“ 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
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 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

 Cholinergic Anti-inflammatory Pathways

 Efferent Pathway of the inflammatory reflex
 Regulates response to injury
 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
3. Fatty Acid derivatives
 Cholesterol: glucocorticoids, androgens, estrogens,
mineralocorticoids
 Arachidonic acid: prostaglandins, leukotrienes
 HORMONES
 HYPOTHALAMIC CONTROL:
corticotropin releasing hormone,
thyrotropin releasing hormone,
growth hormone releasing
hormone, luteinizing hormone-
releasing hormone
 AUTONOMIC SYSTEM: NE, epi,
aldosterone, renin-angiotensin
system, insulin, glucagon,
enkephalins
 ANTERIOR PITUITARY
CONTROL: ACTH, TSH,
thyroxine, triiodothyronine,
growth hormone,
gonadotrophins, sex hormones,
insulin like growth factor,
somatostatin, prolactin,
endorphins
 POSTERIOR PITUITARY
CONTROL: vasopressin,
oxytocin
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
release CRH ant. Pituitary incr adenylate cyclase
incr cAMP incr ACTH  increase glucocorticoid
production
 Excessive ACTH causes Adreno-cortical Hypertrophy
 Inhibited by: GABA, substance P, endogenous opioids, 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)

 Injury incr 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: decr LH, FSH decr estrogen, androgen
menstrual irregularity, decr libido
 Estrogens:
 Decr cell mediated immunity, natural killer cell activity,
neutrophil function
 ^ antibody mediated immunity
 ^ estrogen, ^ Infectious complications
 Androgens: immunosuppressive
ANTERIOR PITUITARY HORMONES
 Prolactin
 In injury
 Adults: increased amenorrhea
 Children: decreased
ANTERIOR PITUITARY HORMONES
 Endogenous opioids
 Elevated
 Beta endorphins- attenuate pain perception, ^
natual 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 : elevated ADH > 1 wk
 Inc water resorption at the distal tubules
 vasoconstriction, hepatic glycogenolysis & gluconeogenesis
increases glucose inc. 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
 Adrenal gland HORMONES
 Cortisol/glucocorticoids
 Potentiates action of glucagon and epinephrine
 inhibits insulin
 increases gluconeogenesis
 Potentiates FA and Triglyceride release
 Plasma: 10% free, active form incr injury
90% bound alb/glob decr 50%
 Remains elevated during stress
 Burn patients > 4 wks
 Soft tissue injury, hemorrhage > 4 weeks
 Returns to normal once volume is restored
 Adrenal gland HORMONES
 Cortisol/glucocorticoids
 used as immunosuppressive agent (exogenous)
 Can cause lymphopenia, monocytopenia, eosinopenia,
neutrophilia thymic involution, decr cell mediated
immune response
 Can cause adrenal gland atrophy acute adrenal
insufficiency
 Life threatening
 S/Sx: weakness, nausea, vomiting, fever, hypotension,
hypoglycemia from decr gluconeogenesis, hypoNa from
impaired Na resorption, incr K from kaliuresis
 ANS HORMONES
 Catecholamines
 Injury/stress  sympathetic NS ^ NE

 Effects: increases blood glucose

 Liver: ^ glycogenolysis, gluconeogenesis, lipolysis,
ketogenesis, decr. Insulin, ^ glucagon
 Peripherally: ^ lipolysis in adipose tissues,  inc gluconeogenesis 
increase blood glucose  more energy
 Increases BMR
 ^ thyroid & parathyroid hormones, renin, decr aldosterone
 ^ neutrophils, lymphocytosis
 ANS HORMONES
 Aldosterone
 Synthesized in the adrenal zona glomerulosa
 ^ by: angiotensin, hyper K, aldosterone stimulating
factor (ASF), ACTH
 Effect: maintain volume by conserving Na, eliminating K
and H ions in kidneys
 ^ aldosterone edema, ^ BP, decr K, metabolic alkalosis
 Decr aldosterone decr BP, ^K
 ANS HORMONES
 Renin-angiotensin

 Maintains volume homeostasis

 Hypovolemia: Kidney renin  converts angiotensinogen
(liver) to angiotensin I converted by angiotensin
converting enzyme (lungs) angiotensin II
 Angiotensin II- potent vasoconstrictor:
• stimulates aldosterone and vasopressin synthesis,
• regulates thirst,
• increases HR, myocardial contractility,
• activates sympathetic NS to increase glycogenolysis and
gluconeogenesis
 ANS HORMONES
 Insulin
 Derived from pancreatic Beta cells
 Increased by elevated glucose, AA, free fatty acids, ketone bodies
levels
 Decreased by sympathetic stimulation
 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
 secreted: low 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
 For tissue healing and act against microbial invasion
 Produced 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
 Synthesis occurs in the 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

 Regulates immune responses, inflammatory reactions,
and hematopoiesis
 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 detectible
 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 for 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; additional biomarker for the risk
of MOF
 Does not produce hemodynamic instability

 Interleukin 10
 Modulator of TNF A activity
 ^ 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 for 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
 Type of prostaglandin derived from arachidonic acid
 Decreased during injury
 Effects:
1. Vasorelaxation
2. Most potent inhibitor of platelet aggregation
3. Reduces pulmonary hypertension esp in pediatric patients

 Endothelins
 Increased by injury, thrombin, IL-1, angio II, AVP, catecholamines,
anoxia, transforming growth factor B (TGF-B)
 Most Potent vasoconstrictor, 10x > angio II
 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. Increases 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 vasodilation,
2. Increases fluid and electrolyte excretion by
inhibiting aldosterone and preventing
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. Plt aggregation
3. Chronotropic, inotropic
 OTHER INFLAMMATORY
MEDIATORS
 Histamine
 Derived from histidine in neurons, skin, gastric mucosa,
mast cells, basophils, plt
 2 receptors:
1. H1 : bronchoconstriction, GI motility, ^ heart contractility
2. H2: stimulant of cAMP
 Effect:
1. Vasodilation
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: attenuates the inflammatory response by reducing
oxygen metabolites, T helper cell Type 2(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
 NSAID inhibit TXA production
 CELL MEDIATED INFLAMMATORY
RESPONSE
 Lymphocytes and T-cell immunity
 Injury impairs 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
 Earliest moments to hours
(48-72H)
 Decreased effective
circulating volume
 Decreased total BEE
 Decreased urinary Na loss
 ^ catecholamines, cortisol
 FLOW PHASE
 ^ compensatory mechanisms
 Volume restoration
 ^ O2 consumption
 ^ glucose production
 ^ immune system activity
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