role of reactive oxygen species in septic shock sepsis 082702.p… · summary of role of no in...
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Role of Reactive Oxygen Species in Septic Shock
Richard E.Richard E. KlabundeKlabunde, Ph.D., Ph.D.Associate Professor of PhysiologyAssociate Professor of Physiology
OUCOMOUCOM27 August 200227 August 2002
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Outline
• General introduction and definitions• Pathophysiology of shock• Pathogenesis of shock• Current research and potential new
therapies– Nitric oxide – Reactive oxygen species– Peroxynitrite
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Sepsis
• Systemic inflammatory response to a confirmed infectious process (most commonly caused by bacterial products (e.g., endotoxin)
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Severe Sepsis
• Sepsis with either hypotension or systemic manifestations ofhypoperfusion– Lactic acidosis, oliguria, altered mental
status
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Septic Shock
• Cardiovascular dysfunction associated with sepsis resulting in hypotension and organ hypoperfusion despite adequate fluid resuscitation
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Endotoxemia & Endotoxic Shock
• Endotoxemia– Elevated levels of bacterial endotoxins (e.g.,
lipopolysaccharide, LPS) in the blood.
• Endotoxic Shock– Similar to septic shock (hypotension and
organ hypoperfusion despite fluids), but with specific involvement of bacterial endotoxins.
New Slide
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Systemic Inflammatory Response Syndrome (SIRS)
• A more general, inclusive term• Systemic inflammatory response to a variety
of severe clinical insults (e.g., infection, burns, trauma, pancreatitis)
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Multiple Organ Dysfunction Syndrome (MODS)
• Progressive distant organ failure following severe infectious or noninfectious insults
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Morbidity/Mortality of Sepsis and Septic Shock
• Most common cause of death in ICUs• U.S. cases per year:
– Sepsis = 400,000– Septic Shock = 200,000– Death = 100,000
J.E. Parrillo, N. Eng. J. Med. 328:1471-1477, 1993
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Pathophysiology of Septic Shock
General Clinical Signs
• Flu-like symptoms– chills followed by fever– general malaise, irritability, lethargy, mental
confusion• Warm skin (early sign)• Site of infection may or may not be evident
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Pathophysiology Cont.
Cardiovascular• Systemic vasodilation and hypotension (Psys < 90
mmHg); increased SVR in late stages• Tachycardia (>100 beats/min)• Increased cardiac output (hyperdynamic),
although contractility is depressed; hypodynamic in late shock
• Ventricular dilation; decreased ejection fraction • Loss of sympathetic responsiveness
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Pathophysiology Cont.
CardiovascularCont.
• Hypovolemia due to vascular leakage; central venous pressure may be decreased or increased depending upon fluid resuscitation
• Compromised nutrient blood flow to organs; decreased organ oxygen extraction
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Cardiogenic Shock
Hemorrhagic Shock
Septic Shock
Primary CV Origin
Cardiac Volume Vascular
Cardiac Output
↓ ↓ ↑↓
Vascular Resistance
↑ ↑ ↓↑
Blood Volume
↑ ↓ ↓
Management Mechanical Inotropes
Vasopressors Vasodilators
IV Fluids/Blood Vasopressors
IV Fluids Antibiotics
Vasopressors Inotropes
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Pathophysiology Cont.
Pulmonary & Renal
• Hyperventilation with respiratory alkalosis• Pulmonary hypertension and edema• Hypoxemia (arterial pO2 < 50 mmHg) • Reduced pulmonary compliance; increased work• Respiratory muscle failure • Renal hypoperfusion and oliguria despite
elevated cardiac output• Acute tubular necrosis and renal failure
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Pathophysiology Cont.
Other
• Disseminated intravascular coagulation (DIC)• Blood dyscrasias
– leukopenia– thrombocytopenia– polycythemia
• Central and peripheral nervous dysfunction• Increased lactate occurs early
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Pathogenesis of Septic Shock
Infectious triggers
Cytokine and inflammatory mediator cascade
Cardiac dysfunction and microvascular injury
Hypotension and shock
Revised Slide
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Bacterial-Mediated Sepsis(Gram-negative)
Bacteria MacrophageLPS + LBP
+death
Mediatorsof
InflammationLPS = LipopolysaccharideLPS = Lipopolysaccharide
LBP = LPSLBP = LPS--Binding ProteinBinding Protein
CD14
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VasodilationCardiac DepressionMicrovascular LeakagePlatelet AggregationLeukocyte Adhesion
ENDOTOXIN
Tumor Necrosis FactorTumor Necrosis FactorInterleukinsInterleukins
Gamma InterferonGamma InterferonPlatelet Activating FactorPlatelet Activating Factor
LeukotrienesLeukotrienesThromboxanesThromboxanesProstaglandinsProstaglandins
HistamineHistamineNitric OxideNitric Oxide
Oxygen Free RadicalsOxygen Free Radicals
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Nitric Oxide Formation
EndotoxinCytokines
NO + citrulline
AcetylcholineBradykininSubstance-PInsulin
iNOS cNOS
L-arg
NO
L-arg
++
cGMP
GTP
GC+
Ca++
+ R
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Actions of Nitric Oxide
• Vasodilation (direct via cGMP and indirect via inhibition of NE and ET-1 release)
• Inhibits leukocyte-endothelial cell adhesion
• Inhibits platelet adhesion/aggregation• Modulates vascular permeability• Scavenges superoxide radicals• High concentrations are cytotoxic
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What role does NO play inseptic shock?
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NO Formation in Septic ShockN
O P
rodu
ctio
n
0 12 24Time (hours) Post-Endotoxemia
cNOS
iNOS
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Pretreatment with NOS Inhibitors
• Hypothesis: – Increased NO production during sepsis causes
systemic vasodilation, cardiac depression, increased capillary permeability (leading to decreased blood volume) and hypotension.
• Therefore:– Pretreatment with a NOS inhibitor in animal models
of sepsis should prevent NO-induced hypotension and edema.
– Treatment with a NOS inhibitor during sepsis should reverse cardiovascular changes.
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80
100
120
140
160M
ean
Arte
rial P
ress
ure
(mm
Hg)
Effects of Pretreatment with NOS Inhibitor
Saline
Saline
Saline
SalineLPS LPS LPS LPSLPS
NNA_H NNA_L AG DEX NNA_H
8
7
6 5
5
4
*
*6 Hours Post-LPS
8
1 2 3 4 5 6 7
Klabunde and Coston. Shock 3:73-78, 1995.
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NO and Microvascular Leakage
0 30 60 90 120Time (min) Post-LPS
-40
0
40
80
120
160
200FI
TC L
eaka
ge (%
Cha
nge)
Control (5)
LPS (14)
DEX+LPS (4)
L-NAME+LPS (7)
PAF Antg + LPS (4)
Laniyonu, Coston and Klabunde. Shock 7:49-54, 1997.
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Other Studies
• Pretreatment with NOS inhibitors:– Prevents fall in systemic vascular resistance– Prevents arteriolar hyporesponsiveness to
catecholamines
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Therapeutic Efficacy of NOS Inhibitors in Endotoxic Shock
0 50 100 150 200 250
Time (min)
-100
-50
0
50
100
150Pe
rcen
t Cha
nge
MAPCOSVRFBF
NMA30 mg/kg
LPS (E. coli), 250 ng/kg/min
Klabunde and Ritger. Biophys Biochem Res Commun 178:1135-1140, 1991.
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Summary of Role of NO in Septic Shock
• Increased NO production decreases SVR and leads to hypotension.
• Non-specific NOS inhibition restores arterial pressure, but reduces cardiac output and organ perfusion
• NO is involved in microvascular leakage during endotoxemia
• Other studies:– NOS inhibition causes pulmonary dysfunction and
increases mortality.– Selective iNOS inhibition being investigated for
therapeutic potential; non-selective inhibitors increase mortality
– Clinical studies show no benefit on survival
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Are nitric oxide inhibitors good or bad in septic shock?
• Bad – NOS inhibitors increase– Cardiac depression and organ hypoperfusion– Thrombosis– Leukocyte-endothelial adhesion and inflammation– Superoxide anion (NO normally scavenges superoxide)– Increase mortality in many studies
• Good – NOS inhibitors prevent– Excessive vasodilation and hypotension– Possible cardiac depression– Formation of new, damaging free radical species (e.g.,
peroxynitrite)
New Slide
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Formation of Reactive Oxygen Species
CytokinesEndotoxins
⋅⋅OO22--
H2O2 ⋅OH-H2O
SOD
CatalaseCellular
Damage &Dysfunction
VasodilationNegative inotropy
Microvascular leakage
NAD(P)H oxidasesCyclooxygenase
Xanthine OxidaseNitric Oxide Synthase
HOCl
MPO
GSHpx
MacrophagesNeutrophils
Endothelial CellsMyocytes
etc.
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Free Radicals in Septic Shock
• Reactive oxygen species (ROS) are elevated in sepsis– In rat models of acute endotoxemia,
superoxide anion increases 3-fold within 60 min and plateaus after about 4 hours (Brovkovych et al, J Physiol Pharmacol 48:633, 1997)
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Free Radicals in Septic Shock cont.
• Endogenous antioxidant and scavenging systems can become depleted in severe sepsis, particularly– Alpha-tocopherol– Ascorbic acid– β-carotene
• Survival in septic patients with organ dysfunction is inversely correlated with the reduction in plasma antioxidant potential (Cowley et al., Crit Care Med 24:1179, 1996)
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Free Radicals in Septic Shock cont.
• In animal studies, treatment with ROS scavengers can improve clinical status and decrease mortality
• Animal studies suggest that the following treatments may improve outcome:– N-acetyl-L-cysteine (scavenges hydroxyl radical and
hypochlorus acid; replenishes glutathione)
– Alpha-tocopherol– Ascorbic acid (treatment during bacteremia in rats prevents
hypotension - Armour et al., J Appl Physiol 90:795, 2001)
– TEMPO (SOD mimic)
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-10 0 10 20 30 40 50 60 70 80
Time (hr)
0
1
2
3
4
5
Sum
med
Mor
bidi
ty In
dex
Combined Morbidity* of Endotoxic Rats(LPS = 15 mg/kg, ip)
(9/15 Survived)
(8/16 Survived)
Control
Alpha-tocopherolAscorbic acidN-acetyl-cysteine
*Responses Included:Uprighting
LocomotoryToe Pinch
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Effects of ROS Scavenging on LPS-Induced Microvascular Leakage
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Unresolved Issues with Antioxidant Therapy
• Is there one antioxidant that is best or should a cocktail be use?
• What is the therapeutic window for antioxidant therapy?
• Do antioxidants increase survival?• Is there a therapeutic role for inhibitors on ROS
production? e.g., xanthine oxididase inhibitors (allopurinol), NAD(P)H oxidase inhibitors
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Nitric Oxide and Superoxide Anion Interactions
⋅⋅OO22--
ONOO-
L-Arg
H2O2
··NONO
⋅OH-H2O
+
SOD
Catalase
NOS
HOCl
MPO
O2
NAD(P)H oxidase,XO, COX, NOS
Sepsis(Peroxynitrite)
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Superoxide Scavenging of NO and the Formation of Peroxynitrite
• Increased ROS decreases NO, which may contribute to:– Leukocyte and platelet adhesion (leading to vascular
plugging)– Vasoconstriction (leading to impaired perfusion)
• Peroxynitrite formation can cause vasodilation and cardiac depression, as well as cellular damage in general
• Decreasing ROS by antioxidants, for example, may enhance hypotension by increasing NO bioavailability.– Therefore, therapy may need to be directed against both
ROS and NO.
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Nitric Oxide Contributes to ROS-Induced Microvascular Leakage
0
20
40
60
80
100M
ax L
eaka
ge (%
TPI)
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Peroxynitrite Formation Contributes to PAF-Induced Microvascular
Leakage
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ax L
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***
Klabunde and Anderson, J Vasc Res 39:338, 2002.
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Summary
• Cardiovascular manifestations of septic shock include:– Cardiac depression– Systemic vasodilation, hypovolemia and hypotension– Reduced organ perfusion
• NO and ROS are implicated in contributing to these cardiovascular changes
• ROS scavengers and selective iNOS inhibitors may provide a new therapeutic approach to improving survival in septic patients