The document outlines the pathophysiology of sepsis, focusing on the role of toll-like receptors, the effects of microbial components on immune cells, and the balance between pro-inflammatory and anti-inflammatory responses. It discusses mechanisms of cellular injury and the impact of sepsis on various organ systems, including the cardiovascular, pulmonary, gastrointestinal, renal, and nervous systems. Additionally, it covers pro-inflammatory cytokines and anti-inflammatory mediators involved in the immune response to sepsis.

1. Pathophysiology
of
sepsis
Discussion
points:
1.
Discuss
the
role
of
toll-­‐like
receptors
(TLRs)
in
the
pathophysiology
of
sepsis
2.
Briefly
state
the
effects
of
the
binding
of
microbial
components
to
host
immune
cell
surface
receptors
3.
State
3
pro-­‐inflammatory
cytokines
that
are
involved
in
the
pathophysiology
of
sepsis
4.
The
host
immune
response
to
sepsis
is
regulated
by
two
counter-­‐balance
processes:
the
pro-­‐inflammatory
and
anti-­‐inflammatory
processes.
Why
is
this
important?
5.
The
pro-­‐inflammatory
mediators
are
mentioned
as
above.
State
2
anti-­‐
inflammatory
mediators
that
are
involved
in
the
host
response
to
sepsis.
6.
Tumor
necrosis
factor-­‐alpha
(TNFa)
and
interleukin-­‐1
(IL-­‐1)
share
a
series
of
beneficial
biological
effects.
List
these
effects.
7.
Briefly
discuss
when
would
pro-­‐inflammatory
process
leads
to
the
development
of
systemic
inflammatory
response
syndrome
(SIRS)/sepsis
8.
Explain
two
possible
reasons
why
a
local
immune
response
to
an
infection
can
become
generalized
and
systemic
(as
in
SIRS)
9.
Discuss
three
possible
mechanisms
of
cellular
injury
in
SIRS.
10.
Discuss
on
the
effects
of
sepsis
on
the
following
organ
systems:
i. Cardiovascular
system:
ii. Lungs:
iii. Gastrointestinal
tract:
iv. Renal
system:
v. Cerebral
Nervous
System:

2. MCQ
In
the
pathophysiology
of
bacterial
sepsis
A. Toll-­‐like
receptors
bind
to
the
cell
components
of
the
micro-­‐organism
B. Leukocytes
are
activated
prior
to
aggregation
C. Nitric
oxide
is
an
anti-­‐inflammatory
mediator
D. Expression
of
TNF-­‐alpha
is
a
sign
of
cellular
death
E. Phagocytosis
is
a
main
cellular
mechanism
to
combat
the
micro-­‐organism
Below
are
the
effects
of
fever
in
sepsis
patient
A. It
slows
the
growth
of
the
invading
micro-­‐organism
B. It
mobilizes
polymorphonuclear
cells
to
site
of
infection
C. It
potentiates
the
role
of
TNF-­‐alpha
D. It
attenuates
the
activity
of
interferon-­‐gamma
E. It
increases
phagocytosis
Which
of
the
following
statements
regarding
cellular
injury
in
sepsis
are
true?
I. Anti-­‐inflammatory
mediators
results
in
mitochondrial
dysfunction
II. Increased
apoptosis
aggravates
cellular
injury
III. Micro-­‐thrombosis
is
a
complication
of
cellular
injury
IV. Oxidative
stress
reaction
is
a
cause
of
mitochondrial
injury
A. I
and
II
B. II
and
III
C. III
and
IV
D. I,
II
and
III
E. I,
II
and
IV

3. Pathophysiology
of
sepsis
Discussion
points:
1.
Discuss
the
role
of
toll-­‐like
receptors
(TLRs)
in
the
pathophysiology
of
sepsis
Answer:
Toll-­‐like
receptors
are
a
type
of
pattern
recognition
receptors
(PRRs)
on
the
surface
of
host
immune
cells
that
recognize
and
bind
to
the
pathogen-­‐associated
molecular
patterns
(PAMPs)
of
microorganisms.
Examples:
• the
peptidoglycan
of
Gram-­‐positive
bacteria
binds
to
TLR-­‐2
on
host
immune
cells
• the
lipopolysaccharide
of
Gram-­‐negative
bacteria
binding
to
TLR-­‐4
2.
Briefly
state
the
effects
of
the
binding
of
microbial
components
to
host
immune
cell
surface
receptors
Answer:
The
binding
of
immune
cell
surface
receptors
to
microbial
components
causes:
• A
signaling
cascade
that
induces
in
the
release
of
proinflammatory
cytokines
• Activation
of
polymorphonuclear
leukocytes
(PMNs)
that
causes
the
expression
of
adhesion
molecules,
which
in
turn,
results
in
their
aggregation
and
margination
to
the
vascular
endothelium.
3.
State
3
pro-­‐inflammatory
cytokines
that
are
involved
in
the
pathophysiology
of
sepsis
Answer:
Tumor
necrosis
factor
alpha
[TNFa],
interleukin-­‐1
[IL-­‐1],
chemokines
(such
as
the
intercellular
adhesion
molecule-­‐1
[ICAM-­‐1]
and
vascular
cell
adhesion
molecule-­‐1
[VCAM-­‐1])
and
nitric
oxide.
4.
The
host
immune
response
to
sepsis
is
regulated
by
two
counter-­‐balance
processes:
the
pro-­‐inflammatory
and
anti-­‐inflammatory
processes.
Why
is
this
important?
Answer:
Pro-­‐inflammatory
process
leads
to
cellular
injury
whereas
anti-­‐inflammatory
process
leads
to
cellular
repair.
The
balance
of
pro-­‐inflammatory
and
anti-­‐inflammatory
mediators
regulates
the
inflammatory
processes,
including
adherence,
chemotaxis,
phagocytosis
of
invading
bacteria,
bacterial
killing,
and
phagocytosis
of
debris
from
injured
tissue.
If
the
mediators
balance
each
other
and
the
initial
infectious
insult
is
overcome,
homeostasis
is
restored
and
the
end
result
is
tissue
repair
and
healing.

4. 5.
The
pro-­‐inflammatory
mediators
are
mentioned
as
above.
State
2
anti-­‐
inflammatory
mediators
that
are
involved
in
the
host
response
to
sepsis.
Answer:
Although
such
cytokines
have
anti-­‐inflammatory
effects,
they
are
not
universally
anti-­‐inflammatory.
For
example,
IL-­‐10
and
IL-­‐6
are
considered
anti-­‐inflammatory,
they
both
enhance
B
cell
function
(proliferation,
immunoglobulin
secretion)
as
well
as
encourage
the
development
of
cytotoxic
T
cells.
Note:
Anti-­‐inflammatory
cytokines
are
defined
as
cytokines
that
inhibit
the
production
of
TNFa
and
IL-­‐1.
6.
Tumor
necrosis
factor-­‐alpha
(TNFa)
and
interleukin-­‐1
(IL-­‐1)
share
a
series
of
beneficial
biological
effects.
List
these
effects.
Answer:
• Fever
• Hypotension
• Acute
phase
protein
response
• Induction
of
IL-­‐6
and
IL-­‐8
• Coagulation
activation
• Fibrinolytic
activation
• Leukocytosis
• Neutrophil
degranulation
and
augmented
antigen
expression
(TNF)
• Increased
endothelial
permeability
(TNF)
• Stress
hormone
response
• Enhanced
gluconeogenesis
(TNF)
• Enhanced
lipolysis
(TNF)
7.
Briefly
discuss
when
would
pro-­‐inflammatory
process
leads
to
the
development
of
systemic
inflammatory
response
syndrome
(as
in
SIRS)/sepsis
Answer:
Systemic
inflammatory
response
syndrome/sepsis
occurs
when
the
release
of
proinflammatory
mediators
in
response
to
an
infection
exceeds
the
boundaries
of
the
local
environment,
leading
to
a
more
generalized
response.
8.
Explain
two
possible
reasons
why
a
local
immune
response
to
an
infection
can
become
generalized
and
systemic
(as
in
SIRS)
Answer:
It
is
uncertain
why
immune
responses
that
usually
remain
localized
sometimes
spread
beyond
the
local
environment
causing
sepsis.
The
cause
is
likely
to
be
multifactorial
and
these
factors
include:

5. 1. Effects
of
microorganisms:
Certain
bacterial
cell
wall
components
(endotoxin,
peptidoglycan,
muramyl
dipeptide,
and
lipoteichoic
acid)
and
bacterial
products
(staphylococcal
enterotoxin
B,
toxic
shock
syndrome
toxin-­‐1,
Pseudomonas
exotoxin
A,
and
M
protein
of
hemolytic
group
A
streptococci)
may
lead
to
the
progression
of
a
local
infection
to
sepsis.
2. Excess
proinflammatory
mediators:
Large
quantities
of
proinflammatory
cytokines
released
in
patients
with
sepsis
may
spill
into
the
bloodstream,
contributing
to
the
progression
of
a
local
infection
to
sepsis.
3. Genetic
predisposition:
In
addition,
some
individuals
may
be
genetically
susceptible
to
developing
sepsis.
The
single
nucleotide
polymorphism
(SNP)
is
the
most
common
form
of
genetic
variation.
Various
SNPs
are
associated
with
increased
susceptibility
to
infection
and
poor
outcomes.
9.
Discuss
three
possible
mechanisms
of
cellular
injury
in
SIRS.
Answer:
1. Tissue
ischemia:
Metabolic
derangement
results
in
imbalance
between
oxygen
availability
and
oxygen
delivery.
Microcirculatory
lesions
developed
as
a
result
of
imbalances
in
the
coagulation
and
fibrinolytic
systems
also
disrupt
tissue
oxygenation
causing
tissue
ischemia
and
cellular
injury.
2. Mitochondrial
dysfunction:
Proinflammatory
mediators
also
cause
mitochondrial
dysfunction
(e.g.,
impaired
mitochondrial
electron
transport)
via
a
variety
of
mechanisms,
including
direct
inhibition
of
respiratory
enzyme
complexes,
oxidative
stress
damage,
and
mitochondrial
DNA
breakdown.
3. Delayed
Apoptosis:
Apoptosis
(programmed
cell
death)
is
the
principal
regulatory
mechanism
by
which
senescent
or
dysfunctional
cells
are
normally
eliminated.
This
is
the
dominant
process
that
terminates
the
inflammation
once
an
infection
has
subsided.
However,
during
sepsis,
proinflammatory
cytokines
may
delay
apoptosis
in
activated
macrophages
and
neutrophils,
thereby
prolonging
or
augmenting
the
inflammatory
response
and
contributing
to
the
development
of
multiple
organ
failure.
*
Note:
But
the
apoptosis
of
other
inflammatory
cells
such
as
the
lymphocytes
is
increased,
which
alters
the
immune
response
efficacy
resulting
in
decreased
clearance
of
invading
microorganisms.

6. 10.
Discuss
on
the
effects
of
sepsis
on
the
following
organ
systems:
i. Cardiovascular
system:
Sepsis
results
in
hypotension
due
to
the
following
mechanisms:
o Excessive
vasodilation:
! This
is
caused
by
the
release
of
vasodilators
such
as
nitric
oxide
(NO)
and
prostacyclin
from
the
endothelial
cells.
! Impaired
compensatory
secretion
of
antidiuretic
hormone
(vasopressin)
is
another
postulation
resulting
in
excessive
vasodilation.
o Redistribution
of
intravascular
fluid:
! This
is
a
consequence
of
both
increased
endothelial
permeability
and
reduced
arterial
vascular
tone
leading
to
increased
capillary
pressure.
Impaired
myocardial
contractility
due
to
the
release
of
myocardial
depressant
substances.
ii. Lungs:
Endothelial
injury
in
the
pulmonary
vasculature
during
sepsis
disturbs
capillary
blood
flow
and
enhances
microvascular
permeability,
resulting
in
interstitial
and
alveolar
pulmonary
edema.
This
results
in
ventilation-­‐
perfusion
mismatch
and
leads
to
hypoxemia.
Acute
respiratory
distress
syndrome
is
a
manifestation
of
these
effects.
iii. Gastrointestinal
tract:
Gut
mucosal
ischemia
depresses
the
gut's
normal
barrier
function.
This
results
in
translocation
of
bacteria
and
endotoxin
into
the
systemic
circulation
(as
well
as
possibly
via
lymphatics),
thus
extending
the
septic
response.
iv. Renal
system:
Sepsis
can
results
in
acute
renal
failure.
This
may
be
due
to
acute
tubular
necrosis
secondary
to
hypoperfusion
and/or
hypoxemia.
Other
contributing
factors
include
the
release
of
cytokines
(e.g.,
tumor
necrosis
factor),
and
activation
of
neutrophils
by
endotoxin
causing
renal
injury.
v. Cerebral
Nervous
System:
Sepsis
causes
altered
mental
status.
This
could
be
due
to:
o cerebral
microabscesses
possibly
due
to
hematogenous
infection
o changes
in
cerebral
metabolism
and
alterations
in
cell
signaling
o dysfunctional
blood
brain
barrier
allowing
increased
leukocyte
infiltration,
exposure
to
toxic
mediators,
and
active
transport
of
cytokines
across
the
barrier

7. Reference:
Neviere
R.
Pathophysiology
of
sepsis.
In:UpToDate,
Manaker
S,
Sexton
DJ
(Eds).
UpToDate,
Waltham,
MA.
Available
at
URL:
www.uptodate.com.
Accessed
10
September
2014.
Cinel
I,
Dellinger
RP.
Advances
in
pathogenesis
and
management
of
sepsis.
Curr
Opin
Infect
Dis.
2007;20(4):345-­‐52.