Acute and Chronic Inflammation Flashcards
Acute cellular infiltrate
mainly neutrophils
Chronic cellular infiltrate
monocytes / macrophages / and lymphocytes
Acute - tissue injury / fibrosis
usually mild and self limited
Chronic - tissue injury / fibrosis
often severe and progressive
Local and systemic signs of acute
prominent
Local and systemic signs of chronic
less prominent / may be subtle
Acute (innate vs adaptive?)
acute is largely innate, with increasing chronicity more of a coordinated response involving innate and adaptive
stimuli for acute inflammation (4)
infection
trauma (anything that causes necrosis)
foreign material
immune reaction (hypersensitivity)
acute inflammation the process (4 steps)
recognition (receptors)
vascular change
leukocyte recruitment
leukocyte activation
Step 1 in acute - recognition - where are receptors located?
pattern recognition receptors are located on a large variety of cells (inflammatory and non)
Step 1 acute
what do pattern recognition receptors detect?
microbe derived substances, toxins, material from necrotic cells, Fc portions of Abs
step 1 acute
where are pro-inflammatory receptors located? (3)
plasma membrane
endosome
cytosol
where are TLR located?
plasma membrane and endosome
What happens when TLRs are stimulated?
–> trainscription factors –> mediators of inflammation and anti-microbial products
Aside from TLRs what is the other receptor we discussed?
Inflammasome
What is the inflammasome?
receptors in acute inflammation / complex of proteins that mediate cellular response, esp. in response to stuff dead or damaged cells release (but also microbes)
what does the inflammasome sense?
uric acid (from DNA breakdown), atp, decreased intracellular potassium (pm injury), DNA
what does the inflammasome do?
activates caspase-1 –> interleukin 1B –> inflammation
what is a known stimulator for IL1B? i.e. IL1B is good target for treatment
Gout (urate crystals)
Vacular changes in acute inflammation - key component of the inflammatory reaction, quickly bringing cells and other materials needed for a response to injury or threat - two major changes?
increased blood flow
increased permeability
vascular changes lead to many of the early clinical signs of infection
Increased flow –> ? (2)
Increased permeability –> ? (1)
increased flow –> congested capillary beds –> erythema (rubor)
increased flow –> local warmth (calor)
increased permeability –> exudate of fluid into tissues –> swelling (tumor)
Acute vascular changes - flow - arterioles serving the involved capillary beds dilate, flooding these capillaries - what is the major stimulus for this?
histamine’s action of smooth muscles in the vascular wall
vascular changes - increased permeability results from (3)
endothelial cell contraction
endothelial injry
transcytosis
what causes endothelial cell contraction? early and late?
early - histamine / bradykinin
late - IL1 / TNF
what causes endothelial cell injury (increased permeability)
can come from a variety of places (external e.g. burn, internal e.g. toxic compounds from responding leukoctyes)
- cell die / detach incomplete endothelium
transcytosis?
material transported through the endothelial cell via vesicles
EXUDATE common cause? protein content? cell content? specific gravity?
cause - increased vascular perm
protein - increased
cell - increased: inflam / rbc
specific grav - high
TRANSUDATE common cause? protein content? cell content? specific gravity?
cause - increased hydrostatic pressure with decreased colloid osmotic pressure
protein - decreased
cell - few cells
specific gravity - low
exudate results from?
incrased vascular permeability usually related to inflammation
transudate results from?
altered iv pressure (either from hemodynamic or osmotic) - increased capillary pressure from cardiac failure
decreased blood protein from liver disease
acute vascular changes - lymphatics
drain?
complication?
clinical?
drain accumulating edema along with all the debris that inflammation may produce
sometimes are a route to more widespread infection
changes to the draining lymphatic channels and lymph nodes may produce clinical exam findings (lymphadenitis)
Four main phases of leukocyte recruitment in acute inflammation
margination / rolling
adhesion
transmigration
chemotaxis
In ____________ leukocytes accumulate on endothelium - principals of laminar flow, larger/slower moving leukocytes get pushed to the periphery of the column - vascular permeability thicker and slower moving blood (“stasis”)
margination
In ____________ stimulated cells express adhesion moleucles which have affinity for sugars on leukocytes (transient, not strong binding)
Rolling
In rolling, what induces endothelium to move adhesion molecules for leukocytes to the surface?
chemical mediators:
histamine –> P-selectin
IL-1 –> E-selectin
In leukocyte recruitment
1.
2.
3.
location tissues detect threat
chemical mediators released
associated small blood vessels become sticky
In leukocyte recruitment, when does adhesion occur?
when the leukoctyes reach an a area of activation signaled by chemokines
What happens once a leukocyte is activated?
they alter integrins (CD11/CD18) on surface to a high infinity state -
In addition to activated leukocytes altering integrin expression, what happens to the endothelium in leukocyte recruitment?
Endothelium is activated by specific medatiors (IL-1, TNF) increases expression of ligands for integrins (e.g. ICAM1 that binds C11/CD18)
In leukocyte recruitment, what results from adhesion
stable attachment of leukocytes at the site of inflammation
Once the luekocytes are adhered to the endothelium near the site of inflammation, what happens?
transmigration
what is transmigration
leukocytes (using CD31) squeeze between endothelial cells: termed “diapedesis”
where does diapedesis occur?
mostly in venules
in addition to squeezing through endothelial cells, what else must leukocytes do in transmigration?
secrete enzymes (e.g. collagenase) to break up basement membrane of vessels
once the luekocytes transmigrate, what happens?
CHEMOTAXIS
What is chemotaxis?
leukocytes move toward site of inflammation following chemical gradients of increasing density
Are endogenous or exogenous substances chemotatic?
Both can be
bacterial products, cytokines, compliment proteins, arachidonic acid metabolites
which compliment protein is especially chemotatic
C5
which arachidonic acid metabolite is especially chemotatic?
LTB4
What about leukocytes allows chemotaxis to yield movement/
Contractile elements of leukocytes are tied to chemotatic receptors - direction of greatest chemotactic chemical density determines the direction of movement
when do leukocytes become activated?
when they encounter certain substances (microbial products, cellular debris, certain cellular mediators)
once activated, leukocytes (4)
- readily phagocytize materials
- are poised to kill/degrade engulfed material
- readily secrete material to kill/degrade
- produce inflammatory meatiors (amplifies inflammatory process)
3 steps of phagocytosis?
- recognition / attachment of particle to leukocyte
- engulfment and formation of vacuole
- killing / degradation of vacuolated material
phagocytosis - 2 general ways to bind material
- receptors for specific products of microbes or necrotic cells
receptors for opsonins
what are opsonins?
host proteins present in blood or produced locally that coat microbes
examples IgG, C3b, Collectins
how does phagocytosis kill microbes?
chemicals toxic to microbes are generated in lysosomes and fuse with the phagasome containing microbe
What is in lysosome that kills microbe? (4)
- ROS formed by oxidation of NADPH by phagocyte oxidase converts oxygen to superoxide ion –> superoxide ion spontaneously converts to hydrogen peroxide
myeloperoxidase and chloride ion convert hydrogen peroxide to hypochlorous radical which is stronger oxidizer
similarly toxic nitrogen compounds especially NO
Other lysosomal enzymes kill microbes and breakign down other materials
in addition to phagocytosis, how to activated luekocytes degrade extracellular materials / microbes?
by secreting compounds
- include enzyme and antimicrobial proteins
- if material cannot be ingested lysosomal contents may be released extracellularly
- neutrophil extracellular traps composed of nuclear chromatin as scaffolding with embedded antimicrobial compounds
- -> provide concentrated area of antimicrobial material that traps microbes
Outcomes of acute inflammation (3)
- resolution
- chronic inflammation
- scarring
Acute inflammation resolution: capability of injured tissue? degree of injury? tissue damage? requires?
capable of regenerating
minimal tissue damage
usually limited degree of injury
requires termination of the inflammatory process
Acute inflammation how do we transition to chronic?
generally occurs when the offending agent not removed by the acute inflammation
can prolonged, followed by resolution or end as scarring
does chronic inflammation always proceed from acute?
no some agents (esp. viral) stimulate a chronic inflammation response from the outset - autoimmune disorders are often mediated by chronic inflammation
Acute inflammation - scarring
occurs if tissue doesnt have capacity to regenerate
often occurs after considerable tissue distruction
results from tissue being filled in CT elements (esp. collagen)
can significantly impair function (e.g. liver cirrhosis)
Innate immune system is not very discriminatory - activated leukocytes generate enzymes as well as substances that can damage host tissues just as well as microbes
Host tissue damage can occur in: (3)
tissue surrounding infectious agents (esp. resistant infections)
cleaning up necrotic tissue by the inflammatory process may cause additional damage
inflammatory process directed against host tissues
deficits in leukocyte function lead to increased susceptibility to?
infections
What is different in presentation of chronic vs acute inflammation?
acute inflammation often presented as sequential steps BUT chronic inflammation processes may occur concurrently
- mononuclear cell infiltrate, incl lymphocytes, plasma cells, monocytes / macrophages
- tissue destruction
- repair : neovascularization and fibrosis
In chronic inflammation, injury and repair may occur together
occurs over longer periods of time
settings characterized by chronic inflammation (3)
persistent infections
immune mediated disease (autoimmune and allergy)
prolonged exposure to toxins (endogenous and exogenous)
chronic inflammation cells:
macrophages
lymphocytes
eosinophils
mast
Where do macrophages come from?
blood monocytes circulate for about a day and some give rise to macrophages in teh peripheral tissues - take up residence in most tissues in the body
Role of macrophages (3)
ingest microbes and necrotic cellular debris (main phagocytes of adaptive immune system)
initiate tissue repair, often results in fibrosis (scar)
secrete inflammatory mediators (cytokines, eicosanoids) that promote inflammation
present antigens to adaptive immune system
chronic inflammation - macrophage - two types?
M1 - classical activation
M2 - alternative activation
M1 - classical activation macrophages
what activates?
what do they produce?
what are their functions
activated by -
endotoxin; IFN-gamma (T cells cytokine); foreign material
what do they produce -
ROS; NO; lysosomal enzymes; pro-inflammatory cytokines
functions
- killing microbes; chronic inflammation
Macrophage - M2 - alternative activation
what activates?
what do they produce?
what are their functions?
activated by
- IL-4; IL-13; (from T cells; eosinophils; mast cells)
produce -
growth factors for - new vessel growth; fibroblast activation
function - tissue repair and fibrosis
What types of cells are involved in many chronic inflammatory disorders? Including autoimmune diseases?
lymphocytes
What do CD4+ T cells secrete?
cytokines that promote inflammation
3 classes of CD4 T+ cells?
TH1
TH2
TH17
TH1 secretes?
IFN gamma - which activates the classical (M1) macrophage pathway
TH2?
IL4, IL5, IL13: activates alternative pathway (M2) macrophages; also activates eosinophils
TH17?
secretes IL17: recruitment of neutrophils and monocytes
Eosinophil recruitment in chronic inflammation?
similar to neutrophils, but includes specific chemokines (eotaxin)
What 2 specific scenarios are notable for eosinophil recruitment?
parasites (major basic protein is toxic to parasites)
allergic rxns mediated by IgE
mast cells
inflammation involvement?
both acute and chronic
what do mast cells release?
inflammatory mediators (histamine and arachidonic acid)
what triggers mast cell mediator release?
coated with IgE
In addition to their notoriety for anaphylactic reactions - what else can mass cells do?
provide a widely distributed and quickly triggered response to infections
What is granulomatous inflammation?
histologically distinctive pattern of chronic inflammation
What is a granuloma?
enlarged macrophages that form nodule, which is often surrounded by lymphocytes
granulomas can form around?
some organisms - but some can evade
what often accompanies long standing granulomas?
fibrosis
granulomatous inflammation should raise suspicion for? (4)
- some organisms not typically eradicated by other inflammatory reactions (tb, leprosy, fungi)
- some immune mediated diseases - Crohns?
- Foreign material (suture)
- Sarcoidosis - (no details_
Three main processes of chronic inflammation
- mononuclear cell infiltrate
- tissue destruction
- repair
Chronic inflammtion Characteristic settings (3)
- persistent infections
- immune mediated diseases
- prolonged exposure to toxins
Cells of chronic inflammation (4)
macs
lymphs
eos
mast
type of inflammation associated with chronic?
granulomatous
Acute phase reaction is the result of?
(systemic effect of inflammation)
Result of mediators produced by involved cells (leukocytes)
- systemic distribution
What mediators are associated with Acute phase reaction?
TNF
IL1
IL6
Examples of systemic effects of inflammation? (3)
fever
increased acute phase protein in blood
leukocytosis
fever (pyrexia) - systemic effect of inflammation - what happens?
Vascular cells in hypothalamus stimulated by pyrogens to produce prostaglandins (esp. PGE2) that act locally to cause a central increase in body temp
Exogenous pyrogens and fever - how do they cause it - bacteria?
e.g. bacterial components cause leukocytes to release endogenous pyrogens (IL-1, TNF) which then act on teh hypothalamus vasculature cells
Exogenous pyrogens and fever - how do they cause it - endogenous
in addition to bacterial components causing leukocyte release of IL1 and TNF - exogenous pyrogens also act directly on the hypothalamus vasculature cells
what is the increased body temperature thought to do in inflammaiton?
aid in fighting some infections
In systemic inflammation, we also see increased acute phase proteins in the blood
what does liver respond to?
how is used clinically?
what do they do? (3 e.g.)
in response to IL6 - hepatocytes produce several proteins in greater abundance
clinically used to detect and monitor progress of inflammatory processes
Two of these
C-reactive protein and serum amyloid A are known to adhere to cell walls and may act as opsonins
fibrinogen binds RBCs causing them to form stacks that quickly form sediments. This forms the basis for the erythrocyte sedimentation rate (ESR), a long used test for the presence of inflammation
Leukocytosis in systemic inflammation
stimulus?
what is left shift?
what does continued inflammatio lead to?
under the influence of TNF and IL1, more leukocytes are released from teh bone marrow
may see an increased number of immature white blood cells (early release): commonly referred to as a “left shift” of the leukocytes
continued inflammation leads to increased production of colony stimulating factors (CSFs) that increase bone marrow production of leukocytes (as opposed to releasing more cells that have already formed)
neutrophilia (increased neutrophils) indicates?
bacterial infection
lymphocytosis (increased lymphocytes) indicates?
viral infections
eosinophilia (increased eosinophils) indicates?
asthma / parasitic infections
leukopenia (decreased leukocytes) indicates?
specific infections, e.g. Typhoid fever
