“ Surgeons must

be very careful
when they take
the knife.
Underneath
their fine
incisions stirs
the culprit-
LIFE”
-Emily Dickinson
DR. OWEN WANGESTEEN. For more than half a century, was a
leading teacher of surgeons at the University of Minnesota
SYSTEMIC RESPONSES TO
INJURY

yellow colour= fr exams

 SYSTEMIC RESPONSE TO
INJURY
 Designed to restore tissue function and eradicate
invading microorganisms
 Minor injuries: minimal intervention
 Major injuries: overwhelming inflammatory response
 Systemic Inflammatory Response Syndrome
(SIRS), phases:
1. Proinflammatory phase: activation of cellular processes
restore tissue function, eradicate microorganisms
2. Antiinflammatory phase: prevention of excessive
proinflammatory activities and restoration of homeostasis
 CLINICAL SPECTRUM OF
INFECTION
 Infection - identifiable microbial insult
 SIRS: 2 or more of the ff:
1. Fever (T > 38 C or < 36 C)
2. Tachycardia (> 90/min)
3. Tachypnea (> 20/min)
4. PaCO2 < 32 mm Hg
5. Leukocytosis (4000 < > 12000/uL)
 Sepsis - identifiable source + SIRS
 Severe sepsis - sepsis + organ dysfunction
 Septic shock - Sepsis + CVS collapse
 CNS REGULATION
Reflex Inhibition:
 Injury/stimuli  afferent pathway  hypothalamus
 efferent pathway (antiinflammatory messages) 
site of inflammation
 Autonomic Nervous System (ANS)
 Medulla oblongata
 Involuntarily regulates the inflammatory response

 Regulates CR, BP, RR, T … (vital signs)and GI

motility
 Regulates inflammation
 CNS REGULATION
 Afferent signals
 Circulatory pathway ( baro, chemo and thermoreceptors)
 Neural pathway: vagal sensory input (cytokines, TNF, IL’s)
 Vagal stimulation: decrease HR, Increase GI motility,
arteriolar dilatation, pupillary constriction=… parasympathetic
effects
 Cholinergic Anti-inflammatory Pathways
 Acetylcholine- primary neurotransmitter (PS)
 Reduce tissue macrophage activation- reduce release of TNF,
IL-1, IL-18
 CLASSIFICATION OF
HORMONES
 According to control:
1. Hypothalamo-pituitary axis
 Hypothalamus: CRH, TRH, GHRH, LHRH
 Pituitary: ACTH, cortisol/glucocorticoid, TSH,
thyroxine, T3, GH, gonadotropin, sex hormones,
somatostatin, prolactin, endorphin (anterior); AVP,
oxytocin (posterior)
2. Autonomic nervous system control
 NE, EPI, aldosterone, renin-angiotensin, insulin,
glucagons, enkephalin
 CLASSIFICATION OF
HORMONES
 According to chemical structure
1. Polypeptides: LH, insulin, glucagons, AVP,
oxytocin, IL, TNF, IFN, endothelin, opioids
2. AA derivatives: thyroxine, EPI, NE, dopa,
serotonin, histamine, T3…
(neurotransmitters)
3. Fatty Acid derivatives
 Cholesterol: glucocorticoids, androgens, estrogens,
mineralocorticoids
 Arachidonic acid: prostaglandins, leukotrienes
 HORMONES
 ANTERIOR PITUITARY
HYPOTHALAMIC CONTROL:
CONTROL:
corticotropin
ACTH, releasing
TSH, thyroxine,
hormone,
thyrotropin releasing
triiodothyronine, growth
hormone,
hormone,
growth
gonadotrophins,
hormone releasing
sex hormones,
hormone,
luteinizing
insulin like hormone-releasing
growth factor, somatostatin,
hormone prolactin, endorphins

 AUTONOMIC SYSTEM: NE,

POSTERIOR PITUITARY epi, aldosterone,
CONTROL: renin-angiotensin
vasopressin, oxytocin
system, insulin, glucagon, enkephalins
DR. CHARLES HIGGINS. University of Chicago. Nobel Prize
Awardee for his studies on the effects of hormones on tumor
growth
 ANTERIOR PITUITARY
HORMONES
 Adrenocorticotropic Hormone (ACTH)
 Pain, fear, anxiety or emotional arousal stimulate
CRH ant. Pituitary incr adenylate cyclase incr
cAMP incr ACTH  increase CORTISOL/
glucocorticoid
 Excessive ACTH causes Adreno-cortical Hypertrophy
 Inhibited by: GABA, substance P, endogenous opiods,
L-arginine
 ANTERIOR PITUITARY
HORMONES
 TSH
 During injury
 TSH normal
 Decr T4 conversion to T3 due to inhibitory effects of
cortisol and increased conversion of T4 to inactive T3…
euthyroid sick syndrome/nonthyroidal illness
 Incr thyronine (deiodinated) effects:
1. Enhances membrane transport of glucose incr glucose
oxidation/ utilization = more energy
2. Incr formation of fat, when CHO intake is excessive
3. Incr O2 consumption incr leukocyte metabolism
4. Incr heat production
 ANTERIOR PITUITARY
HORMONES
 Growth Hormones (GH)

 Hypothalamus GHRHincr GH during sleep

 Decreased initially during acute phase of injury
 Promotes protein synthesis , fat mobilization , hepatic
ketogenesis during recuperation

Decreased by: IL 1 alpha, TNF alpha, IL-6

 ANTERIOR PITUITARY
HORMONES
 Gonadotrophins and sex hormones
 During injury: Decreased  menstrual irregularity,
decreased libido
 Estrogens:
 Decreases cell mediated immunity, natural killer cell activity,
neutrophil function
 Increases antibody mediated immunity
 Increases estrogen, increases Infectious complications
 Androgens: immunosuppressive
 ANTERIOR PITUITARY
HORMONES
 Prolactin
 In injury
 Adults: Increased  amenorrhea
 Children: Decreased
 ANTERIOR PITUITARY
HORMONES
 Endogenous opiods
 Elevated in injury
 Beta endorphins- attenuate pain perception, ^
natural killer cell activity, T cell blastogenesis,
hypotension, ^ sugar, ^ insulin
 Enkephalins - decr BP

 In GIT: decr peristalsis( ileus ), decr fluid

secretion
 POSTERIOR PITUITARY
HORMONES
 ADH
 Stress/trauma increases ADH > 1 wk
 Kidneydistal tubules, ducts water resorption
 Peripherally ^ vasoconstriction, ^ hepatic glycogenolysis &
gluconeogenesis ^ glucose ^ osmotic effect restore
volume
 In head trauma/burns SIADH (decr UO, urine
concentration (dilutional hyponatremia)
 absent ADH, coma diabetes insipidus
(^^UOhyperNa, shock) Tx: water, vasopressin
 Oxytocin: unknown role during injury
 ANS HORMONES
 Catecholamines
 Injury/stress  sympathetic NS ^ NE
 chromaffin cells, adrenal medulla
 EPI
 Effects:
 Liver: ^ glycogenolysis, gluconeogenesis, lipolysis, ketogenesis,
decr. Insulin, ^ glucagon
 Peripherally: ^ lipolysis in adipose tissues, inhibits insulin ^
muscle glucose uptake hyperglycemia
 ^ thyroid & parathyroid hormones, renin, decr aldosterone
 ^ neutrophils, lymphocytosis
 ANS HORMONES
 Aldosterone
 Synthesized in the adrenal zona glomerulosa
 ^ by: angiotensin, hyperK, aldosterone stimulating
factor (ASF), ACTH
 Effect: maintain volume by conserving Na,
eliminating K and H ions in kidneys
 Decr aldosterone decr BP, ^K
 ^ aldosterone edema, ^ BP, decr K, metabolic
alkalosis
 ANS HORMONES
 Renin-angiotensin

 Maintains volume homeostasis

 Kidney: renin + angiotensin (pulmo circulation)

angiotensin I angiotensin converting enzyme
angiotensin II

 Angiotensin II- potent vasoconstrictor: stimulates

aldosterone and vasopressin synthesis, regulates thirst,
^ HR, ^ myocardial contractility, ^EPI, ^CRH,
activates sympathetic NS, ^glycogenolysis and
gluconeogenesis
 ANS HORMONES
 Insulin
 Derived from pancreatic Beta cells
 Increased by Increased glucose, AA, free fatty acids, ketone
bodies levels
 Decreased by epinephrine, sympathetic stimulation … means
blood glucose level is high.
 Effects:
1. Promotes hepatic glucogenesis and glycolysis
2. ^glucose transport into cells
3. ^adipose tissue lipogenesis
4. ^protein synthesis
5. In injury
 First phase: w/ in few hours suppression
 Late phase: returns to normal, but w/ peripheral
resistancehyperglycemia
 ANS HORMONES
 Glucagon
 Pancreatic islet alpha cells
 Catabolic
 Increased by plasma glucose, exercise
 Effects:
1. ^ glycogenolysis, gluconeogenesis (75% glucose -
liver)
2. After injury decr glucagon12H ^ 
24H ^^^
 CYTOKINE RESPONSE TO
INJURY
 Cytokines: TNF, IL-1, 2, 3,4,5,6,8, 10, 12, 13, 15, 18, 21,
IFN gamma, GM-CSF
 Small proteins, lipids secreted by immunocytes
 Important in tissue healing and against microbial invasion
 Produced by cell types at the site of injury
 Cell to cell interaction
 Activate intracellular signaling pathwaysmodulation of gene
transcription
 Influence immune cell production, differentiation, proliferation
and survival
 Regulate production of other cytokines (proinflam, antiinflam)
 Direct response vs infection/injury; wound healing
 s/sx: fever, leukocytosis, changes in CR, RR, sptic shock, muscle
wasting, cachexia…(SIRS)
 CYTOKINE RESPONSE TO
INJURY
 Tumor necrosis factor (TNF) alpha
 Earliest, one of the most potent mediators of inflammation
 Produced by monocytes, macrophages and T-cells
(peritoneum, splanchnic tissues, liver (Kupffer cells)
 Rapid and short lived release 90 min to 4H (half life <
20min)
 Effects:
1. Muscle catabolism, cachexia during stress
2. Activation of coagulation
3. Release of adhesion molecules, PGE2, platelet activating factor
(PAF), glucocorticoids, eicosanoids
 CYTOKINE RESPONSE TO
INJURY
 Interleukin 1
 Induced by TNF alpha
 Released by activated macrophages and endothelial
cells
 Induces Fever and anorexia
 Augment T cell Proliferation
 Synergestic with TNF
 CYTOKINE RESPONSE TO
INJURY
 Interleukin 2
 Half life < 10 minnot easily detectable
 Effects:
1. Promotes T-lymphocyte proliferation
2. Increases Ig production
3. Increases gut barrier integrity
4. Attenuated during injury, CA, AIDS, BT
immunocompromised patient
 CYTOKINE RESPONSE TO
INJURY
 Interleukin 4
 Produced by activated type 2 T helper lymphocytes
 Important in antibody mediated immunity and
antigen presentation
 Effects:
 Anti Inflammatory
 Anti Allergy
 Anti helmentic
 CYTOKINE RESPONSE TO
INJURY
 Interleukin 6
 TNF A and IL-1 are potent inducers
 Levels are proportional to the extent of injury
 Proinflammatory and antiinflammatory role
 Indicator of SIRS
 Predictor of operative morbidity
 Mediator fo hepatic acute phase protein response
 ^IL 6  immunosuppression post-op infections
 CYTOKINE RESPONSE TO
INJURY
 Interleukin 8
 Chemoattractant
 Potent activator of neutrophils
 Similar to IL-6
 Biomarker for the risk of MOF
 Does not produce hemodynamic instability
 Interleukin 10
 Modulator of TNF A activity
 Increases IL-10 decr TNF A levels, mortality
 CYTOKINE RESPONSE TO
INJURY
 Interleukin 12
 Promote differentiation of T-helper cells and IFN
gamma
 Prevents programmed cell death( apoptosis)
 Proinflammatory
 Interleukin 13
 Similar w/ IL-4
 Antiinflammatory
 inhibits nitric oxide production
 CYTOKINE RESPONSE TO
INJURY
 Interleukin 15
 Promotes lymphocytic activation
 Induces IL18 production
 Enhances phagocytic function
 CYTOKINE RESPONSE TO
INJURY
 Interleukin 18
 Promotes early resolution of infection
 CYTOKINE RESPONSE TO
INJURY
 Interferon gamma (IFN G)
 Induces production of IL 2,12 &18
 Detectable by 6H
 elevated x 8 days
 activates tissue macrophages
 Induces lung inflammation
 CYTOKINE RESPONSE TO
INJURY
 Granulocyte-Macrophage Colony-
Stimulating Factor (GM CSF)
 Induced by IL-2 and endotoxin
 Delays apoptosis (programmed cell death) of
macrophages and neutrophils
 May cause ARDS
 CYTOKINE RESPONSE TO
INJURY
 High Mobility Group Box-1
 DNA transcription factor
 released 24-48 hrs after onset of sepsis
 peak levels associated w/ ARDS and mortality
 induces "sickness behavior"
ENDOTHELIAL CELL MEDIATORS
OF INJURY RESPONSE
 Prostacyclin
 From arachidonic acid
 Effects:
1. Vasorelaxation
2. Platelet deactivation by increasing cAMP
3. Reduces pulmonary hypertension esp in pediatric patients

 Endothelins
 ^ : injury, thrombin, IL-1, angio II, AVP, catecholamines,
anoxia, transforming growth factor B (TGF-B)
 Most Potent vasoconstrictor, 10x > angio II
 Balance between ET=EDNO normal vascular tone
 Reversed by acetylcholine
 ENDOTHELIAL CELL
MEDIATORS OF INJURY
RESPONSE
 Platelet activating factor (PAF)
 Natural phospholipid of cell membranes
 Secreted by : cell membranes, macrophages, PMN’s,
mast cells, basophils, neutrophils
 Effects:
1. Decrease BP
2. ^ vascular permeability
3. Hemoconcentration
4. pulmonary HPN
5. bronchoconstriction
6. Thrombocytopenia/leukopenia
ENDOTHELIAL CELL MEDIATORS
OF INJURY RESPONSE
 Atrial natriuretic peptides
 Released by CNS and atrial tissues
 Effects:
1. Induce vasodilatation, fluid and electrolyte excretion
2. inhibit aldosterone and prevent readsorption of Na
DR. FRANCIS D. MOORE, Leading investigative surgeon who
defined objective aspects of metabolism in surgical patients.
 OTHER INFLAMMATORY
MEDIATORS
 Serotonin (5 hydroxytryptamine (5HT))
 GI tract, platelet
 Effect:
1. Vaso/broncho constriction
2. Platelet aggregation
3. Chronotropic, inotropic
 OTHER INFLAMMATORY
MEDIATORS
 Histamine
 From histidine in neurons, skin, gastric mucosa, mast
cells, basophils, plt
 2 receptors:
1. H1 : ^ uptake of histidine  bronchoconstriction, GI
motility, ^ heart contractility
2. H2: inhibit histamine release
 Effects:
1. Vasodilatation
2. Increases vascular permeability
 Released in: bleed, trauma, burns, endotoxemia,
sepsis
 If given decr BP, peripheral pooling, ^ capillary
permeability, decr venous return, heart failure
CELL SIGNALING PATHWAYS
 Heat Shock Proteins (HSP)
 Stress proteins
 Role: to attenuate the inflammatory response by
reducing oxygen metabolites, promoting type 2 T helper
cell (TH2) proliferation and inhibiting nuclear factor
(NF)-k B activation

 Ligand-Gated Ion channels

 Permit rapid influx of ions across cell membranes
 Neurotransmitters function this way
 Nicotinic acetylcholine receptor
CELL SIGNALING PATHWAYS
 G-protein receptors
 Guanosine-5’-triphosphate (GTP)- binding
proteins (G-proteins)- largest family of signaling
receptor cells
 2 major second messengers:
1. Cyclic adenosine monophosphate (cAMP)
2. Calcium (released from ER)
 Activates protein kinase C (PKC) NF-k B
CELL SIGNALING PATHWAYS
 Receptor Tyrosine Kinases
 Insulin, platelet derived growth factor (PDGF), IGF-1,
epidermal growth factor (EGF), vascular endothelial
growth factor (VEGF)
 Imporant for gene transcription and cell proliferation
 Suppressors of Cytokine signaling (SOCS)
 Block JAK and STAT
 Regulate signaling of certain cytokines
 Decr SOCS cell hypersensitivity to certain stimuli:
inflammatory cytokines, growth hormones
 CELL MEDIATED
INFLAMMATORY RESPONSE
 Platelets
 Clot formation ^inflammatory mediators,
neutrophil, monocyte proliferation (mediated by
serotonin, PAF, PGE2)
 Important source of eicosanoids and vasoactive
mediators
 NSAIDS inhibit TXA production
 CELL MEDIATED
INFLAMMATORY RESPONSE
 Lymphocytes and T-cell immunity
 Injury impairment of cell mediated immunity and
macrophage function
 T Helper Lymphocytes:
1. TH1 cytokine production- reduced in severe
infections and injury shift to TH2
2. TH2 cytokine response- in burns
 CELL MEDIATED
INFLAMMATORY RESPONSE
 Eosinophils
 Similar to neutrophils: migrate to inflamed
endothelium
 Preferentially migrate to sites of parasitic infection and
allergen challenge
 ^ : IL-3, GM-CSF, IL-5, PAF, complement
anaphylatoxins C3a, C5a
 CELL MEDIATED
INFLAMMATORY RESPONSE
 Mast cells
 First responders to sites of injury
 Produce: histamine, cytokines, eicosanoids, proteases
and chemokines
 Effects:
1. Vasodilation
2. Recruitment of other immunocytes

3. Capillary leakage
 TNF secreted rapidly
 CELL MEDIATED
INFLAMMATORY RESPONSE
 Monocytes
 In sepsis reduction in monocyte surface TNF receptor
 Neutrophils
 Injury endothelial adherence of neutrophils cell
migration
 G-CSF primary stimulus for neutrophil maturation
 Mediate important functions in acute inflammation:
acute lung injury, ischemia/reperfusion injury, IBD
 PHASES OF REPONSE
 EBB PHASE
FLOW PHASE
 ^ compensatory
Earliest momentsmechanisms
to hours (48-72H)
 Decreased
Volume restoration
effective circulating volume
 Decreased
^ O2 consumption
total BEE
 Decreased
^ glucose production
urinary Na loss
 ^ immune
catecholamines,
system activity
cortisol repair process
 Catabolic: weight loss, weakness, ^N loss
 Anabolic: compensation prevails, strength restored
 SUMMARY
 Direction of endocrine change
1. Conservation of salt and water
2. Maintenance of BP
3. Gluconeogenesis
4. Lipolysis
5. Provision of energy to vital organs