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SYSTEMIC RESPONSE

TO INJURY
WILFREDO T. POLIDO JR. MD
Chief, Liver Transplant
St. Lukes Medical Center
A/Professor
Department of Surgery
FEU-NRMF Medical Center
SYSTEMIC RESPONSE TO INJURY
Inflammation (Latin, inflammatio, to set on fire) is
the complex biological response of vascular
tissues to harmful stimuli, such as pathogens,
damaged cells, or irritants.
Designed to restore tissue function
Major insults are associated with overwhelming
inflammatory response
Acute inflammation
Short-term process characterized by the classic signs of
inflammation due to the infiltration of the tissues by
plasma and leukocytes.
Chronic inflammation
Not characterized by classic signs of acute inflammation
Characterized by infiltration of mononuclear immune cells
(monocytes, macrophages, lymphocytes, and plasma
cells), tissue destruction, and attempts at healing
(angiogenesis and fibrosis).
SYSTEMIC RESPONSE TO INJURY
Systemic response to injury
Proinflammatory Phase activation of cellular events
Counterregulatory Phase restoration of homeostasis
Sepsis
Identifiable source of infection + SIRS
Severe Sepsis: Presence of organ dysfunction
Septic Shock: Cardiovascular collapse
SYSTEMIC RESPONSE TO INJURY
Systemic Inflammatory Response Syndrome
Presence of 2 or more of the following
Temp 38C or 36C
Heart rate 90beats/min
Respiratory rate 20 breaths/min or PaCO
2
32mmHg
Abnormal white blood cell count (>12,000/L or <4,000/L)
SIRS: Same pathophysiologic properties regardless of
etiology
Stage I: Local cytokine production incite inflammatory
response promoting wound repair and recruitment of the
reticular endothelial system.
Stage II: Local cytokines are released into circulation to
improve the local response leading to growth factor
stimulation and recruitment of macrophages and platelets.
CARS restore homeostasis.
Stage III: Homeostasis not restored. Activation of humoral
cascades and reticular endothelial system lead to loss of
circulatory integrity and end-organ dysfunction.
SYSTEMIC RESPONSE TO INJURY
CNS Regulation of Inflammation
Reflex Inhibition of Inflammation
Autonomic signaling regulates heart rate, BP, respiration,
temperature
Afferent Signaling
Immunologic input from circulatory (humoral) and neural
pathways
Vagal stimuli include cytokines (TNF- & IL-1; both of
which affect membrane integrity), chemoreceptors
Cholinergic Anti-Inflammatory Pathways
Primary transmitter is acetylcholine
Reduces macrophage activation
Reduce release of proinflammatory mediators
(TNF, IL-1&18, and High Mobility Group protein)
Signals target precisely the site of injury (vs. Humoral)
Hormonal Response to Injury
Virtually hormones of hypothalamic-pituitary-adrenal
axis influences the response to injury and stress.
Hormone receptors generate signals through the
following:
Receptor Kinases: Insulin and insulin-like GF
Guanine Nucleotide Binding: PGE and neurotransmitters
Ligand-gated Ion Channels: GABA and nicotinic receptors

SYSTEMIC RESPONSE TO INJURY
Adrenocorticotropic Hormone
Elevation is proportional to severity of injury
Boosts synthesis of corticosteroids
Glucocorticoids
Cortisol is the major glucocorticoid
Potentiates action of glucagon and epinephrine
Ensure additional energy source
Down regulates proinflammatory cytokine (TNF-, IL-1 & IL-6)
Increase anti-inflammatory IL-10
Insulin
Generally inhibited by stress response
Enhance T-cell proliferation and cytotoxicity
Increases functional B-cell population
SYSTEMIC RESPONSE TO INJURY
Macrophage Inhibitory Factor
Glucocorticoid antagonist
Reverse immunosuppressive effect
Potentiates septic shock
Aldosterone
Conserve sodium and eliminate potasium hydrogen ions
Growth Hormones
Promotes protein synthesis and mobilize fats
Catecholamines
Induces a hypermetabolic state
Increase thyroid, parathyroid and renin secretion
SYSTEMIC RESPONSE TO INJURY
Cytokine Response to Injury
Tissue macrophages, monocytes, mast cells,
platelets, and endothelial cells are able to produce a
multitude of cytokines.
The cytokines tissue necrosis factor-a (TNF-) and
interleukin (IL)1 are released first and initiate
cascades.
The release of IL-1 and TNF- (or the presence of
endotoxin or exotoxin) leads to cleavage of the
nuclear factor- (NF-) inhibitor.
Once the inhibitor is removed, NF- is able to
initiate the production of mRNA, which induces the
production other proinflammatory cytokines.
SYSTEMIC RESPONSE TO INJURY
Tumor Necrosis Factor-
Among the earliest and most potent mediator of host
response (monocyte and macrophages).
Induce muscle catabolism and cachexia
Interleukin-1
Induces fever and promote endorphin release
Primarily released by macrophages and endothelial cells
Interleukin-2
Primary promoter of T-lymphocyte proliferation Ig
productionand GUT barrier integrity
Interleukin-6
Demonstrate both pro- and anti-inflammatory roles
Induce neutrophil activation
Attenuate TNF- and IL-1 activity
SYSTEMIC RESPONSE TO INJURY
Interleukin-10
Modulates TNF- activity
Interleukin-12
Promote differentiation of T
H
1 cells
Interferon-
Produced by T-helper lymphocytes
Activates circulating and tissue macrophage
Promotes ARDS

SYSTEMIC RESPONSE TO INJURY
Cellular Response to Injury
Gene Expression and Regulation
Often determined by the production of corresponding
mRNA
Transcription factors become important because of
controlling their pathways mean ability to regulate cellular
response
Cell Signaling Pathways
Heat Shock Proteins: attenuate response by reducing O
2

metabolites, promoting T
H
2 cell proliferation, inhibit NF-
activation
Mitogen-Activated Protein Kinase: regulate cell proliferation
and death (inhibited by HSP)
Nuclear Factor-: delay apoptosis of activated immune
cells
TNF-: delay macrophage and neutrophil apoptosis
Suppressor of Cytokine Signaling (SOCS): down regulates
cytokines
SYSTEMIC RESPONSE TO INJURY
Cellular Response to Injury
Cell-Mediated Inflammatory Response
Platelets: Clot formation serves as the principal attractant
for neutrophils and monocytes mediated by serotonin, PAF
and PGE
2

Lymphocytes: Injury is associated by acute impairment of
macrophage and cell-mediated immunity
Both T
H
1 and T
H
2 produce IL-3, TNF- and GM-CSF
T
H
1 produce IFN-, IL-2, IL-12 and TNF-
Monocytes: Down regulated in non-surviving patients
Neutrophils: Mediates every form of acute inflammation
Mast Cells: pre-existent in tissues and are important first-
responders
Leads to vasodilation, recruitment of immunocytes and
capillary leakage
SYSTEMIC RESPONSE TO INJURY
Endothelium-Mediated Injury
The correlation between inflammation and
coagulation is critical to understanding the potential
progression of SIRS.
IL-1 and TNF- directly affect endothelial surfaces, leading
to the expression of tissue factor which initiates the
production of thrombin promoting coagulation.
Fibrinolysis is impaired by IL-1 and TNF- via production of
plasminogen activator inhibitor-1 which may lead to
thrombosis.
Neutrophil-Endothelium Interaction
Increased vascular permeability is intended to facilitate
oxygen delivery and immunocyte migration
Accumulation of neutrophil contribute to cytotoxicity
SYSTEMIC RESPONSE TO INJURY
Endothelium-Mediated Injury
Nitric Oxide
Formed through oxidation of L-arginine
From endothelial surfaces in response to acetylcholine
stimulation or cellular injury
Reduce thrombosis and mediates protein synthesis
Prostacyclin
Endothelium derived vasodilator

SYSTEMIC RESPONSE TO INJURY
Cytokine Producing Cell Action
IL-1 Macrophages
Initiate inflammation, induces hypothalamus to increase
body temperature
IL-2 T cells
Proliferation of activated T and B cells, induces antibody
synthesis
IL-3 T cells
Induces growth and differentiation of immune cells in
bone marrow
IL-4 T cells Promotes B cell growth and differentiation
IL-5 T cells Induces differentiation of B cells
IL-6
T cells,
Macrophage
s
Costimulator of T cells, induces growth in B cells
IL-10 T cells Activates B cells and inhibits Macrophage function
IL-12 Macrophages Activates T cells and NK cells
IL-13 T cells Proliferation of B cells and differentiation of T cells
Cytokine Producing Cell Action
IFN- T cells, NK cells Activates Macrophages
TNF Macrophages
Induces inflammation and fever. Induces catabolism of
muscle and fat
Transforming
Growth
Factor
T cells,
Macrophages
Inhibits T cell growth and Macrophage activation
Lymphotoxin T cells Similar to TNF
Histamine Mast cells
Not a cytokine but an important chemical mediator
inducing vasodilation and increases cell permeability
SYSTEMIC RESPONSE TO INJURY

Pro-inflammatory mediators, like TNF-, IL-1,
IL-6, and PAF are released.
Body launches compensatory mediators, like
IL-4 and IL-10 which down regulate the initial
pro-inflammatory response.
Pro-inflammatory cytokines like IL-1 and
TNF- induce the expression of Tissue
Factor (TF) on endothelial cells and
monocytes initiating coagulation.
First step is the binding of factor XII to a sub-
endothelial surface protein exposed by an
injury leading to thrombin production
Fibrinolytic abnormalities develop
Increased plasminogen activator inhibitor-1
(PAI-1)
Decreased tissue plasminogen activating factor
(t-PA)
Decreased Protein C and plasminogen levels
Increased thrombin activatable fibrinolysis
inhibitor (TAFI)
Coagulopathy progresses with profound
Protein C deficiency, prolonged aPTT and
PT, elevated fibrin monomers, reduced
fibrinogen, and elevated D-dimer levels
SYSTEMIC RESPONSE TO INJURY
SYSTEMIC RESPONSE TO INJURY
No drugs of choice exist for SIRS.
Medications target specific diagnoses, preexisting
comorbidities, and prophylaxis regimens for
complications.
Important to understand the pathophysiologic responses
The mortality rates in the Rangel-Fausto study
were 7% (SIRS), 16% (sepsis), 20% (severe
sepsis), and 46% (septic shock).
The medial time interval from SIRS to sepsis was
inversely related to the number of SIRS criteria
met.
Respiratory rate is the most sensitive marker of
the severity of illness.
SYSTEMIC RESPONSE
TO INJURY
WILFREDO T. POLIDO JR. MD
Chief, Liver Transplant
St. Lukes Medical Center
A/Professor
Department of Surgery
FEU-NRMF Medical Center