6. Acute Inflammation II Flashcards
Left: In order to have inflammation > stimulus (microbe, necrotic tissue, etc.); in order to initiate inflammatory response: recognize the stimulus (the sentinel cells are responsible [____, and ____]); then, recruitment of cells (in acute: mostly ____); then, removal/elimination of microbes; then, ____ of inflammatory cells (regulated because when neutrophils enter, they release mediators that kill microbes but also cause tissue damage), and lastly repair of the tissue
Middle, top: without inflammation a wound doesn’t heal properly
Right, top: pregnancy gingivitis > when someone is pregnant they are more sensitive to the presence of ____; can be a good or bad thing; necrotic tissue with inflammation surrounding it, and the inflammation responds in order to remove the dead tissue
Right, bottom: freezer burn, inflammation responds in order to heal it
All of these phrases to describe middle bottom > ____: inflamed tissue (red); erythematous: same as hyperemia; edematous: lots of fluid; and tender
mast cells
macrophages
neutrophils
regulation
bacteria
hyperemia
Left, top: inflammatory response to peanuts, this swelling is not protective > potentially lethal because it is activated inappropriately
Left, bottom: infected appendix > ruptured colon (if inflammation is produce in an ____ inflammation can be lethal); and meningitis > ____
Middle: periapical abscess > can spread ____ giving ____ thrombosis and can spread south giving ____ (appendicitis migrates ____)
open cavity
closed cavity
north
???
ludwig’s angina
laterally
A > surface of heart pericardium; this is an exudate > ____
B > lung > ____exudate (purulent implies necrotic tissue, but this has no necrotic tissue, so sometimes this is called a “____” exudate)
C > skin > blister > ____ exudate (very light fluid)
D > ____: loss of epithelium
E > bowel mucosa > red material > inflamed > yellowish material sitting on it: ____ exudate
F > abscess (____ exudate contained within a cavity)
fibrinous purulent neutrophilic serous ulcer purulent purulent
Inflammatory (Exudate) Pathogenesis: \_\_\_\_ Status of vessel: \_\_\_\_ Protein in tissue: \_\_\_\_ Tendency to clot: \_\_\_\_ Pain: \_\_\_\_ Inflam. cells: \_\_\_\_ Examples: \_\_\_\_
Non-inflammatory (Transudate) Pathogenesis: \_\_\_\_ Status of vessel: \_\_\_\_ Protein in tissue: \_\_\_\_ Tendency to clot: \_\_\_\_ Pain: \_\_\_\_ Inflam. cells: \_\_\_\_ Examples: \_\_\_\_, \_\_\_\_, \_\_\_\_, \_\_\_\_, \_\_\_\_
loss of vascular barrier increased perm. to proteins yes yes usually present yes/no inflammatory disorders
abnormal fluid dynamics unaltered: retains plasma protein no no usually absent no CHF kwashiorkor cirrhosis cancer elephantiasis
Middle: longitudinal section of BV; showing only protein
Exudate: when fluid and protein are ____
Transudate: fluid in the extravascular tissue but the protein is retained within the ____
Both are edemas, but differ in the location of the protein
Exudate would clot because now ____ are in the EC space
Mediators are produced in exudate so they trigger the ____ > pain
Exudate > ____ exudate will have inflam cells; ____ and ____ will have no inflam cells; transudate > no protein, no cells
CHF = congestive heart failure; kwashiokor: protein ____, and the others result of edema in extravascular tissue, and that edema is transudate
outside
BV
clotting factors inflammatory response purulent serous fibrinous
malnutrition
Transudate: Altered fluid dynamics/Diseases
• Increased Hydrostatic Pressure:
– Disorders with impaired ____ return
– Congestive ____, Deep ____
• Reduced Osmotic Pressure:
– ____ (malnutrition or inadequate synthesis)
– ____, Liver ____
• Lymphatic Obstruction:
– Lymphedema (____)
– Lymphedema (Breast Cancer ____)
– Lymphedema (____)
venous
heart failure
vein thrombosis
albumin
kwahiorkor
cirrhosis
breast cancer
treatment
fibrosis/elephantiasis
Increased Hydrostatic Pressure
Hyperemia (____)
Defintion: Increased ____ within tissue
Etiology: Irritation/Injury (____), Increased ____ (exercise)
Pathogenesis: Arteriolar ____/increased ____ (Active)
Gross appearance: ____
Microscopic appearance: Capillaries/Arterioles ____, Engorged with ____
Congestion (____)
Definition: Increased ____ within tissue
Etiology: ____ failure, ____ Obstruction
Pathogenesis: Impaired outflow from of ____ from tissue (Passive)
Gross appearance: ____
Microscopic appearance: Capillaries/venules ____ with blood, ____ in lung (Left sided HF)
active blood volume inflammation demand dilation blood flow redness/heat dilated blood
passive blood volume cardiac venous venous blood red blue (cyanosis) engorged hemosiderin
Increased HP
Right-sided heart failure > problem with outflow > edema (generalized ____, ____)
Left-sided heart failure > edema would develop in the ____ (____)
Deep venous thrombosis in one leg > localized edema (____)
Depending on where the heart failure is located, and whether or not there is a thrombosis, each of these examples will ensue
Increased hydrostatic pressure > ____
edema
transudate
lung
transudate
transudate
transudate
Increased HP
Middle: normal lung, and BV are tightly packed
Left: pneumonia > fluid accumulate into alveolar space and BV dilate and loss of BV > with time, formation of “____” exudate (purulent)
Left-sided heart failure > fluid w/o any protein (____), and capillaries are engorged and packed with fluid and because they are very thin you may have RBC leaking out which contain ____ > alveolar macrophages containing hemosiderin engulf dead RBC (____ cell)
neutrophilic
transudate
hemosiderin
heart failure
Reduced Osmotic Pressure: Kwashiorkor
- Severe ____ in some poor countries.
- ~25% of children may be affected.
- ____ give rise to general edema.
- Severe cases; weight ~60% of normal but the true weight lost is masked by increased ____.
Not enough protein > the blue is affected > hypoalbuminia (reduced albumin content in plasma) > if this content is reduced, then the three components are impaired > ____ forces fluid out, but not enough ____ to pull fluid back in and fluid accumulates
Weight loss masked by increased edema > if you were to not account for the fluid in their body, the weight loss would be much more than 60%
The fluid is a ____
protein-energy malnutrition (PEM)
hypoalbuminemia
edema
hydrostatic pressure
osmotic pressure
transudate
Reduced Osmotic Pressure: Liver Cirrhosis
- ____: Replacement of normal liver with fibrotic (scar tissue).
- ____ and reduced plasma osmotic pressure.
- Transudate (____)
- Portal ____.
Condition where normal liver tissue is replaced with fibrotic tissue > liver is not functioning properly (____)
Liver makes the ____, and as you destroy the liver you do not make enough albumin > hypoalbumenia > reduced ____
Fluid that accumulates in peritoneum = ____; ascites is a general term that says how there is fluid in ____, this fluid can be either exudate or transudate; if a response of liver > fluid is transudate; if infection in cavity > exudate
cirrhosis
hypoalbuminemia
ascites
hypertension
chronic alcoholism
albumin
osmotic pressure
ascites
peritoneum
Lymphatic Obstruction: Breast cancer
- ____: swelling caused by compromised lymphatic system.
- Obstruction of superficial lymphatics by breast cancer cells.
- Edema of overlying skin
- “____”
If lymphatics do not drain properly > fluid in EV space
How can you have a compromised lymphatic system > breast cancer that is initially localized and then metastasizing by invading the nearby lymph nodes > breast cancer cells will obstruct ____ > cannot drain as much fluid as it normally does
Woman has breast cancer, the redness (orange circle) = ____ > this breast cancer is invading the lymphatics > obstructing resulting in fluid accumulation
lymphedema
peau d’orange
lymphatic nodes
peau d’orange
Lymphatic Obstruction: Resection/Irradiation
• Lymphedema caused by breast cancer treatment:
– ____
– ____
• ____ lymph nodes from other body parts to relieve pain and swelling?
Woman has been treated for breast cancer by resection (removal of breast) or irradiation; if breast is removed > local lymph nodes are removed; if treating by irradiation > destroying the lymphatics
Left breast removed > the ____ can also swell up (due to the transudate) because of lymph node resection (along with breast) or destroyed because of irradiation
resection
irradiation
transplanting
left arm
Lymphatic obstruction: Filariasis/Elephantiasis
If lymphatic becomes ____ inflamed and they become ____ (replace normal lymph node with collagenous tissue) and the normal function is gone; cannot drain fluid and there is fluid accumulation in the EV space
Middle: don’t really need to know this, but if bitten by ____, they transmit a ____ that can enter lymphatic and destroy it (by bringing in macrophages as well, etc.); if fibrosis it takes a long time to occur; and once they’re destroyed you’ll have swelling of the extremities
Can be ____ or ____, depends on what part of body is infected
chronically
fibrosis
mosquito
parasite
unilateral
generalized (both legs)
Mediators of vascular permeability
Mediators as they relate to increased vascular permeability
Mast cells are located close to ____, and they have tons of granules that are released almost ____ following activation
____ mediators, and mediators that come from ____ (cytokines that come later in the inflammation process)
BV
immediately
plasma
macrophages
Mediators can be derived from the cell or from the plasma
The most important mediator released early in inflammation > ____ (can come from ____, some believe it comes from ____, and ____)
Newly synthesized (5-10 mins) mediators are PGs/LTs; they come from ____ and all ____ (macrophages and neutrophils)
Cytokines come from ____, and for acute inflammation they come from ____ and ____, and ____
Plasma-derived mediators
In terms of timing there are ____ (histamines: seconds and minutes) (PHs/LTs overlap in minutes) and cytokines [from macrophages and other listed above] take hours (you need ____ and ____ of genes)
histamine
basophils
plasma cells
mast cells
mast cells
leukocytes
macrophages
endothelial cells
mast cells
lymphocytes
overlap
transcription
translation
Left: skin, langerhans cells within epidermis, within the BV there are T cells, eosinophils and neutrophils, and mast cells are surrounding in the ____ and are in close proximity to ____ and ____ (found in the connective tissue layer of skin [____], not epidermal)
Middle: mast cells: granules are packed with ____
Right: SEM of activated mast cells, as soon as activated the ____ are released and they release their contents > the most important content of the granule: histamine [activated quickly]
dermis
BV
nerve endings
dermis
histamine
granules
How are mast cells activated?
In response to ____ > close to nerve endings (NP)
(NP) > ____ [pain?]
AMP > ____ peptides
____ component (C3a, C5a)
There are different ____ on mast cells for each of these; important ____ because they can sense almost anything that can initiate inflammation
Once mast cell is activated, granules are released, and histamine exits these granules (claritin and benadryl > ____, used for runny nose and allergic diseases)
trauma
substance P
anti-microbial
complement
receptors
sentinels
anti-histamine
Mast Cells
Function of histamine: ____ of arterioles > as a result > the tissue looks ____ and feels ____ because of hyperemia (increased blood flow); it also increases ____ to protein > ____ formation
dilation red warm vascular permeability exudate
Lipid derived mediators
Left: membrane phospholipids, when phospholipases are activated (____) they cleave ____ > resulting in ____ or ____ pathway
Once cyclooxygenase is activated (PGG2 to ____) > in mast cells ____ and ____ > increase vasodilation and increase vascular permeability; ____ initiates, and ____ maintain the effect [after] because histamine is cleaved
Endothelial cells > produce ____ > ____, but also inhibits platelet ____ and ____
Platelets > ____ > causes ____ and promotes platelet ____ (important in wound healing)
A2/C
arachadonic acid
COX
5-lipoxygenase
PGH2 PGD2 PGE2 histamine PGs/LTs
PGI2
vasodilation
activation
aggregation
thromboxin A2
vasoconstriction
aggregation
Lipid mediators
Lipoxygenase pathway > leukotrienes (C4, D4, E4) from ____ > increase vascular ____, but also cause ____ from interaction of mast cells > ____ used for treatment of asthma (involved with the bronchoconstriction)
Leukocytes > neutrophils > ____ > mediator for ____
In order for neutrophils to provide normal function > ____ (produced from neutrophils and platelets) > inhibit ____
Steroids > inhibit ____ and block the entire time; if you have inflammatory reaction, it blocks everything
COX inhibitors > inhibit ____ and any pain ____
HPETE
permeability
bronchoconstriction
leukotriene inhibitors
leukotriene B4
neutrophil chemotaxis
lipoxins
neutrophil adhesion/chemotaxis
phospholipases
COX pathway
production
Plasma derived mediators
Three different sources, but activated by a similar mechanism
3 interrelated systems, one is ____, other is ____, and the last is ____ (most well known)
Normally all three are circulating, and they’re not activated, but during inflammation they are activated, how? > inactive enzyme, and something happens during inflammation that activates it and it works on substrate, and once cleaved you have formation of product > increased vascular permeability in inflammation
Kinin system: Pre-K (____ is produce in liver, when comes into contact with damaged endothelial cells, it converts Pre-K into ____) > substrate = ____, which is already present in blood > converted into ____ > increased vascular permeability and pain (in acute inflammation)
Plasmin > also uses ____, cleaves plasminogen into ____, which works on ____ and once cleaved it forms ____ > increased vascular permeability
Complement > C1-C9 (activated by three different pathways: ____, ____, ____) > converted into ____ > C3/C5 > ____ > activated ____ to increase vascular permeability
kinin
plasmin
complement
factor XII
kallikrein
kininogen
bradykinin
factor XII
plasmin
fibrin
peptides
Ag/Ab
LPS
plasmin
C3 conver
C3a, C5a
mast cells
Cytokines (local inflammation) • Polypeptides produced by \_\_\_, \_\_\_ and \_\_\_ • IL-1, TNF, IL-6 • IL-1 and TNF: (Effect on \_\_\_ cells) • Increased vascular \_\_\_ • Increased expression of \_\_\_ molecules
• Chemokines (CXC and CC)
- –• CXC: ___ (___)
- –• CC: ___ (___)
Cytokines are produced ___ > effect on local inflammation
Formation of TNF, IL-1 (from mast cells, macrophages or endothelial cells) > activate leukocytes to release chemokines
Play a role in increasing vascular permeability pf endothelium later in the process
Chemokines are important for recruitment of neutrophils and monocytes
IL-1
TNF
IL-6
endothelial
permeability
adhesion
IL-8
neutrophils
MCP-1
monocytes
last
Mediators for Retraction: cell-derived (histamine), then PG/LT, then plasma derived and then cytokines [___ (histamine), ___ (PG/LT, plasma) to ___ (cytokines)]
How to increase vascular permeability > receptors for all things are on endothelial cells, and as activated they ___ and pull away from one another, creating space for proteins to go through
Cell injury produced by other mediators (___, ___), can be ___ or ___; after sun-bathing > skin is red > sun has damaged endothelial cells and producing ___, which takes a while > creating increased vascular permeability and redness
seconds
minutes
hours
retract
burns IL-1 rapid long-lasting IL-1
Histamine, PGs, C3a/C5a, Kinins (Cytokines? TNF, IL-1, IL-6): ___
Histamine, PGs, LTs, C3a/C5a, Kinins, cytokines: ___
PGs, Kinins: ___
PGs, Cytokines: ___
C3a/C5a > ___ > ___
Cytokines do not play an important role in ___
vasodilation
increased vascular permeability
pain
fevers
vasodilation
Fever: Acute phase reaction
- Bacterial products (LPS, ___ pyrogen) causes the release of ___ and ___ from leukocytes (___ Pyrogens).
- TNF−α /IL-1 → ___ → AA →___
- In hypothalamus PGE2 → ___
- Reset temperature set point at ___ level
Pyrogen > something that causes fever
exogenous
TNFalpha
IL-1
endogenous
COX
PGE2
NT
higher
Elevated plasma acute phase proteins
- Mostly synthesized in ___ (~100 fold increase)
- C-reactive Proteins (CRP)
- Serum Amyloid A (SAA)
- CRP and SAA activate ___ →Microbe elimination
- Fibrinogen →___
C-reactive protein (CRP) and serum amyloid A (SAA)> synthesized in the liver in response to ___ > production of these proteins are increased 100-fold
CRP/SAA > activate ___ pathway > contribute to elimination of microbe
liver
complement
rouleaux (ESR)
IL6/IL1
complement
Leukocytosis and other Manifestations
- Common in ___ infection
- Increases to ___/mm3
- ___, ___ and ___ cause release from reserve in bone marrow
- Infections cause the release of ___ from Mac/Fibroblasts
- G-CSF causes increased production of ___ in bone barrow
- Increased ___
- ___
- ___
Normal is 4-6,000 mm3
Either increased ___ or increased ___ from BM
___ > don’t feel well; these symptoms are a result of leukocytosis (and systemic inflammation)
bacterial 15,000-20,000 TNF IL-1 IL-6 G-CSF neutrophils
heart rate
shivering/chills
malaise
production
release
malaise
PAMPs and DAMPs
PAMP: ___
DAMP: ___
Mast cells are a sentinel cell, but macrophages are also important sentinel cells > expression of ___ (nine or eleven different types, some present on PM, and some intracellularly) > these receptors bind to ___ that are present on pathogens (EC: ___; IC: ___, ___, and ___)
DAMP > as a result of ___ tissue (not apoptotic tissue, because it doesn’t release anything outside of the cell, releases anti-inflam cytokines); necrotic tissue release danger-signals: ___ that can cleave on EC matrix proteins to generate ___, or activate ___ pathway > C3a/C5a, and there are IC DAMPs > bind ___ > generate ___ > cause inflammation
pathogen-associated molecular pattern
danger-associated molecular pattern
TLR receptors LPS ssRNA ssDNA dsDNA
necrotic proteases EC DAMPs complement TLR IL-1
Inflammasome, IL-1β and Acute Inflammation
Inflammasome complex:
• ___ protein: NLR pyrin domain- containing-3 (NLRP3)
• ___ protein: (ASC; apoptosis- associated speck-like protein with CARD)
• Enzyme: ___; Pro-IL-1β to IL-1β
Cytosolic complex, and contains three components: sensor protein > senses ___ and ___; adaptor protein > binds to sensor; enzyme > caspase-1; the whole complex is known as an inflammasome complex
When activated > activation of caspase-1 > pro-IL1beta is inactive that is present because of activation of other receptors, caspase1 cleaves this > IL1beta > ___
sensor
adaptor
caspase
PAMP
DAMP
acute inflammation
Autoinflammatory versus Autoimmune Diseases
Autoinflammatory: • Malfunction in \_\_\_ immune system • Macrophages/mast cells/Neutrophils • No \_\_\_ (presence of \_\_\_, IL-1) • \_\_\_ (CAPS, FMF, PAAND) • \_\_\_ effect (Fever, skin rash)
Autoimmune • Malfunction in \_\_\_ immune system • \_\_\_ cells and \_\_\_ cells • Presence of \_\_\_ or antigen-specific T cells. • \_\_\_; ~80 types described e.g. \_\_\_/\_\_\_ • \_\_\_ specific
innate autoantibodies cytokines rare systemic
adaptive B T autoantibodies common rhematoid arthritis pemphigus vulgaris tissue
Cryopyrin-Associated Periodic Syndrome (CAPS)
• Cryopyrin is a protein that is encoded by the ___ gene
• ___ mutations in cryopyrin
• Constitutively active ___
• Excessive production of ___
Cryopyrin > encoded by NLRP3 gene > gain-of-function mutation > inflammasome complex is constitutively active > IL1beta production > excessive ___
Etiology > ___
Pathogenesis > constitutive ___ activation resulting in IL1beta production
Disease: ___
NLRP3
gain of function
caspase-1
IL-1beta
acute inflammation
mutation
caspase
autoinflammatory
CAPS: Clinical manifestations, diagnosis and treatment
• ___ different subtypes; Episodes of Rash, fever, chills, eye redness, fatigue
• Diagnosis: (challenging) ___ composed mostly of ___ and does not
respond to ___.
- During episodes: ___ (30,0000 PMNs/mm3) and elevated ___.
- ___ testing.
- ___ antagonist (Anakinra; ___ injection), ___ (Rilonacept, ___), ___ (Canakinumab, every ___ weeks)
Challenging because many other illnesses contain ___
Diagnose this by ___ testing
Can treat this by targeting IL1:
IL1R antagonist ___ is low, need to inject daily in order for it to work
IL-1 trap > protein that binds and removes the IL1 from system > inject weekly
Anti-IL-1beta antibody > antibody that binds IL1 and removes from circulation > use every 8 weeks
three rash neutrophils neutrophils anti-histamine
leukocytosis
ESR
genetic
IL-1R daily IL-1 trap weekly Anti-IL-1B antibody 8
rashes
genetic
half-life
Familial Mediterranean Fever (FMF)
• Well-characterized hereditary ___disorder
• In 1997; Mediterranean fever gene identified (___)
• MEFV encodes a protein called ___ (“Pyrin inflammasome”)
• ___ mutation in pyrin (V726, M690V, M680I)
• Constitutively active ___
• ___ production
Similar mechanism to CAPS
Pyrin from MEFV is a different ___ for the inflammasome
Constitutively producing IL-1beta because of constitutively active caspase-1
autoinflammatory MEFV pyrin gain of function caspase-1 IL-1beta
sensor
FMF: Clinical manifestations diagnosis and treatment
- Recurrent episodes of fever, ___, skin rash (often below ___), joint pain, ___ redness, fatigue (lasting ___ hours).
- Long term ___ complications (hematuria, ___).
- Diagnosis: clinical and ___ testing.
- Colchicine (1972); affect Leukocyte ___
- ___ (Anakinra), ___ (Rilonacept), ___ (Canakinumab)
Patients may have blood and protein in the urine
Can be treated by same drugs of CAPS
serositis
knee
eye
12-72
renal
proteinuria
genetic
migration/gene expression
IL-1R
IL-1 trap
anti-IL-1B
Pyrin-associated Autoinflammation with neutrophilic dermatosis (PAAND)
- Three generation of a Belgian family of 22 individuals
- 12 individuals developed ___ disease
- ___ onset, recurrent episodes of ___ (lasting several ___)
- ___: Acne, sterile skin abscess, (pyoderma) neutrophilic vasculitis
- Elevated ___
- Ser242Arg (S242R) mutation in ___ (encoded by the ___ gene)
auto-inflammatory childhood fever weeks neutrophilic dermatosis plasma IL-1 pyrin MFMF
PAAND: Clinical Presentation:
___
___ Acne
___: Perivascular and interstitial Neutrophils
Right: BV, inflammation of the BV (vasculitis); presence of neutrophils
One would predict that this disease can also be treated by the same drugs that target ___
pyoderma
pustular
vasculitis
IL1
Summary of major cytokines in acute inflammation
TNF Principal source: \_\_\_/\_\_\_ Major Actions in Acute: • \_\_\_ molecules on Endothelial cells • Secretion of other \_\_\_ • \_\_\_ effects
IL-1 Principal source: \_\_\_/\_\_\_/\_\_\_ Major Actions in Acute: • Similar to \_\_\_ • \_\_\_ • (\_\_\_, \_\_\_, \_\_\_)
IL-6 Principal source: \_\_\_/\_\_\_ Major actions in Acute: • \_\_\_ effects • \_\_\_ response
Chemokines
Principal source: ___/___
Major actions in Acute:
• Recruitment of ___
macro's mast cells adhesion cytokines systemic
macro's mast cells epithelial cells TNF fever CAPS FMF PAAND
macro’s
mast cells
systemic
acute phase
macro’s
mast cells
neutrophils/monocytes
