?

A

remember the pathway to make the bleach (HOCl-):

O2 to O2- via NADPH-oxidase

O2- to H2O2 via SOD

then H202 to HOCl- via MPO

  • So, you need hydrogen-peroxide (H2O2) to make the bleach. patients who lack NADPH-oxidase typically do not have a problem with other organism because bacteria within our body actually provide H2O2 as one of their byproducts. thus, we have bleach to destroy phagolysosomes

but!! some bacteria ALSO produce catalase, which destroys H2O2 (the same H2O2 the bact produce).

so if both these pathways get knocked out, no bleach.

51
Q

how do you screen for CGD?

A

nitroblue tetrazolium test

  • turns blue if NADPH-oxidase can convert O2 to O2-
  • remains colorless if NADPH-oxidase is defective
52
Q

whats with MPO deficiency?

A

results in defective conversion of H2O2 to HOCl-

  • increased risk for Candida Infections; most pts are actually asymptomatic
  • NBT test is normal
53
Q

describe the O2-independent killing

A
  • less effective
  • occurs via enzymes present in leukocyte secondary granules (lysozyme and major basic proteins)
54
Q

step 7 - resolution

A
  • netrophils undergo apoptosis
  • disappear within 24 hours after resulotion of inflammatory stimulus
55
Q

what predominates after the neutrophil phase?

A

the macrophage phase

  • peaks 2-3 after inflammation begins
56
Q

where do the macrophages come from?

A
  • derived from monocytes in the blood
  • arrive the same way neutrophils do: margination, rolling, adhesion, and transmigration sequence
57
Q

what do macrophages do once in their proper location?

A

ingest via phagocytosis

destroy phagocytosed material using enzymes in secondary granules (lysozyme)

(predominantly O2-independent)

58
Q

what other roles do macrophages have?

A

they are managers: they determine the next step of the acute inflammatory response:

  • resolution and healing (via IL-10 and TGF-Beta - both of which are anti-inflammatory)
  • continued acute inflammation (if shits not good, and need more neutrophils, it send the signal aka IL-8)
  • Abscess (can create fibrous pocket)
  • chronic inflammation
59
Q
A

MOD - 2 - Cells: Adaptation, Injury, and Death (10 decks)

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