Systemic Inflammatory

Response to Injury
Abdulaziz Ahmed, MD

(Orthopedics Resident)

Important definitions
Infection
Identifiable source of
microbial insult

SIRS (2 or more)
Temp >38 or <36
HR > 90
RR >20 or PaCO2 <32 or
mechanical ventilation
WBC >12,000 or <4000 or
>10% bands

Sepsis
Infection + SIRS

Severe Sepsis
Sepsis + organ dysfunction

Septic shock
Sepsis + cardiovascular
collapse (requiring
vasopressor support)

Tissue and cellular

injury
Activation of the innate immune
system to produce a systemic
inflammatory response to restore
homeostasis.
The degree of the systemic
inflammatory response following
trauma is proportional to injury
severity and is an independent
predictor of subsequent organ
dysfunction and resultant mortality.

Systemic response

It includes two general responses:

(a) an acute proinflammatory response resulting from innate
immune system recognition of ligands
(b) an anti-inflammatory response that may serve to modulate the
proinflammatory phase and direct a return to homeostasis

Basic Science Correlate

Endogenous damage-associated
molecular patterns (DAMPs)
E.g (IL-1a, Heat shock proteins, etc)
are produced following tissue and cellular
injury.
These molecules interact with immune and
nonimmune cell receptors to initiate a
sterile systemic inflammatory response
following severe traumatic injury.

CNS Regulation on Inflammation

in response to injury
The central nervous system (CNS)
receives and integrates information to
generate a coordinated response.
It receives information regard to
injury-induced inflammation both via
soluble mediators as well as direct
neural projections that transmit
information to regulatory areas in the
brain

Afferent Signals on CNS

Direct pathway
CNS areas devoid of BBB
Cytokines (TNF), chemokines adhesion molecules etc

Neural pathway
Vagus nerve Solitary Nucleus
Examples of actions after Vagal stimulation
Leads to Parasympathetic release of Ach
Leads to modulation of HPA +Glucocorticoids
Stimulates Sympathetic Nervous System

Neuroendocrine Response to Injury

Hypothalamic regulation
1. CRH
2. GHRH
3. LHRH/GnRH

Posterior Pituitary
regulation
1. Vasopressin
2. Oxytocin

4. TRH

Autonomic System
Anterior Pituitary regulation
5.
6.
7.
8.
9.

ACTH cortisol
GH
Somatostatin
Prolactin
Endorphins

10. TSH T3/T4

11. Gonadotrophins
12. Sex hormones

3. NE / E
4. Aldosterone
5. Renin-angiotensin
system
6. Glucagon
7. Insulin

CRH / ACTH / Cortisol (+)

a. CRH

Stimulated by Cytokines and Vagal stimulation.

b. ACTH

Stimulated by CRH and Cytokines (which explains its highly elevated

during injury).

levels

c. Cortisol
1. favors gluconeogenesis; insulin resistance in muscles & adipose tissue.
2. induces protein degradation in the skeletal muscle & releases lactate for
hepatic gluconeogenesis
3. potentiates release of FA, triglycerides & glycerol from adipose tissue for
energy source
4. It downregulates proinflammatory cytokines production (TNF alpha, IL-1, IL6); and increases the production of anti-inflammatory mediator IL-10

Acute adrenal Insufficiency (AAI):

Life threatening complication
Commonly due to adrenal suppression from exogenous
administration of glucocorticoid
Manifestation:
1. weakness, n / v, fever & hypotension
2. Hypoglycemia (due to low gluconeogenesis)
3. Hyponatremia & Hyperkalemia (impaired renal tubular
reabsorption due to insufficient aldosterone)

CRH/ACTH/Cortisol levels are proportionate to

severity of Trauma

Growth Hormone +
GH helps in mobilization of fat stores,
increases protein synthesis and blood glucose
level.
GH increased in injury
Somatostatin increased in injury
IGF-1 decreased in injury
the effects of IGF-1 is inhibited by
proinflammatory cytokines (TNF, IL-1 and
IL-6)

Endogenous Opioids (+)

Endorphins, enkephalins
Secreted by Ant.Pituitary
Elevated after injury & surgery
Decrease pain and cause
hypotension by serotonin

Macrophage Inhibitory Factor

(+)

Produced by:
a. Anterior pituitary gland
b. T lymphocytes at the site of inflammation.

Actions:
a. A glucocorticoid antagonist (suppresses the
immunosuppresive effects of cortisol).
b. It is a proinflammatory mediator.

TRH / TSH (-)

In injury:
a. Decreased TSH release
b. Conversion of T4 > T3 in the target
organs is impaired due to cortisol.
c. T4 is converted to an inactive T3 called
rT3 Euthyroid Sick Syndrome
d. T3 decreased but rT3 increased

Gonadotrophins & Sex Hormones

(-)

Injury, stress or severe illness ----> (-) GRH

----> (-) LH and (-) FSH ---> decrease estrogen
and androgen secretions.
Causes post traumatic menstrual irregularities
and decrease libido.

Prolactin (+)

Elevated level after injury in adults not

seen in children.
Causes amenorrhea.
Due to decreased Gonadrotrophins,
Dopamine.

Catecholamines (Epi/NE) +
Causes hypermetabolic state following
severe injury
3 4fold increase of E & NE in the
plasma for 24 48 hrs.
Causes:
a.
b.
c.
d.
e.

Promotes glycogenolysis, gluconeogenesis, lipolysis and

ketogenesis.
Decreased insulin release & increase glucagon secretion.
Peripherally, it increases lipolysis in adipose tissue and
induces insulin resistance in skeletal muscle
It inhibit the release of aldosterone.
Immune function: -- enhances neutrophilia and
lymphocytosis

Mineralocorticoids (+)
Released by adrenal zona glomerulosa
ACTH is the most potent stimulator
Major function is to maintain
intravascular volume by conserving Na &
eliminating potassium and H+ in the
early distal convoluted tubules of
nephron

Renin - Angiotensin
Renin in Juxtaglomerular apparatus is released
by:
a.
b.
c.

ACTH
Baroreceptor respond to decrease blood pressure
Macula densa detects changes in chloride
concentration.

Action of angiotensin II:

d.
e.
f.
g.

Vasoconstrictor
(+) aldosterone
(+) ADH
Increase heart rate and contractility

Glucagon and Insulin

Glucagon: (Increased)
catabolic role
elevated release after injury

Insulin: (Decreased)
Inhibit its release in injury:
a.
b.
c.
d.
e.

Catecholamine
Glucagon
Somatostatin
Beta endorphins
IL-1

Vasopressin (ADH) +
Causes
a. readsorption of H2O in DCT
b. Vasoconstriction peripherally

Elevated plasma osmolality is its major stimulus:

Location of osmoreceptors: hypothalamus, portal
circulation

Oxytocin +

Elevated during injury but its

contribution is unknown.
Maybe due to its molecular similarity
to ADH.

Mediators of
Inflammation
Cytokines
Heat shock proteins
Reactive oxygen metabolites
Reperfusion injury

Eicosanoids
Includes prostaglandins, leukotrienes, thromboxane

Fatty Acid metabolites

Kallikrien-Kinen system
Serotonin
histamine

Cytokines

Most potent mediator of the inflammatory response

Eradicates invading microorganisms and promotes wound
healing
If excessively released can lead to septic shock and multiple
organ failure

Heat Shock Proteins

Intracellular protein modifiers and transporters that

protect cells from the deleterious effects of
traumatic stress.
Action Induced by: Hypoxia, Trauma, Heavy metals

Reactive Oxygen Species

Oxygen radicals are produced by reduction of oxygen to
superoxide anion, and further metabolized to form H2O2
(Hydrogen peroxide) & hydroxyl radicals
Causes injury by oxidation of unsaturated fatty acids w/in
cell membranes.
Activated leukocytes are potent generators for reactive
oxygen metabolites.
Cells are protected from this metabolite by oxygen
scavengers: GLUTATHIONE & CATALASES.

Eicosanoids

Products of oxidation of Arachidonic Acid

Synthesized rapidly upon tissue injury, cytokines and other
mediators

Kallikrein-Kinin System

Kinins (Bradykinin)
Potent Vasodilator
Increase capillary permeability
Evoke pain
Bronchoconstriction

Serotonin

Neurotransmitter
Tryptophan derivative in chromaffin cells of the
intestines
Vasoconstriction
Bronchoconstriction
Platelet aggregation

Histamine

Derived from Histidine

Stimulation of both H1 and H2 receptors causes:
Hypotension
Peripheral pooling of blood
Decrease venous return
Increase capillary permeability and Edema

Cell-Mediated Inflammatory
Response

1. Platelets:
Clot formed at the site of injury releases inflammatory
mediators w/c serves as the principal chemo-attractant
for neutrophils and monocytes.
Migration of platelets & neutrophils through the vascular
endothelium occurs w/in 3 hrs of injury

Cell-Mediated Inflammatory
Response
2. LYMPHOCYTES
CMI = Macrophages , NK
cells, Cytotoxic T Cells

Antibody-mediated =
Immunoglobulin production

Cell-Mediated Inflammatory
Response
3. Eosinophils:
Migrate to inflamed endothelium and
release cytoplasmic granules that are
cytotoxic
It preferentially migrate to sites of
parasitic infection and allergy
Resides in GIT, lung and genitourinary
tissues

Cell-Mediated Inflammatory
Response

4. Mast Cells: (Capillary leak and

vasodilation)
When activated it produce:
a.
b.

c.
d.
e.

Histamine
Cytokines (IL-3, IL4, IL-5, IL-6, IL-10, IL-13, IL-14 &
migration-inhibitory factor (MIF).
Eicosanoids
Proteases
Chemokines

Cell-Mediated Inflammatory
Response

5. Monocytes
.Monocytes are mononuclear phagocytes that
circulate in the bloodstream and can differentiate
into macrophages.

Cell-Mediated Inflammatory
Response

6. Neutrophils
.Neutrophils are among the first responders to sites of infection
and injury
.Neutrophils are circulating immunocytes with short half-lives (4
to 10 hours). Which can be prolonged by signals.
.Phagocytosed bacteria are killed using NADPH oxygenasedependent generation of ROS or by releasing lytic enzymes.

Endothelium-Mediated Injury
1. Neutrophil-Endothelium Interaction: (Leukocyte
Extravasation)

Endothelium-Mediated
Injury

Nitric Oxide
Prostacyclin
Endothelins
Platelet-Activating Factor
Atrial Natriuretic Peptides

Have a good day