SYSTEMIC RESPONSE TO INJURY Flashcards
occurs as a
consequence of the local or systemic release of
“damage-associated” molecules to mobilize the
necessary resources required for the restoration
of homeostasis
inflammatory response
Traumatic injury activates the innate immune
system to produce a __________ in an attempt to limit damage
and to restore homeostasis.
systemic inflammatory
response (SIR)
2 GENERAL RESPONSES (CELLULAR INJURY)
acute proinflammatory response
anti-inflammatory response
Systemic inflammatory response (SIRs)
is achieved clinically by two or more of
the following criteria:
■ If you have hypothermia or
hyperthermia
■ Tachycardia or Tachypnea
■ Abnormal WBC count
Endogenous molecules that are produced as
a consequence of tissue damage or cellular
stress
DAMAGE- ASSOCIATED MOLECULAR PATTERNS
(DAMPS) OR ALARMINS
DAMPS interact with immune and
non immune cell receptors to initiate a
“______” systemic inflammatory response
following severe traumatic injury.
Sterile
In many cases, DAMP molecules are sensed by
______, which
are the same receptors that cells use to sense
invading pathogens.
pattern recognition receptors (PRRs)
Identifiable source of microbial insult
Infection
In SIRS, 2 or more of the following criteria are met:
Temperature:____
Heart rate:_______
Respiratory rate:____
PaCO2:_____
- ≥38c (100.4F) or ≤36C (96.8F)
- ≥90 beats per minute
- ≥20 breaths per minute
- ≤32 mmHg
Identifiable source of infection + SIRS
Sepsis
Sepsis + organ dysfunction
Severe sepsis
Sepsis + Cardiovascular collapse
Septic shock
Released passively from damaged or necrotic
cells and is detected rapidly in the circulation
within 30 minutes post injury.
HIGH-MOBILITY GROUP PROTEIN B1
In particular, HMGB1 binding to TLR24 triggers
the proinflammatory cytokine release that
mediates____
“sickness behavior”
activation of TLRs mainly occurs in ____
myeloid
cells
Acute Lung Injury (ALI) is caused by ____ in
Traumatic Brain Injury (TBI)
HMGB1
can act as
DAMPs by triggering an inflammatory response
to necrosis and cellular stress.
Mitochondrial proteins and/or DNA
Leaked from damaged mitochondria, leads both
to inflammasome activation and activation of the
_______
stimulator of interferon gene pathway (STING)
Function as molecular chaperones to monitor
and maintain appropriate protein folding,
physiological seen in our cytoplasm which
discard improperly folded proteins
HEAT-SHOCK PROTEINS
Surface and cytoplasmic receptors that sense
DAMPS and mediate the innate immune
response
PATTERN RECOGNITION RECEPTORS (PRRS)
Classes of receptors that are important for
sensing damaged cells and cell debris / DAMPs
which are the same receptors that cells use to
sense invading pathogens
PATTERN RECOGNITION RECEPTORS (PRRS)
molecularly diverse group of molecules that
share a conserved mode of action defined by
complement activation, agglutination and
neutralization, and opsonization
SOLUBLE PATTERN RECOGNITION MOLECULES: THE
PENTRAXINS
short pentraxin; first PRM to be
identified
C-REACTIVE PROTEIN (CRP
has 51% sequence similarity to human
CRP, also contains the pentraxin
molecular signature
SERUM AMYLOID PROTEIN (SAP)
A long pentraxin family member, in the
“sterile” inflammatory response
associated with cellular stress
PENTRAXIN 3 (PTX3)
CNS receives information with regard to
injury-induced inflammation via _____ as well as direct neural projections
that transmit information to regulatory areas in
the brain
soluble
mediators
NEUROENDOCRINE RESPONSE TO INJURY
● Hypothalamic-Pituitary-Adrenal Axis
● Sympathetic nervous system
HYPOTHALAMIC- PITUITARY- ADRENAL AXIS (pathway)
Injury → Circulating cytokines or direct neural
input via vagal fibers → hypothalamus →
corticotropin-releasing hormone (CRH) release
→ anterior pituitary → ACTH release → zona
fasciculata of the adrenal glands →
glucocorticoids release
Major glucocorticoid in humans, with
anti-inflammatory actions
CORTISOL
atrophic adrenal glands
caused by exogenous steroid administration
Adrenal insufficiency
exaggerated proinflammatory response
associated with a blunted adrenocortical
response
Critical illness-related corticosteroid
insufficiency (CIRCI)
Counteract the anti-inflammatory activity of
glucocorticoids
MACROPHAGE MIGRATION INHIBITORY FACTOR
Expressed by the pituitary gland that has both
metabolic and immune-modulatory effect
GROWTH HORMONE
Insulin enhances enhanced hepatic synthesis of
________
insulin-like growth factor-1 (IGF-1)
Anabolic growth factor that is known to improve
the metabolic rate, gut mucosal function, and
protein loss after traumatic injury
INSULIN-LIKE GROWTH FACTOR-1 (IGF-1)
T or F
IGF-1 is decreased in critical illness, leading to a
catabolic state
True
appetite stimulant that is secreted by the
stomach
GHRELIN
Ghrelin is a natural ligand for _____
GH-secretagogue receptor 1a (GHS-R1a)
T or F
low ghrelin levels were a positive predictor of
ICU-survival in septic patients
False
are
hallmarks of injury and critical illness due to the
catabolic effects of circulating mediators,
including catecholamines, cortisol, glucagon,
and growth hormone.
Hyperglycemia and insulin resistance
A mineralocorticoid released by the zona
glomerulosa of the adrenal cortex
ALDOSTERONE
T or F
Aldosterone also gives positive feedback to
anti-inflammatory effects by inducing
pro-inflammatory cytokines.
False
-negative feedback
are small molecules that are
highly reactive due to the presence of unpaired
outer orbit electrons
Reactive oxygen and nitrogen species (ROS,
RNS, respectively)
Reactive oxygen and nitrogen species (ROS,
RNS, respectively)-These are commonly known as ____
Free radicals
a way of disposing of
damaged organelles and debris aggregates,
ROS
AUTOPHAGY
Autophagy is stimulated by Th1 cytokines with
activation of TLR in macrophages but is
inhibited by________
Th2 cytokines
Mechanism for clearing senescent or
dysfunctional cells without promoting an
inflammatory response
APOPTOSIS
the side effects of too much cortisol and growth hormone
insulin resistance and hyperglycemia
Aldosterone reduces expression of the insulin-sensitizing factors which contribute to ________________
insulin resistance
ROS has also been shown to have important roles as signaling messengers, particularly in the immune system through their ability to modulate________
cysteine residues by oxidation
Provides negative feedback for ROS synthesis
Pyruvate kinase
Important proteins involved in the unfolded protein response are:
IRE1, PERK, ATF6
Neutrophil apoptosis is inhibited by _______
Inflammatory products
Is activated through the binding of death receptors, which leads to the recruitment of Fas-associated death domain protein and subsequent activation of capsase 3
Extrinsic pathway
proceeds through protein mediators that influence mitochondrial membrane permeability
Intrinsic pathway
(Increased membrane permeability leads to the release of mitochondrial cytochrome c, which ultimately activates caspase 3 an thus induces apoptosis)
Difference between apoptosis and necroptosis
Necroptosis- nucleus of the cell remains intact
Form of regulated cell death that is dependent on the activity of the proinflammatory caspase enzyme associated with inflammasome
Pyroptosis
