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Objective
• Clinical Spectrum of SIRS.
• Signaling
– Humoral
– Neural
– Hormonal
• Inflammatory Mediators.
• Cell Mediated Inflammatory response.
• Surgical Metabolism.
Introduction
• Inflammatory response to injury
– to restore tissue function
– Eradicate invading microorganisms
• Local- limited duration, restores function
• Major
– overwhelming inflammatory response
– Potential multi-organ failure
Clinical Spectrum of SIRS
• Infection
–
Identifiable source of
microbial insult
• Sepsis
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• SIRS = 2 or more:
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Temp ≥38˚C or ≤36˚C
HR ≥ 90 bpm
RR ≥ 20 breaths/min or
PaCO2 ≤ 32 mmHg or
mechanical ventilation
WBC ≥ 12,000 or ≤ 4000
or ≥ 10% immature forms
Infection + SIRS
• Severe Sepsis
–
Sepsis + Organ Dysfunction
• Septic Shock
–
Sepsis + Cardiovascular
Collapse (requires
vasopressors)
Signaling
• Humoral – inflammatory mediators in the
circulation can induce fever and anorexia
i.e. TNF-α
• Neural – parasympathetic vagal
stimulation attenuates the inflammatory
response via Ach release
– Reduces HR, increases gut motility, dilates
arterioles, constricts pupils, and decreases
inflammation
– Reduces macrophage activation
– Reduces macrophage release of pro-inflammatory
mediators (TNF-α, IL-1, IL-18)
Hormone Signaling
Adrenocorticotropic Hormone
• Synthesized anterior pituitary
• Regulated by circadian signals
• Pattern is dramatically altered in injured
patients
• Elevation is proportional to injury severity
• Released by: pain, anxiety, vasopressin,
angiotensin II, cholecystokinin,
catecholamines, and pro-inflammatory
cytokines
• ACTH signals increase glucocorticoid
Glucocorticoids
• Cortisol – elevated following injury,
– duration of elevation depends on severity of
injury
• Potentiates hyperglycemia
– Hepatic gluconeogenesis
– Muscle and adipose tissue –> induces
insulin resistance
– Skeletal m.–> protein degradation, lactate
release
– Adipose -> reduces release of TG, FFA,
Exogenous administration
• Adrenal suppression in the acutely ill
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Acute Adrenal Insufficiency
Atrophy of the adrenal glands
Weakness, n/v, fever, hypotension
Hypoglycemia, hyponatremia, hyperkalemia
• Immunosuppression
– Decreased T-killer and NK fcn, graft vs host
rxns, delayed hypersensitivity responses,
inability of monocyte intracellular killing,
inhibition of superoxide reactivity and
chemotaxis in neutrophils
Macrophage Inhibitory Factor
• Glucocorticoid antagonist
• produced by anterior pituitary & Tlymphocytes
• Reverses immunosuppressive effects of
glucocorticoids
Growth Hormone
• During stress -> protein synth, fat
mobilization, and skeletal cartilage growth
• Injury reduces IGF1 levels
• IGF1 inhibited by pro-inflammatory
cytokines
– TNF-α, IL-1α, IL-6
Aldosterone
• Synthesized, stored, released from the
adrenal zona glomerulosa
• Maintains intravascular volume
– Conserves Na.
– Eliminates potassium and hydrogen ions
– Acts on the early distal convoluted tubules
• Deficiency- hypotension, hyperkalemia
• Excess- edema, HTN, hypokalemia, metab
alkalosis
Insulin
• Stress inhibited release + peripheral
insulin resistance = hyperglycemia
• Injury has 2 phases of insulin release
– Within hours- release is suppressed
– Later- normal/xs insulin production with
peripheral insulin resistance
• Activated lymphocytes have insulin
receptors -> enhanced Tcell proliferation
and cytotoxicity
• Tight control of glucose levels esp. in
Acute Phase Proteins
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Nonspecific markers
Produced by hepatocytes
Response to injury, infection, inflammation
Induced by IL-6
C-reactive protein best reflects
inflammation
– No diurnal variation, not affected by feeding
– Affected only by preexisting hepatic failure
– Accuracy surpasses that of ESR
Inflammatory Mediators
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Heat Shock Proteins
Reactive Oxygen Metabolites
Eicosanoids
Fatty Acid Metabolites
Kallikrein-Kinin System
Serotonin
Histamine
Cytokines
Heat Shock Proteins
• Induced by hypoxia, trauma, heavy
metals, and hemorrhage
• Requires gene induction by a transcription
factor
• ACTH sensitive
• Production seems to decline with age
Reactive Oxygen Metabolites
• Cause tissue injury by oxidation of
unsaturated fatty acids within cell
membranes
• Produced by anaerobic glucose oxidation
and reduction to superoxide anion in
leukocytes
• Further metabolized to hydrogen peroxide
and hydroxyl radicals
• Cells are protected by oxygen scavengers
– glutathione and catalases
• In ischemia- production of oxygen
Eicosanoids
Eicosanoids
• Secreted by nucleated cells (not
lymphocytes)
• Induced by hypoxic injury, direct tissue
injury, endotoxin, norepinephrine,
vasopressin, ang II, bradykinin,
serotonin, ACh, cytokines, histamine
• Diverse systemic effects
• Adverse effects include acute lung
injury, pancreatitis, renal failure
Fatty Acid Metabolites
• Omega 6 FA – precursors of
inflammatory mediators (PG, platelet
activating factor)
– found in enteral nutrition formulas
• Substituting Omega 3 FA attenuate
the inflammatory response
– Reduces TNFα, IL6, PGE2
– Reduces the metabolic rater, normalizes
glucose metabolism, attenuates weight loss,
improves nitrogen balance, reduces
endotoxin induced acute lung injury,
minimizes reperfusion injury to the
myocardium, small intestine, and skeletal
muscles.
Kallikrein-Kinin System
• Bradykinins are potent vasodilators
• Stimulated by hypoxic and ischemic
injury
– Hemorrhage, sepsis, endotoxemia, tissue
injury
– Magnitude proportional to severity of injury
• Produced by kininogen degradation
by kallikrein
• Kinins increase capillary permeability
Serotonin
• Present in intestinal chromaffin cells &
platelets
• Vasoconstriction, bronchoconstriction,
platelet aggregation
• Myocardial chronotrope and ionotrope
• Unclear role in inflammation
Histamine
• Stored in neurons, skin, gastric mucosa,
mast cells, basophils, and platelets
• H1 – bronchoconstriction, VD, increases
intestinal motility and myocardial
contractility
• H2 – stimulates gastric parietal cell acid
secretion.
• H3 – downregulation of histamine release.
Cytokines
• Most potent mediators of inflammation
• Local- eradicate microorganisms,
promote wound healing
• Overwhelming responsehemodynamic instability (septic shock)
or (muscle wasting)
• Uncontrolled- end-organ failure, death
• Self-regulatory production of antiinflammatory cytokines, but
Tumor Necrosis Factor α
• Secreted from monocytes, macrophages,
Tcells
• Responds early, T ½ < 20min
• Potent evocation of cytokine cascade
• Induces muscle catabolism/cachexia,
coagulation, PGE2, PAF, glucocorticoids,
eicosanoids
Interleukin-1
• Released by activated macrophages,
endothelial cells
• IL1α- cell membrane associated
• IL1β- circulation
• Synergistic with TNF- α
• T ½ = 6 min
• Induces febrile response by stimulating
PG activity in the anterior hypothalamus
• Release of β-endorphins after surgery
reduce perception of pain
Interleukin-2
• Promotes T-lymphocyte proliferation, Ig
production, gut barrier integrity
• T ½ < 10 min
• Major injury or perioperative blood
transfusions reduce IL-2 activity leading to
a transient immunocompromised state
• Regulates lymphocyte apoptosis
Interleukin-4
• Produced by type 2 T Helper lymphocytes
• Important in antibody-mediated switching
and antigen presentation
• Induces class switching to promote IgE &
IgG4
– Important in allergic and antihelmintic
responses
• Anti-inflammatory- downregulates IL-1,
TNF-α, IL-6, IL-8 and oxygen radical
production
Interleukin-5
• Released from T lymphocytes,
eosinophils, mast cells and basophils
• Promotes eosinophil proliferation and
airway inflammation
Interleukin-6
• Induced by IL-1 and TNF-α
• Levels are detectable within 60 min of injury, peak
4-6 hours, and persist up to 10 days
• Levels are proportional to extent of tissue injury
• Pro-inflammatory
– Induces and prolongs neutrophil activity
• Anti-inflammatory
– Attenuate TNF-α and IL-1 activity
– Promote release of circulating TNF- α receptors & IL1 antagonists
Interleukin-8
• Released from monocytes, macrophages,
T lymphocytes
• Activity similar to IL-6
• Chemoattractant for PMNs, basophils,
eosinophils, and lymphocytes, activates
PMNs
Interleukin-10
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Anti-inflammatory
Released from T lymphocytes
Down-regulates TNF-α activity
Also attenuates IL-18 mRNA in
monocytes
• Reduces mortality in animal sepsis and
ARDS models
Interleukin-12
• Promotes differentiation of type 1 T
Helper cells
• Promotes PMN and coagulation activation
Interleukin-13
• Similar to IL-4, overall anti-inflammatory
• Promotes B-lymphocyte function
• Unlike IL-4, has no effect on T
lymphocytes
• Inhibits NO production and endothelial
activation
Interleukin-15
• Derived from macrophages
• promotes lymphocyte activation.
• promotes neutrophil phagocytosis in
fungal infections
Interleukin-18
• Produced by macrophages
• Pro-inflammatory, similar to IL-12
• Increased levels are pronounced
(especially in sepsis) and can last up to
21 days
• high levels found in cardiac deaths
Interferon-γ
• Helper T lymphocytes activated by
bacterial antigens, IL-2, IL-12, or IL-18
produce IFN-γ
• IFN-γ can induce IL-2, IL-12, or IL-18
• Detectable in circulation by 6 hrs and
remain elevated for up to 8 days
• Activate circulating and tissue
macrophages
• Induces acute lung inflammation by
activating alveolar macrophages after
surgery or trauma
Granulocyte-Macrophage ColonyStimulating Factor
• Delays apoptosis of macrophages and
PMNs
• Promotes the maturation and recruitment of
PMNs in inflammation and perhaps wound
healing
• May contribute to organ injury such as
ARDS
High Mobility Group Box 1
• DNA transcription factor
• Facilitates the binding of regulatory protein
complexes to DNA
• Secreted by macrophages, natural killer
cells, and enterocytes.
• Expressed 24-48 hrs after injury
• Associated with weight loss, shock, SIRS
and Sepsis.
• Peak levels are associated with ARDS and
death
Cell Mediated Inflammation
• Platelets
– Source of eicosanoids and vasoactive
mediators
– Clot is a chemoattractant for
PMNs/monocytes
– Modulate PMN endothelium adherence
– Migration occurs within 3 hrs of injury
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Mediated by serotonin, PAF, PGE2
• Eosinophils
– Migrate to parasitic infection and allergen
challenge to release cytotoxic granules
– Reside in the GI, lung, and GU tissues
– Activated by IL-3, GM-CSF, IL-5, PAF, and
anaphylatoxins C3a and C5a
Cell Mediated Inflammation
• Lymphocytes
– T-helpers produce IL-3, TNF-α, GM-CSF
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TH1: IFN-γ, IL-2, IL-12
TH2: IL-4, IL-5, IL-6, IL-9, IL-10, IL-13
Severe infection – shift toward more TH2
• Mast Cells
– First responders to injury
– Produce histamine, cytokines, eicosanoids,
proteases, chemokines, TNF-α (stored in
granules)
– Cause vasodilation, capillary leakage, and
Cell Mediated Inflammation
• Monocytes
– Downregulation of receptor TNFR is clinically
and experimentally correlated with CHF,
nonsurvival in sepsis
• Neutrophils
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Modulate acute inflammation
Maturation is stimulated by G-CSF
Rolling (L-selectin (fast), P-selectin (slow)
Adhesion/transmigration – ICAM 1, 2,
PECAM 1, VCAM 1, CD18
Endothelium-Mediated Injury
• Neutrophil-Endothelium Interaction
– Increased vascular permeability – facilitate
oxygen delivery and immunocyte migration
– Accumulation of neutrophils at injury sites
can cause cytotoxicity to vital organs
– Ischemia-reperfusion injury potentiates this
response by releasing oxygen metabolites
and lysosomal enz.
– Neutrophils – rolling 10-20min (p-selectin),
>20min
Nitric Oxide
• Derived from endothelial surfaces
responding to Ach, hypoxia, endotoxin,
cellular injury, or shear stresses of
circulating blood
• T ½ = seconds
• Reduces microthrombosis, mediates
protein synthesis in hepatocytes
• Formed from oxidation of L-arginine.
Prostacyclin (PGI2)
• Endothelium derived in response to shear
stress and hypoxia
• Vasodilator
• Platelet deactivation (increases cAMP)
• Clinically used to reduce pulmonary
hypertension (especially pediatric)
Endothelins
• Produced as a response to a variety of
factors – injury, anoxia, thrombin, IL-1,
vasopressin
• ET-1 is a potent vasoconstrictor, 10x more
potent than angiotensin II
Platelet Activating Factor
• Phospholipid component of cell
membranes, constitutively expressed at
low levels
• Released by PMNs, platelets, mast cells,
monocytes during acute inflammation
• Further activates PMNs and platelets
• Increases vascular permeability
• PAF antagonists reduce
ischemia/reperfusion injury
Metabolism During Fasting
• Comparable to
changes seen in
acute injury
• Requires 25-40
kcal/kg/day of
carbs, protein, fat
• Normal adult body
contains 300-400g
carbs (glycogen) –
75-100g hepatic,
Metabolism During Fasting
• A healthy 70kg adult will use 180 g /d of
glucose to support obligate glycolytic cells
(neurons, RBCs, PMNs, renal medulla,
skeletal m.)
• Glucagon, Norepi, vasopressin, AngII
promote utilization of glycogen stores
• Glucagon, Epi, and cortisol promote
gluconeogenesis
• Precursors include lactate (sk.m., rbc,
pmn), glycerol, and aa (ala, glutamine)
Metabolism of Simple Starvation
• Lactate is not sufficient for glucose
demands
• Protein must be degraded (75 g/d) for
hepatic gluconeogenesis
• Proteolysis from decreased insulin and
increased cortisol
• Elevated urinary nitrogen (up to 30 g/d or
more)
Metabolism of Prolonged Starvation
• Proteolysis is reduced to 20g/d and
urinary nitrogen excretion stabilizes to
2-5g/d
• Organs (myocardium, brain, renal
cortex, sk.m) adapt to ketone bodies
in 2-24 days
• Kidneys utilize glutamine and
glutamate in gluconeogenesis
• Adipose stores provide up to 40%
calories (approx 160 g FFA and
glycerol)
– Stimulated by reduced insulin and increased
glucagon and catecholamines
Metabolism Following Injury
• Magnitude of expenditure is proportional
to the severity of injury
• Changes in
– Lipid Absorption
– Lipid Oxidation
– Carbohydrate metabolism
Influence of injury severity on resting metabolism
Lipid Absorption
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Oxidation of 1g fat = 9 kcal energy
Dietary lipids require pancreatic lipase and
phospholipase to hydrolyze TG into FFA and
monoglycerides within the duodenum
After gut absorption, enterocytes resynthesize TG
from monoglycerides + fatty acyl-CoA
Long chain TG (>12 carbons) enter the circulation as
chylomicrons. Shorter FA chains directly enter portal
circulation and are transported via albumin
Under stress, hepatocytes utilize FFA as fuel
Systemically TG and chylomicrons are used from
hydrolysis with lipoprotein lipase (suppressed by
trauma and sepsis)
Fatty Acid Oxidation
• FFA + acyl-CoA = LCT are transported
across the mitochondrial inner membrane
via the carnitine shuttle
• Medium-chain TG (MCT) 6-12 carbons
long, freely cross the mitochondrial
membrane
• Fatty acyl-CoA undergoes β-oxidation to
acetyl-CoA to enter TCA cycle for
oxidation to ATP, CO2, and water
• Excess acetyl-CoA is used for
ketogenesis
Carbohydrate Metabolism
• Carbohydrates + pancreatic intestinal
enzymes yield dimeric units (sucrase,
lactase, maltase)
• Intestinal brush border disaccharidases
break them into simple hexose units
which are transported into the intestinal
mucosa
• Glucose and galactose are absorbed via
a sodium dependent active transport
pump
• Fructose absorption via facilitated
Carbohydrate Metabolism
• 1g carbohydrate = 4 kcal energy
• IV/parenteral nutrition 3.4 kcal/g dextrose
• In surgical patients dextrose
administration is to minimize muscle
wasting
• Glucose can be utilized in a variety of
pathways – phosphorylation to G6P then
glycogenesis or glycogenolysis, pyruvic
acid pathway, or pentose shunt
Protein and Amino Acid Metabolism
• Average adult protein intake 80-120 g/day
– every 6 g protein yields 1 g nitrogen
– 1g protein = 4 kcal energy
• Following injury, glucocorticoids increase
urinary nitrogen excretion (>30g/d), peak
at 7d, persist 3-7 wks
The effect of injury severity on
nitrogen wasting
References
The material was directly adapted from:
Schwartz's Principles of Surgery, 8th ed.