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INFLAMMATION (HEALING (EXAMPLES (4. Describe the process of healing in…
INFLAMMATION
HEALING
EXAMPLES
Describe the process of healing of
superficial abrasions, surgical incisions
and
partial thickness skin wounds
superficial
epidermal
abrasion
epidermal regeneration
blood and serum coagulum (scab)
, epithelial cell monolayer
multilayering by mitotic activity
scab sloughs,
superficial keratinization
surgical incisions
require
minimal tissue loss
minimal bacteria
good margin approximation
V fills with fibrin-rich coagulum, joins edges, neutrophils enter, basal cell monolayer forms
surface scab sloughs off, macrophages phagocytose debris, capillaries and fibroblasts > granulation tissue
collagen thickens > increased tensile strength, vascularity reduced, sutures removed
minimal
fibrous
scar
shrinks
over
time
Describe the process of healing by
second intention
cause
large wound cavity
edges approximated inadequately
full-thickness
skin wound
secondary infection common
fills with coagulum and exudate, attempted epithelial growth, large mound of granulation tissue
limited contracture, epithelium slowly grows in from edges of granulation bed
balance between fibrous
scarring and epithelialization
reduced
strength,
thin scar
liable to
damage
necrotic debris and exudate must be removed
initial inflammatory reaction and phagocytosis often protracted
List the
factors
that may influence wound healing
local
site
tissue/organ
blood supply
drainage
movement
necrotic tissue, blood
infection
foreign bodies
direction, extent, depth
systemic
age
nutrition
disease
drugs
4. Describe the process of healing in
bone
(1) Haematoma formation - periosteum contained
(2+3) Inflammatory response, phagocytosis of necrotic bone and debris - osteoclasts remove fragments
(4) Granulation phase - mesenchymal and capillary proliferation
(5) Callus phase - mesenchymal cells differentiate, osteoblasts > osteoid > woven bone > unite bone ends
(6) Lamellar bone phase - cartilage matrix invaded by blood vessels and osteoblasts - osteoclasts remove callus - osteoblasts > new osteoid (Haversian systems)
(7) Remodelling phase - remodelled, marrow cavity reform - joints should be immobilised or callus fails to ossify - ‘false joint’
Give examples of healing in
other organs
with reference to the
cell type
involved
intestinal mucosa
labile cells regenerate quickly
crypt cells
impairs regeneration
liver
stable tissue type
hepatocyte regen + size > functional reserve
BM essential
kidney
stable cell type
hypertrophy of remaining nephrons
no new nephrons if BM destroyed
Describe the different
temporal phases
of the healing process
Explain and give examples of the
problems
that can occur in wound healing
Explain the development of
adhesions
body cavity
can limit organ function
metaplasia
stem cells try to cover area
adult cell type is replaced by another
less well differentiated stem cells differentiate along a different (less specialised) line
usually reversible
can be precursor to neoplasia
hypertrophic scar
collagen and fibroblast proliferation
projecting mass not covered by epithelium
Explain the processes involved in the
proliferation
and
remodelling phases
of the healing process
remodelling phase
granulation tissue > mature CT
months/years
MMPs
fibroblasts, macrophages, neutrophils, endothelial cells
degrade ECM
matrix metalloproteinases
proliferation phase
granulation tissue
fibroblasts, collagen, proliferating capillaries
fibroplasia/desmoplasia: CT proliferation
angiogenesis:
vascular proliferation
proteolysis of BM, capillary bud (epidermal and vascular endothelial GFs)
migration of endothelial cells (mediated by integrins)
proliferation of endothelial cells
new lumena, BM, (+muscle, CT), maturation, inhibition of further growth
Describe the process of
angiogenesis
epithelialisation: epithelial proliferation
ECM synthesis
TGFβ
fibroblasts
collagen
myofibroblasts
contractile
proteoglycans
water retention
Define the terms
epithelialisation, angiogenesis
and
fibroplasia
6. Describe how the healing
process can be influenced
by the
severity
of the wound
CHRONIC
Describe a
foreign body reaction
mainly macrophages (no antigen)
lymphocytes (pro-inflammatory cytokines)
persistent activation
scarring
Name
common denominators
of chronic inflammation
Give
examples
of diseases
with chronic inflammation
foreign body response, or infection (e.g. mycobacteria) or of an antigen (e.g. autoantigen).
persistence
of an irritant substance
some infections may initiate chronic not acute
Describe
main immune effector cells
involved in chronic inflammation
lymphocytes, macrophages,
~ neutrophils
Explain terms
granuloma
and
amyloidosis
granuloma
aggregations of T cells and macrophages
differentiate into epitheloid cells
fuse to giant cells
~ surrounding fibrous wall
caseation (necrosis)
amyloidosis
deposition of host proteins > amyloid
resistant to proteolytic breakdown so cumulative
function limiting
primary
immunoglobulin
light chain
secondary
serum
amyloid A
ROLE OF PROSTAGLANDINS AND LEUKOTRIENES
Define the term
eicosanoid
20 carbons lipid mediator
derived from essential fatty acid
→ arachidonic acid (ω6)
role in haemostasis and inflammation
GPCR mediated
Discuss the
prostaglandins
in relation to factors inducing production, biosynthetic pathway, receptors and role of the prostaglandins in inflammation.
biosynthesis
action
can act
differently
depends
on Gα
subunit
Discuss the
leukotrienes
in relation to stimulation of production, site of production, biosynthesis, receptors and role in inflammation
biosynthesis
Briefly discuss the types of
drug
which may be used to modulate eicosanoid production and/or effects and state their clinical relevance
NSAIDs target the COX enzyme
COX isoforms COX-1 COX-2
COX-1 homeostasis
COX-2 inflammation
COXIBs designed to be COX-2 selective
HISTAMINE AND 5-HT
Describe the
synthesis, storage
and
metabolism
of histamine and serotonin
Histamine
high conc in skin, bronchial and intestinal mucosa
Histidine → histamine (enzyme L-histidine decarboxylase)
stored in mast cells
slow turnover
faster production in other sites
metabolism
Histamine [Methylhistamine] → Methylimidazole acetic acid [N-methyl transferase] → Mono amine oxidase
Serotonin
dietary tryptophan
platelets, GI tract, CNS
platelets store,
synthesise
enterochromaffin cells store and synthesise
→ 5-hydroxytryptophan → 5-hydroxytryptamine
metabolism
→ 5-HIAA
Explain the factors, which induce
release
of these neurotransmitters
Histamine
allergy (IgE-mast cell)
physical injury
drugs/chemicals
Serotonin ?
Place the
effects
that these transmitters have in the context of their role in inflammation but also
understand their physiological role within the body
Histamine
intestinal smooth muscle contracts
respiratory
bronchoconstriction (rabbits)
bronchorelaxation (sheep)
tracheal relaxation (cats)
uterine smooth muscle contracts
cardiovascular
large vessels constrict
small vessels dilate
permeability (cadherin phosphorylation)
exocrine glands
gastric acid secretion
release of cytokines and other inflammatory mediators
function of macrophages, T & B cells, cytokine production, MHC II expression
Serotonin
GI tract
inhibitory/excitatory
control gastrointestinal function
CNS
sleep, behaviour, anxiety
platelets
promotes aggregation, local vasoconstriction and permeability
important role in autoimmunity
Illustrate the
receptors
involved in mediating histamine and 5HT effects
Histamine
H1
GPCR: phospholipase C
intracellular calcium ^
H2
GPCR: adenylyl cyclase
cAMP ^
Serotonin
5-HT-1,2,4 = GPCRs
5-HT-3 = ion gated
Describe the types of
drug classes
, which may be used to interact with these neurotransmitter/ receptor effects
Anti-histamines
receptor antagonists (usually H1)
don't inhibit release of histamine
Serotonin
agonist
antagonist
reuptake inhibitors
ACUTE
ACUTE 1
Name
stimuli
for inflammatory reactions
microbial
bacterial/fungal toxins/products, viral induced cell death, parasites
physical
cut, burn, fracture, foreign body
chemical
acid, alkali, industrial chemicals
immunological
normal response to infectious agent, hypersensitivity
Describe
cardinal signs
of inflammation
Heat
Redness
Swelling
Pain
Loss of function
Understand that inflammation is in principle a
protective response
but can become a major driver of
disease/pathology if deregulated
Explain changes in
vascular responses
during inflammation
vasodilation
permeability increase (capillaries/venules)
hydrostatic pressure
increase
, osmotic pressure
decrease
proteins leak out
oedema
Describe
key inflammatory mediators
and their
effects
on the organism
pain
prostaglandins
bradykinin
permeability
histamine
C2a, C3a, C4a, C5a
bradykinin
serotonin
leukotrienes
platelet activating factor
vasodilation
histamine
serotonin
nitric oxide
prostaglandins
cytokines
tumour necrosis factor α (TNFα)
triggers inflammation
interleukin-1 (IL-1α, IL-1β)
fever, lethargy, inappetance
interleukin-6 (IL-6)
from innate immune cells, affects inflammation and acquired immunity - mediator of acute-phase reaction and of septic shock
ACUTE 2
Explain the function of exudates
distributes clotting factors, mediators, antibodies, complement
drains pathogens to lymph nodes for specific immune response
dilutes toxins
Name different types of exudates
catarrhal
abundant, cloudy, thin/restricted, thick, white, sticky, mucous membranes (nasopharynx, airways, lower GI tract, uterus and mucous glands), rich in desquamated epithelial cells and neutrophils
fibrinous
abundant, severe reactions, serous membranes, alveoli, ~CT, fibrinogen > elastic fibrin deposits
serous
abundant, watery, low protein, mild reactions, serous and synovial membranes, CT
supparitive
often bacterial, opaque, viscous, odorous pus, large numbers of dying/dead neutrophils, necrotic tissue debris partly liquefied by proteases, peptidases and lipases. breakdown products cholesterol, lecithin, fats. localised = abscess, spread = cellulitis
haemorrhagic
frank bleeding, inflamm reaction, organs with a rich vascular
supply - lung, udder, intestine, esp. if causal agent actively damages vessel walls, interferes with coagulation
necrotising
cell death, result of ischemia (by spasm/thrombosis of blood supply) or acute venous congestion/stasis (by strangulation/thrombosis of venous return) or potent necrotising toxins
Describe mechanisms of leukocyte adherence and migration
slowed blood flow
rolling
selectins loosely bind and detach
arrest
chemoattractants activate integrin - binds to ICAM-1 on wall
emigration
squeezes through endothelial gaps into tissues
neutrophils first, then monocytes which differentiate into macrophages
chemotaxis
follow chemoattractant gradient
migration promoting factors: C3a, C5a,
PGE1/2, LTB4, IL-8, bacterial products
Explain the functions of neutrophils in inflammation
phagocytosis of foreign particles, bacteria, debris etc
promoted by opsonins - antibodies, complement
short-lived, can't re-synthesise lysozymes
Describe the role of monocytes and macrophages during inflammation
long-lived and re-synthesise a variety of lysozymes
phagocytose (opsonised) pathogens via scavenger, Fc, complement receptors
secrete toxic factors - kill pathogens - H2O2, nitric oxide, proteases
secrete cytokines and chemokines - alert other immune effector cells - IL-1, TNF-α, IL-6
secrete colony stimulating factors - promote differentiation of recruited immature WBCs
likely appropriate to phagocytosed material
SEQUEL
Differentiate between the fundamental processes of healing and progression to suppuration
progression to supparation
intense and prolonged neutrophil emigration
usually associated with localisation of pyogenic bacteria and production of potent toxins
necrosis, massive leakage of exudate, often thrombosis and stasis
Describe processes and mediators involved in the resolution phase of inflammation
Explain and describe what granulation tissue is
Outline processes involved in abscess formation
Describe events associated with progression to chronic inflammation
prolonged or repeated action of a low-grade irritant or causal agent not eliminated
vascular granulation tissue
matures to
fibrous tissue
ACUTE 3
Describe systemic effects of acute inflammation and their role in disease development
Explain the term leukocytosis and the physiological mechanisms behind
increase in the concentration of leukocytes in blood
neutrophilia
local bacterial, viral infections, trauma
temporary neutropenia
release of large numbers of relatively mature
cells from reserves in hematopoietic tissues (bone marrow) r
if prolonged, immature neutrophils released
eosinophilia
parasitic infection
Outline mechanisms of fever induction
severe infections by viruses, bacteria and larger parasites
stimulation of macrophages by infection or microbial products
synthesis and secretion of IL-1 and TNF-a
act on brain to induce PGE2
increase in the hypothalamic thermostat
interaction microbial products with TLR on brain endothelial cells
Name and describe components and mechanisms of acute phase responses
induction of increased synthesis of host proteins
attracting leukocytes into tissues
clearing microorganisms
blood clotting
controlling proteases released
synthesised rapidly by the liver
species specific, diagnostic value
mediated by IL-6 from activated macrophages
acute phase proteins
more IL-6
Describe general pathomechanisms associated with the development of
septic shock
excessive or failing immune response to organism
inappropriate generation and release of inflammatory compounds
pathogen or products enter bloodstream
generalized inflammatory response (fever, ^HR, hyperventilation, low or high blood leukocyte count)
microthrombi and neutrophil aggregations - vascular blockage - tissue ischaemia
dissiminated intravascular coagulation (DIC)
disrupted homeostatic balance - procoagulant:anticoagulant pathways
widespread thrombosis and impaired tissue perfusion
multiple organ dysfunction/failure, often fatal
fever, acute phase responses, and increased vascular dilatation and permeability
massive exudation and emigration of neutrophils into e.g. lung
vascular smooth muscle relaxation
hypotensive shock
HYPERSENSITIVITY
HYPERSENSITIVITY III & IV
Explain
mechanisms
involved in
type IV
hypersensitivity
extension of normal T cell mediated immune responses
T cell cytotoxic action and activation of macrophages
allergic reactions to bacteria, viruses and fungi
specific T cells release lymphokines, attract macrophages, more lymphocytes
other lymphokines (IFN) activate the macrophages
aggressive killing function
ischemia
Outline events that cause
contact sensitivity
allergic reactions to certain simple chemicals
Give
examples
of
type III
hypersensitivity reactions
vasculitis - often vessels of the kidneys, joints, skin and heart
immune complexes-Fcγ receptors on tissue macrophages
synthesize cytokines - attract neutrophils
phagocytose the immune complexes
release proteolytic enzymes which damage cells and vessels
haemorrhagic oedema
necrosis
(certain chronic infections, some autoimmune diseases)
Explain the term
granulomatous inflammation
persistent infection
development of epitheloid cells and giant cells from the pool of activated macrophages
organism is killed - repaired by fibrosis
area of caseous necrosis walled off by CT, secreted by the granulation reaction
can become calcified (mineralisation)
liquifaction due to proteolytic enzymes
bursting of the tubercles
bacteria escape
and spread
granuloma may kill microorganism
Describe how deposited
immune complexes
elicit inflammation
soluble antigen +
circulating IgG or IgM
locally in blood vessels and tissues
'Arthus reaction'
vessels damaged and inflamed
in blood - deposited in blood vessel walls and underlying tissue
HYPERSENSITIVITY I & II
Explain how hypersensitivity reactions are
induced
interaction of the antigen/allergen wiith IgE antibodies
Explain
mechanisms
of
type I
hypersensitivity reactions and
allergy
development
general anaphylaxis
IgE bound to blood basophils
bronchoconstriction, contraction of smooth muscle, increase vascular permeability
rare, often fatal
local anaphylaxis (allergy)
IgE bound to mast cells
degranulation of mast cells > histamine
vascular permeability and smooth muscle spasm
oedema, bronchoconstriction
LTB4 attracts eosinophils
recognise IgE complex
releases more mediators
PGs and LTs > late stages of phase I
Give
examples
of
type II
hypersensitivity reactions
antibody dependent cell-mediated cytotoxicity by killer cells
surface receptor endocytosis or down-regulation
complement-mediated lysis of antibody-coated cells
phagocytosis of antibody-coated/opsonised cells, by liver, spleen, tissue macrophages
antibodies reacting with cell surface antigens
Describe how
systemic anaphylaxis
develops
sudden release of immunological mediators in the skin, respiratory, cardiovascular, and gastrointestinal system
Classify
different types of hypersensitivity reactions
I = immediate anaphylaxis
II = cytotoxic
III = immune complex disease
IV = cell-mediated delayed type (DTH)
Acute 1
Histamine and 5-HT
Role of PGs and LTs
Acute 2
Acute 3
Sequel to acute
Chronic
Hypersensitivity I and II
Hypersensitivity III and IV
Healing
Healing examples
