inflammation Flashcards
triple response
a red scratch mark
red flare around the scratch mark
red swollen area (wheal) around the flare
dr. lewis found that he could eliminate the flare by cutting the autonomic nerve supply
this led to the discovery of histamine which mediates events 1 and 3
5 cardinal signs of inflammation
Dolor (pain) Calor (heat) rubor (redness) tumor (swelling) functiolaesa (loss of function)
identifying plasma cell on slides
round oval nucleus pushed to one side b/c of large ER producing immunoglobulins
what are the stimuli for acute inflammation
infections necrotic tissues hypoxia foreign bodies immune reactions
what happens to blood vessels during inflammation
vasodilation- greater blood flow (redness and heat)
vascular permeability–> leaky endothelial cells (histamine, bradykinin, leukotrienes)
exudation (fluid, proteins, red blood cells, WBC’s) due to increased hydrostatic pressure and increased osmotic pressure extravascularly
vascular stasis –> allows inflammatory cells to emigrate to site of injury
main mediators of vasodilation in inflammation (3)
prostaglandins (PGE2)
nitric oxide
histamine
main mediators of increased vascular permeability in inflammation (7)
histamine serotonin C3a and C5a (by liberating vasoactive amines from mast cells) Bradykinin Leukotrienes C4, D4, E4 PAF Substance P
what are the main mediators of chemotaxis, leukocyte recruitment and activation (7)
TNF IL-1 Chemokines C3a C5a Leukotriene B4 Bacterial products (n-formyl methyl peptides)
main mediators of fever (3)
IL1
TNF
Prostaglandins (PGE2)
main mediators of pain 2
prostaglandins
bradykinin***
main mediators of tissue damage in inflammation 3
lysosomal enzymes of leukocytes
ROS
NO
what mediates increased transcytosis
VEGF
what happens to lymph vessels during inflammation
they proliferate due to increased load of fluid (Edema)
lymphangitis
inflammation of the lymphatics
lymphadenitits
inflammed lymph nodes and vessels
adenitis
infammation of lymph nodes
what is edema
excess fluid in interstitial or serous spaces (can be exudate or transudate)
transudate why is it formed protein content? color? consistency odor? ph cell count enzyme content bacteria inflammation
ultra filtrate of plasma that leaks due to increased hydrostatic pressure or decreased colloid osmotic pressure (decreased protein synthesis –> liver disease or increased protein loss –> kidney disease)
low protein content
clear/water-like thin and watery no odor Alkaline low cell count low enzyme content no bacteria no inflammation present
exudate
why does it form?
color consistency odor? ph? protein content? cell count? enzyme content? bacteria? inflammation?
mix of cells and plasma leaking out of vessels in response to chemical mediators
cloudy, white, yellow or red thick and creamy, may have odor acidic high protein content high cell count (WBC and RBC) high enzyme content bacteria may be present associated with inflammation
serous
yellow to clear
serosanguinous
clear with red tinge
sanguionous
full of blood
purulent
greenish (full of neutrophils)
chylous
milky and white
what is the immediate transient response
immediate response with almost any stimulus
leakage starts with injury (lasts 15-30 min)
endothelial cells contract
driven by histamine, bradykinin, serotonin, leukotrienes, substance P
no neutrophils
mostly venules affected
ex. dermatographism
what is the immediate sustained response
severe thermal or chemical burns or lytic bacterial infection
leakage starts with injury and last several hours to days
venules, capillaries, arterioles affected
endothelial cell necrosis !!
what is the delayed prolonged leakage
patient develops inflammation
leakage starts 2-12 hours AFTER injury
lasts hours to days
bacterial toxins, sun burn,
capillaries and venules affected
what are the steps in leukocyte migration?
stasis - slowing of blood
margination- white cells move to periphery
rolling- weak binding via selectins
adhesion/activation - integrin activation by chemokines and firm adhesion by integrins
migration - diapedesis across endothelial cells (must express collagenase for type IV collagen)
what are 3 selectins
and what controls the expression of selectins and their ligands
L -selectin- expressed on leukocytes
E - selectin - expressed on endothelial cells
P -selectin - one in platelets and on endothelium
expression of selectins and their ligands is regulated by cytokines produced in response to infection and injury (TNF, IL-1 released by macrophages)
ICAM-1
intercellular adhesion molecule 1 provides more firm adhesion of the neutrophil, via integrins on neutrophil surfaces, to the endothelium.
CD31
this cell to cell adhesion molecule aids in diapedesis.
what is the role of IL-8, C5a and LTB4 after deapedesis
chemotaxis is aided by the C5a component from complement activation, along with leukotriene B4, a product of the lipo-oxygenase pathway of arachidonic acid metabolism.
these cause increases in Ca2+ and kinases which leads to polymerization of actin ==> filipodia move in direction of inflammatory stimulus
what is the role of • C3b and IgG
opsonins such as the C3b component from complement activation, as well as immunoglobulin G, coat foreign objects such as bacteria to aid in phagocytosis by binding to leukocyte receptors.
where are weibel - pallade bodies
in endothelial cells - they are the intracellular stores of P =selectin
when there is inflammation hisatmine and thrombin upregulate and resdistribute Pselectin to surface of endothelial cell
what are the exogenous chemotactic factors
bacterial formyl-peptides
what are the 4 major types of receptors on leukocytes ?
TLR’s–> for microbial products
G- protein coupled receptors –> for Lipid mediators, chemokines, and for N-formyl methionyl peptides
Cytokine receptors–> IFN-gamma is the major cytokine that activates macrophages
Receptors for opsonins (proteins that coat microbes which includes antibodies, complement, lectins, etc).
G- protein coupled receptor activation on leukocytes leads to …
cytoskeletal changes and signal transduction:
chemotaxis–> migration into tissues
increased integrin avidity–> adhesion to endothelium
TLR’s activation on leukocytes leads to what
production of mediators (AA metabolites and cytokines) –> amplication of the inflammatory reaction
production of ROS and lysosomal enzymes —> killing of microbes
Cytokine receptor activation leads to what
production of ROS and lysosomal enzymes –> killing of microbes
activation of phagocytic receptor on leukocytes leads to what…
phagocytosis of microbe into phagosome
production of ROS and lysosomal enyzmes –> killing of microbes
Chediak higashi syndrome gene? outcome of mutated gene? symptoms peripheral smear treatment
autosomal recessive
LYST gene malfuntion
defective fusion of phagosomes and lysosomes in phagocytes
symtpoms: albino b/c melanin made in melanocytes can't get to the keratinocytes recurrent infections progressive neurological abnormalities coagulation defects plasma membrane repair impaired
peripheral smear shows:
giant cytoplasmic granules in leukocytes and platelets
neutrophils that have giant azurophilic granules
treatment
hematopoietic cell transplantation
chronic granulomatous disease
x-linked
autosomal recessive
defects in bacterial killing and oxidative burst
results from inherited defects in genes encoding components of phagocte oxidase
x-linked - phagocyte oxidase membrane compoenet
autosomal recessive - phagocyte oxidase cytoplasmic component
bone marrow suppression?
defective production of leukocytes
MPO deficiency
decreased microbial killing because of defective MPO-H2O2 system
what are the cell derived mediators of inflammation that are preformed 2
histamine
serotonin
what are the cell derived mediators of inflammation that are newly synthesized 6
prostaglandins leukotrienes PAF ROS NO Cytokines chemokines substance P
what are the plasma derived mediators of inflammation
complement products (C5a, C3a) Kinins (bradykinin)
what releases histamine 3
basophils
platelets
mast cells
what are the actions of histamine
binds H1 receptors on endothelial cells
causes:
constriction of large arteries
dilation of arterioles
increased venular permeability via endothelial cell contraction
bronchial and intestinal smooth muscle contraction
induces nasal and bronchial mucus secretion
activates sensory nerves (itching)
what is the source of serotonin
what is its release triggered by
present in platelets
released when platelets aggregate after contact with collagen, thrombin, adenosine diphosphate, antigen/antibody complex
what are the effects of serotonin
vasodilation
increased vascular permeability
action of phospholipase A2
converts cell membrane phospholipids to arachidonic acid
cyclooxgenase general function
converts AA to prostaglandins
includes COX1 and COX2
5-lipoxygenase function
converts AA to leukotrienes and lipoxins
what cells produce prostaglandins
mast cells
macrophages
endothelial cells
COX1
constitutively active produces TXA2 (thromboxane)
Cox2
inducible
produces prostacyclin PGI2
Thromboxane A2
what is it produced by?
function?
produced by platelets (b/c platelets contain thromboxane synthetase)
causes platelet aggregation and vasoconstriction
prostacycline (PGI2) function
produced by what?
produced by endothelium (b/c endothelium contains prostacyclin synthetase)
inhibits platelet aggregation and causes vasodilation
PGD2
attracts neutrophils
vasodilation
pain and fever (via cAMP action on temp set point)
PGE2
cuases pain
vasodilation
PGF2
vasodilation
leukotrienes function?
increased vascular permeability
chemotaxis
leukocyte adhesion and activation
LTB4
attracts leukocytes
LTC4, D4, E4
cause vasoconstriction
increased vascular permeability
bronchoconstriction (bronchospasm)
lipoxins
inhibit leukocyte recruitment and inflammation
function of Cox 2 inhibitors
impair endothelial cell production of prostacyclin (which is a vasodilatro and inhibitor of platelet aggregation
side effects>
increased risk of cardiovascular and cerebrovascular events b/c there is now unopposed COx-1 which is a vasoconstrictor and inducer of platelet aggregation
lipoxygenase inhibitors
inhibits production or blocks receptors of 5 -lipoxygenase
note NSAIDs do not affect 5-lipoxygenase
used in the treatment of asthma
broad spectrum inhibitors
including steroids
reduced gene transcription of COX2 , phospholipase A2 and pro-inflammatory cytokines (IL-1 and TNF) and INOS
PAF
made by what
causes what?
made by platelets, endothelial cells and leukocytes
causes platelet aggregation
vasoconstriction and bronchoconstriction
enhanced leukocyte adherence to endothelium (integrin mediated leukocyte binding)
with very low concentrations it causes vasodilation and increased vascular permeability
ROS in inflammation
cause endothelial cell damage with resultant increased vascular permeability
damage to parenchyma cells and erythrocytes
inactivates proteases such as alpha-antitrypsin (normally inhibits elastase)
NO in inflammation
relaxes smooth m. and promotes vasodilation
inhibits leukocyte rolling, adhesions, degranulation
inhibits platelet aggregation and adhesion
inhibits mast cell activated inflammation
endogenous mechanism for preventing inflammation ***
what are the three types of NO and how is their activity increased?
eNOS - endothelial
nNOS- neuronal
iNOS- inducible when monocytes and macrophages are activated by TNF and INF
which cytokines are important in acute inflammation
TNF
IL-1
IL-6
Chemokines
which cytokines are responsible in chronic inflammation
IL-12
IFN-gamma
IL-17
IL-1
what controls its production
what are its functions
what happens in mutations that activate caspases of inflammasome
production controlled by inflammasome
causes endothelial activation (endothelial adhesion, acute phase response, fever, activates fibroblasts and neutrophils)
increased active IL-1 with mutations that activate caspases of infalmmasome causing inherited autinflammatory syndromes (Mediterranean fever)
TNF functions
regulates energy balance - promotes lipid and protein mobilization and suppresses appetite–> cachexia ***
Expression of luekocyte adhesion molecules
procoagulant
leukocyte activation
fever, leukocytosis, increase sleep
substance P
mast cell activation and wheal formation
prominent in GI tract and lungs
causes: pain endocrine cell activation mast cell activation vascular permeability anti-vasopressor activity
hageman factor (XII) is activated by what?
negatively charged surfaces:
- when vascular permeability increases and plasma proteins leak into the extravascular space and come into contact with collagen
- comes in contact with BM exposed as a result of endothelial cell damage
it is produced in the liver
hageman factor stimulates what?
kinin system–> produces vasoactive kinins (bradykinin)
clotting system–> induces formation of thrombin
fibrinolytic system–> produces plasmin
complement system –> produces anaphylatoxins and other mediators
kinin system activation by XII
what are the functions of kallikrein
XII converts prekallikrein to kallikrein
kallikrein converts HMWK to bradykinin
kallikrein makes C5 into C5a
Kallikrein converts plasminogen to plasmin
kallikrein also feedsback and activates more XII
what are the functions of plasmin
converts C3 to C3a
cleaves fibrin into fibrin-split products (inflammation by chemotatic for leukocytes and increased vascular permeability)
what activates thrombin
what are the functions of thrombin
thrombin is activated by XII as it activates teh clotting cascade
thrombin converts fibrinogen to fibrin
what is the fibrinolytic system
XII activates this system by production of kallikrein
kallikrein then activates plasminogen to plasmin
this system counterbalances clotting because plasmin cleaves fibrin
plasmin also cleaves the complement protein C3 to produce C3a
plasmin also activates hageman factor amplifying the cascades
what are the functions of bradykinin
increases vascular permeability
contraction of smooth muscle
dilation of blood vessels
PAIN ***
classically activated macrophages respond to what?
respond to microbial products (TLR ligands)
respond to T cell cytokines (IFN- gamma)
what are the products of classically activated macrophages
ROS
NO
Lysosomal enzymes
IL-1, IL-12, IL-23
chemokines
what are the functions of classically activated macrophages
microbicidal actions
phagocytosis and killing of many bacteria and fungi
pathologic inflammation
what do alternatively activated macrophages respond to
cytokines such as IL-4 and IL-13 (Th2 subset t cell products)
helminths
what are the products of alternatively activated macrophages
IL-10
TGF-beta
Arginase
proline polyaminases
what are the functions of alternatively activated macrophages
anti-inflammatory
wound repair
fibrosis
what makes the MAC
C5b-C9
anaphylatoxins in the complement cascades
C3 a , C4a, C5a
‘
cause histamine release and increase vascular permeability
C5a function
leukocyte activation
chemotaxis
lipoxygenase
C3b
opsonin - promotes phagocytosis
what is the most critical step in the complement cascade
proteolysis of the third component C3
what are the outcomes of acute inflammation
resolution pus formation (abscess)
healing to fibrosis chronic inflammation (angiogenesis, mononuclear cell infiltrate, fibrosis, progressive tissue injury)
what does an elevated CRP mean
when elevated it can be a sign of a patient that is at increased risk of developing MI from atherosclerosis
it is an acute phase reactant and anytime there is inflammation this is elevated
what are diseases that are from acute leukocyte induced injury
acute respiratory distress syndrome (neutrophils)
acute transplant rejection (lymphocytes, antibodies and complement)
asthma (eosinophils, IgE antibodies)
glomerulonephritis (neutrophils, monocytes, antibodies and complement)
septic shock (cytokines)
lung abscess (neutrophils)
what are some disease that are involved in chronic leukocyte - induced injury
arthritis (lymphocytes, macrophages, antibodies)
asthma (eosinophils, IgE antibodies)
Atherosclerosis (macrophages)
chronic transplant rejection (lymphocytes and cytokines)
pulmonary fibrosis (macrophages, fibroblasts)
what are active ways that the acute process is ended
switch in AA products to lipoxins
liberation of anti-inflammatory cytokines (IL-10 and TGF-Beta)
production of anti-inflammatory lipid mediators (resolvins and protectins) derives from polyunsaturated fatty acids (fish-oil)
neural changes (cholinergic discharge) - decrease TNF production by macrophages
what are the acute morphological patterns of inflammation
exudative vs. necrotizing
exudative
- serous (urticarial- itching)
- fibrinous - protein rich
- fibrinoid
- hemorrhagic
- catarrhal- common cold/snot (neutrophils and proteins)
- purulent/suppartive (neutrophils)
a. cellulitis
b. lymphangitic
c. abscess
d. ulcerative
e. pseudo-membranous
necrotizing
-wet gangrene
morphological patterns of chronic inflammation
granulomatous
disease associatred with abscess
multiple bacterial absecess in the lung in the case of bronchopneumonia
what are two examples of pseudomembranous inflammation processes
what is the morphological appearance
c difficilecolitis
c diptheriae pharyngitis
form of exudative inflammation that involves mucous and serous membranes
fibrin in the exudate causes a membrane-like covering that is fairly adherent to the underlying acutely inflamed tissue
what is an example of fibrinous inflammation
appearance?
fibrinous pericarditis
endocarditis
large molecules such as fibrinogen pass the vascular barrier and fibrin is formed and deposited in the extracellular space
what is an ulcer
acute stage versus chronic stage
a local defect or excavation of the surface of an organ or tissue that is produced by the sloughing (shedding) of inflamed necrotic tissue
can only occur when tissue necrosis and resultant inflammation exist on a near surface
what is an abscess
large amounts of pus or puruluent exudate consisting of neutrophils, liquefactive necrosis, edema fluid
abscesses are localized collections of purulent infllammatory tissues caused by suppuration buried in a tissue
they have a central region that appears as a mass of necrotic leukocytes and tissue cells
there is a zone of preserved neutrophils around this necrotic focus
outside this region vascular dilation and parenchymal and fibroblastic proliferation occur indicating chronic inflammation and repair
in time the abscess may be walled off and replaced by connective tissue
what are the causes of chronic inflammation
continued infections (delayed type hypersensitivity) and sometimes this takes a specific pattern called granulomatous reaction
prolonged exposure to toxic/foreign agents
autoimmune diseases (RA, MS, inflammatory bowel, allergic)
malignancies
what are morphological characteristics of chronic inflammation
mononuclear cell infiltrates (macrophages, lymphocytes, plasma cells, basophils, mast cells, eosinophils)
tissue destruction
fibrosis
proliferation of blood vessels
if you get an acute viral infection what goes up in the peripheral blood that is not usually norma l and is an exception
lymphocytes increase instead of neutrophils
macrophages in the .... liver spleen and lymph nodes lungs central nervous system bone skin
kupffer cells sinus histiocytes alveolar macrophages microglia osteoclasts langerhan cells (antigen presenting)
what is the main cell type in chronic inflammation and what is its function
macrophage
products of activated macrophages serve to eliminate injurious agents such as microbes, and to initiate the process of repair
responsible for tissue injury in chronic inflammation (proteases, ROS)
what is the relationship b/w t cells and macrophages and what cytokines are involved
activated T cells produce
1) cytokines that recruit macrophages (TNF, IL-17, chemokines)
2) cytokines that activate macrophages (IFN-gamma)
Activated macrophages in turn stimulate T cells by presenting antigens and by secreting cytokines (IL-12)
what cytokine regulates eosinophils
what are the chemoattractants for eosinophils?
what do eosinophils look like on a slide?
produced in the BM and regulated by IL-3 and IL-5 and GM-CSF
chemoattractants include eotaxin 1 and 2
RANTES
on a slide the eosinophils have little red granules, 1-2 lobes
what are the constituents of eosinophil granules
major basic protein –> toxic to some parasites and causes lysis of mammalian epithelial cells - necrosis
cytotoxic agents (cationic proteins, neurotoxin, peroxidase)
the only parasite touched by eosinophils are helminths
basophils in chronic granulation
circulating leukocytes with large basophilic granules containing histamine and heparin
what is the function of heparin
contained in basophils and acts as an anticoagulant
mast cells in chronic inflammation
wildely distributed in connective tissue
have receptors for Fc portion of IgE molecules
upon stimulation by recognition of antigen –> they degranulate and release mediators such as histamine (itching and vasodilation)
what immunolglobulin activates mast cells
IgE
what cytokine is an important mediator of granulmoatous inflammation
INF-gamma
transforms macrophages into epitheloid cells
what is granulamtous inflammation
microscopic aggregate of activated macrophages that are transformed into epithelium-like cells surrounded by a collar of mononuclear leukocytes, principally lymphocytes and occasionally plasma cells
tuberculosis granuloma on stain shows what
an area of central necrosis surrounded by multiple lagerhan’s type giant cells
epitheloid cells
lymphocytes
foreign body granuloma
sutures, talc
dont incite any specific inflammatory immune response
foreign material in the center of the granuloma
macrophages, collagen, few small lymphocytes, multinucleated giant cells
immune granulomas
inciting agent produces immune response
macrophages engulf foreign protein antigen , process and present to T cell
T cells produce IL-2 and IFN-gamma which activates more macrophages –> converted into mutlinucleate giant cells
mycobacterium tuberculosis is an example
what are diseases that are examples of diseases with granulomatous inflammation
tuberculosis leprosy syphilis cat-scratch disease sarcoidosis crohn's disease
what is a fever caused by?
what cytokines mediate a fever?
what are the systemic manifestations of fever
produced in respones to pyrogens whcih stimulate prostaglandin synthesis in vascular and perivascular cells of the hypothalamus
exogenous pyrogens (bacterial products (LPS) stimulate leukocytes to release cytokines
cytokines are endogenous pyrogens that increase enzymes that convert AA into prostaglandins
Cytokines:
IL-1, TNF, IL-6, Interferon
systemic outcomes:
sympathetic NS stimulation
dermal vasoconstriction
decreased heat dissipation
what are the acute phase proteins
CRP
fibrinogen–> binds to red cells and causes them to form stacks (rouleaux)
serum amyloid A (SAA protein)
what is the problem with elevated hepcidin in the blood (which is produced in the acute phase response)
reduces the availability of iron and are responsible for the anemia associated with chronic inflammation
what occurs in sepsis
large amounts of bacteria and LPS
generates large amounts of cytokines (TNF and IL-1)
activation of coagulation and fibrinolysis (blood clots and then massive bleeding)
=end organ damage
- cardiac failure and vasodilation (NO production) –> decrease in BP
adult acute resp. distress syndrome
what is the cause of chronic granulomatous disease
characterized by reduced killing of ingested microbes b/c of inherited defects in NADPH oxidase system
what diseases cause deficiency in chemotaxis
thermal injury DM malignancy sepsis immunodeficiency
what diseases cause adhesion deficiencies
hemodialysis
DM
what diseases cause phagocytosis and microbicidal activity deficiencies
leukemia anemia sepsis DM neonates malnutrition
neutrophil adherence molecule defects are caused by what diseases
hereditary glucocorticoids dm ethanol recurrent bacterial infections
