Pathophysiology review pt_i

Dept. of PathologyDept. of Pathology
Medical CollegeMedical College
Hunan Normal UniversityHunan Normal University
(( 湖南范大学医学院病理学教研室师湖南范大学医学院病理学教研室师 )) 1
Chapter 2Chapter 2
Water and ElectrolytesWater and Electrolytes
Balance and ImbalanceBalance and Imbalance
（水和解代紊乱）电质谢（水和解代紊乱）电质谢

2
 Physiological Basis of Water and SodiumPhysiological Basis of Water and Sodium
MetabolismMetabolism
 Disorder of Other ElectrolytesDisorder of Other Electrolytes
 Regulation of Water and Sodium BalanceRegulation of Water and Sodium Balance
 Disorder of Water and Sodium MetabolismDisorder of Water and Sodium Metabolism

Distribution of Body Fluids
Plasma
5%
Interstitial
15%
ICF
40%
Extracellular
fluid, ECF
Intracellular
fluid, ICF
Transcellular fluid – secreted fluid
(body cavities) (Third space) 1-2 ％ 3
ECF ICF

Factors Affecting Body Fluid Volume
Fat, Sex, Age
4
Q: Do fat people have more or less body fluid?

Functions of Body Water
 Metabolism of biomoleculesMetabolism of biomolecules
 Body temperatureBody temperature
 LubricationLubrication
 Tissue constituent (boundTissue constituent (bound
HH22O)O)
5

Intake
(ml/day)
Output
(ml/day)
Drinking 1000-1500
Food 700
Metabolism 300
Urine 1000-1500
(min: 500)
Lungs 400
Skin 500
Stool 100
Total 2000-2500
(min: 1500)
Total 2000-2500
Daily Balance of Water
6Q: Do infants require more or less water (per kg body weight)?

Distribution of Body Fluid ComponentsDistribution of Body Fluid Components
Characteristics ：
a. Composition of electrolytes different between ICF and ECF
b. Osmotic balance between ICF and ECF
c. Electrically neutral in each compartment
Blood
Vessel
Cell
Membrane
Proteins
7

Physiologic Functions of Electrolytes
 Maintenance of osmotic pressureMaintenance of osmotic pressure
 Generation of membrane potentialGeneration of membrane potential
- Excitability of nerve and muscle- Excitability of nerve and muscle
 Participation in metabolism andParticipation in metabolism and
functionfunction
8

Intake:
5 -10 g/d
Absorption:
Almost all by small
intestine
Excretion:
Kidney (>97%), skin
Sodium Balance
ECF 50%
ICF 10%
Bone
40%
ECF: Extracellular fluid
ICF: Intracellular fluid
Serum [NaSerum [Na++
] 130~150 mmol/L] 130~150 mmol/L
9

10

11
Regulation of Body Fluids
Two Levels:
 Neural - Thirst
 Hormones – Regulation through kidney
Antidiuretic Hormone (ADH)
Aldosterone (ADS)
Atrial Natriuretic Peptide (ANP)

12
Action of ADH:
Role of Aquaporins
PK = Protein Kinase
PKa = Activated Protein Kinase
Renal tubuleEpithelial cell

13
Regulation of Body Fluids
ADH Osmosis ↑ Distal tubules Reabsorption of H2O>Na+
Blood volume↓ Collecting ducts
ADS Blood volume↓ Distal tubules Reabsorption of Na+
>H2O
↓Na+
/↑ K+
Collecting ducts Excretion of potassium
Thirst Osmosis ↑ Thirst center Drinking water
Blood volume↓
Regulator Stimulator Site of action Effect
ANP Blood volume ↑ Distal tubules Excretion of sodium
Collecting ducts Excretion of water

14
Nephron
ADH
ADS
ANP
Regulation of Body Fluids by Hormones

15
Water and Electrolytes BalanceWater and Electrolytes Balance
and Imbalanceand Imbalance

ECF↓
Hypovolemic
ECF ↑
Hypervolemic
ECF N
Serum Na+
↓
Hyponatremia
Hypovolemic
hyponatremia
(Hypotonic
dehydration)
Hypervolemic
hyponatremia
(Water intoxication)
Normovolemic
hyponatremia
Serum Na+
↑
Hypernatremia
Hypovolemic
hypernatremia
(Hypertonic
dehydration)
Hypervolemic
hypernatremia
(Salt intoxication)
Normovolemic
hypernatremia
Serum Na+
N Hypovolemia
(Isotonic
dehydration)
Hypervolemia
(Edema)
Classification of Water and Sodium Metabolic
Disorders
16

Plasma
ISF ICF
Plasma
ISF ICF
Different Types of Water and Sodium Disorders
Plasma
ISF ICF
ISF
ICF
Plasma
Extracellula Intracellular
17

ECF↓
Hypovolemic
ECF ↑
Hypervolemic
ECF N
Serum Na+
↓
Hyponatremia
Hypovolemic
hyponatremia
(Hypotonic)
Hypervolemic
hyponatremia
(Water intoxication)
Normovolemic
hyponatremia
Serum Na+
↑
Hypernatremia
Hypovolemic
hypernatremia
(Hypertonic)
Hypervolemic
hypernatremia
(Salt intoxication)
Normovolemic
hypernatremia
Serum Na+
N Hypovolemia
(Isotonic)
Hypervolemia
(Edema)
Classification of Water and Sodium Metabolic
Disorders
22

4. Pathogenesis of Edema
I. Fluid interchange across
the blood vessel
- Abnormal distribution
- Total amount of body fluid:
N
23
Two types of balances disrupted
II. Fluid interchange across
the body
- ↑ Retention of water and
sodium
- Total amount of body fluid: ↑

① Capillary hydrostatic pressure (17 mmHg)
② Interstitial hydrostatic pressure (-6.5 mmHg)
③ Plasma colloidal osmotic pressure (28 mmHg)
④ Interstitial colloidal osmotic pressure (5 mmHg)
The normal interchange of body fluid
between plasma and interstitial fluid
24
(17 - (-6.5)) - (28 - 5) = 0.5 mmHg
①
②
③
④

① Increased capillary hydrostatic pressure
② Increased capillary permeability
③ Reduced plasma colloid osmotic pressure
④ Obstruction of lymph return
1) Imbalance of fluid interchange across the
blood vessel
Four Mechanisms:
25

4. The most frequent clinical edema
① Cardiac edema:
Right heart failure.
This kind of edema usually shows up first in
the legs and ankles.
Why? Because good old gravity is pulling all
that "loose" fluid straight down.
So we call it “dependent edema”.
26

27
① Cardiac edema :
Left heart failure
– edema in the lungs (dyspnea).

5. Alternations of metabolism and function
Beneficial roles:
(1) Diluting and neutralizing toxin(s)
(2) Carrying antibodies and complements to edema region
28
Harmful roles:
(1) Resulting in insufficient nutritional supply
(2) Inducing dysfunctions of affected organs
(3) May lead to death (edema of vital organs)
?

29
Water and Electrolytes BalanceWater and Electrolytes Balance
and Imbalanceand Imbalance
 Disorder of Potassium MetabolismDisorder of Potassium Metabolism

Potassium (K+
):
Distribution and Normal Functions
ECF
ICF
(bone)
4.2 mmol/L
(1.4%)
150 mmol/L
(90%)
K+
Distribution
Serum [KSerum [K++
] 3.5~5.5 mmol/L] 3.5~5.5 mmol/L
30

31
Physiological Functions of K+
Cell metabolism
Regulation of osmosis and pH
Generation of resting potential

Generation of Resting Potential
← Resting Potential
= K+
potential
At resting:
Plasma membrane
permeability
K +
>> Na+
32

33
Serum K+
conc. < 3.5 mmol/L
Disturbance ofDisturbance of
Potassium MetabolismPotassium Metabolism
Hypokalemia ( 低钾血症 )
Serum K+
conc. > 5.5 mmol/L
Hyperkalemia ( 高钾血症 )

Changes of ECG in Hyperkalemia
Delayed
repolorization
Flat T wave
U wave
Suppressed ST
Speeded
repolorization
Peaked T wave
Shortened Q-T
34

Chapter 3Chapter 3
Acid-Base Balance andAcid-Base Balance and
ImbalanceImbalance
（酸平衡紊乱）碱（酸平衡紊乱）碱

3636
Acid-Base Balance and ImbalanceAcid-Base Balance and Imbalance
a.a. Acid-base homeostasisAcid-base homeostasis
b.b. Parameters of acid-baseParameters of acid-base
balancebalance
c.c. Simple acid-base disturbanceSimple acid-base disturbance
 Metabolic acidosisMetabolic acidosis
 Respiratory acidosisRespiratory acidosis
 Metabolic alkalosisMetabolic alkalosis
 Respiratory alkalosisRespiratory alkalosis

Concepts of Acid and Base
§2. Base: an acceptor of H+
.
§1. Acid: a donor of hydrogen ions
( H+
).
37

AcidsAcids
 Volatile acid ( 挥发
酸 )
H2CO3
 Fixed acid ( 固定酸 )
Other acids 38

2. Regulation of Acid-Base Balance2. Regulation of Acid-Base Balance
 Buffer Systems
Blood
Cells
Bone
 Lungs
 Kidneys
Three Levels
39

Buffer acid Buffer base
Buffer systems in the bloodBuffer systems in the blood
Ability
53
5
7
35
40

Cells
Volatile
acid (H2CO3)
Fixed
acids
Lungs KidneysPlasma
Production and Regulation of Acids and Bases
Food
Digestion
Absorption
Metabolism
41

4242
balancebalance

1. pH
pH < 7.35: Acidosis
pH > 7.45: Alkalosis
§2. Normal value ：
7.35 ～ 7.45 (average ： 7.40)
43

Henderson-Hasselbalch EquationHenderson-Hasselbalch Equation
pH = pKa + LogpH = pKa + Log
[HCO[HCO33
－－
]]
[H[H22COCO33]]
= pKa + Log= pKa + Log 2424
1.21.2
= 6.1 + 1.3 = 7.4
44

2. PaCO2
Partial pressure of carbon dioxide (CO2) in
plasma (artery)
Significance: respiratory parameter
Normal Value: 33~46 mmHg (Average:
40 ）PaCO2 ↑:
Respiratory Acidosis
Metabolic Alkalosis after compensation
PaCO2 ↓:
Respiratory Alkalosis
Metabolic Acidosis after compensation
45

Normal Value: 22 ～ 27 mmol/L (Average: 24)
[HCO3
-
] measured under “standard condition”
 37~38°C
 Hb fully oxygenated
 PaCO2 @ 40 mmHg
 37~38°C
 Hb fully oxygenated
 PaCO2 @ 40 mmHg
3. Standard Bicarbonate, SB
SB ↑: Metabolic Alkalosis
SB ↓: Metabolic Acidosis
Not affected by respiration.
Only reflecting metabolic factor.
46

Actual Bicarbonate, ABActual Bicarbonate, AB
Reflecting:
Both metabolic and respiratory factors
HCO3
-
measured under “actual condition”.
Sealed off from air
PaCO2 and O2 at original level
Sealed off from air
PaCO2 and O2 at original level
Normal Value: the same as SB (24 mmol/L)
47

AB > SB, PaCO2
↑
Respiratory acidosis
(metabolic alkalosis after compensation)
AB < SB, PaCO2
↓
Respiratory alkalosis
(metabolic acidosis after compensation)
In physiological situation: 　 AB = SB
In pathological situation: AB ≠ SB
AB vs. SB
48

4.4. Buffer Base, BBBuffer Base, BB
Meaning:
BB ↑ － Metabolic alkalosis
BB ↓ － Metabolic acidosis
Normal: 45 ～ 52 mmol/L (Average:
48 )
The sum of all alkaline buffer substances in plasma
(HCO3
-
, HPO4
2-
, Pr-
, Hb-
, HbO2
-
)
49

5. Base Excess, BE
The amount of a fixed acid or base that must be
added to a blood sample to achieve a pH of 7.4 under
standard condition.
Normal value: -3.0 - +3.0
pH 7.35 7.4 7.45 　　　　
　 BE -3.0 0 +3.0
Metabolic acidosis Normal Metabolic alkalosis
§3. Meaning:
50

6.6. Anion GapAnion Gap ，， AGAG
The difference between
undetermined anion (UA) and
undetermined cation (UC) in
the plasma (AG = UA - UC).
AG↑ (AG>16): ↑ Fixed acids
(metabolic acidosis)
AG↓: little clinic meaning
Undetermined
AG = Na+
- (Cl-
+ HCO-
3)
= 140 - (104 + 24)
= 12 mmol/L (10 ~ 14 mmol/L)
51

5252
balancebalance

pH
Acidosis
Respiratory
[HCO3
-
]↓ H2CO3↑
Metabolic
Alkalosis
[HCO3
-
]↑ H2CO3 ↓
Metabolic Respiratory
Types of Acid-Base DisturbanceTypes of Acid-Base Disturbance
53

Example
1. 1 diabetes patient ：
pH 7.32, HCO3
-
15 mmol/L, PaCO2
30 mmHg ；
predict PaCO2
= 1.5×15 + 8±2 = 30.5±2 = 28.5 ～ 32.5
measured PaCO2
= 30, within 28.5 ～ 32.5;
Therefore, simple MAc
Equation ： predict PaCO2
= 1.5×[HCO3
-
] ＋ 8±2
Judgement ：
If measured PaCO2
within predicted PaCO2 , simple MAc
If measured > predicted maximum, CO2
retention, MAc + RAc
If measured < predicted minimum, CO2
too less, MAc + RAl
Metabolic acidosis
54

1.2 shock patient with pneumonia:
pH 7.26 ， HCO3
-
16 mmol/L ， PaCO2
37 mmHg ；
predicted PaCO2
= 1.5×16 + 8±2 = 32±2 = 30 ～ 34
measured PaCO2
=37, exceed predict maximum 34;
Therefore, MAc + RAc
Metabolic acidosis
55

2.1 Pulmonary heart disease patient ：
pH 7.34, HCO3
- 　
31 ， PaCO2 　
60 ；
Predict HCO3
-
= 24 + 0.4(60 - 40)±3 = 29 ～ 35
Measured HCO3
-
= 31, within predicted, simple RAc
Equation ： predict HCO3
-
= 24 + 0.4 PaCO△ 2
±3
Example
Judgement ：
If measured HCO3
-
insofar as predict HCO3
-
, simple RAc
If measured > predict maximum, HCO3
-
retention, RAc +MAl
If measured < predict minimum, HCO3
-
too less, RAc + MAc
56

2.2 Pulmonary heart disease patient given bicarbonate ：
pH 7.40 ， HCO3
- 　
40 ， PaCO2 　
67 ；
Predict HCO3
-
= 24 + 0.4(67 - 40)±3 = 31.8 ～ 37.8
Measured HCO3
-
= 40, exceed predict maximum ，
RAc + MAl
2.3 Pulmonary heart disease patient ：
pH 7.22 ， HCO3
- 　
20 ， PaCO2 　
50 　　
Predict HCO3
-
= 24 + 0.4(50―40)±3 = 25 ～ 31
Measured HCO3
-
=20, below predict minimum ，
RAc + MAc
57

3.1 Pyloric obstruction patient ： pH 7.49 ， HCO3
- 　
36 ， PaCO2
48 ；
Predict PaCO2
= 40 + 0.7(36-24)±5 = 43.4 ～ 53.4
Measured PaCO2
= 48, within predicted, simple MAl
= 40 + 0.7 HCO△ 3
-
±5 　
Example
Judgement ：
If measured PaCO2 insofar as predict PaCO2 , simple MAl
If measured > predict maximum, CO2 retention, MAl + RAc
If measured < predict minimum, CO2 too less, MAl + RAl
Metabolic alkalosis
58

3.2 Septic shock patient given excessive bicabonate and
mechanical ventilation ：
pH 7.65 ，　 HCO3
- 　
32 ，　 PaCO2 　　
30 ；
Predict PaCO2
= 40 + 0.7(32-24)±5 = 40.6 ～ 50.6
Measured PaCO2
= 30, below predict minimum
MAl + RAl
3.3 Pulmonary heart disease patient used the diuretics ：
pH 7.40 ， HCO3
-
36 ， PaCO2
60 ；
Predict PaCO2
= 40 + 0.7(36-24)±5 = 43.4 ～ 53.4
Measured PaCO2
=60, exceed predict maximum
MAl + RAc
= 40 + 0.7 HCO△ 3
-
±5 　
Metabolic alkalosis
59

4.1 Hysteria patient ： pH 7.42 ， HCO3
- 　
19 ， PaCO2
　
29 ；Predict HCO3
-
= 24 + 0.5(40 - 29)±2.5 = 16 ～ 21
Measured HCO3
-
= 19, within predicted, simple RAl
Equation ： predict HCO3
-
= 24 + 0.5 PaCO△ 2
±2.5
Example
Judgement ：
If measured HCO3
-
insofar as predict HCO3
-
, simple RAl
If measured > predict maximum, HCO3
-
retention, RAl + MAl
If measured < predict minimum, HCO3
-
too less, RAl + MAc
60

4.2 ARDS patient with shock:
pH 7.41 ， HCO3
- 　
10.2, PaCO2 　
18 ；
Predict HCO3
-
= 24 + 0.5(18 - 40)±2.5 = 10.5 ～ 15.5
Measured HCO3
-
= 10.2, below predict minimum,
RAl + MAc
61

Changes of Blood Gas ParametersChanges of Blood Gas Parameters
pHpH PaCOPaCO22
--
HHCOCO33
--
ABAB SBSB BBBB BEBE
AcidosisAcidosis
MetabolicMetabolic ↓↓ ↓↓ ↓↓↓↓ ↓↓ ↓↓ ↓↓ ↓↓
RespiratoryRespiratory ↓↓ ↑↑↑↑ ↑↑ ↑↑ ↑↑ ↑↑ ↑↑
AlkalosisAlkalosis
MetabolicMetabolic ↑↑ ↑↑ ↑↑↑↑ ↑↑ ↑↑ ↑↑ ↑↑
RespiratoryRespiratory ↑↑ ↓↓↓↓ ↓↓ ↓↓ ↓↓ ↓↓ ↓↓
Metabolic: changes of pH and others at the same direction;
Respiratory: changes of pH and other at the opposite direction.
62

Chapter 4Chapter 4
FeverFever
（）发热（）发热

6464
FeverFever
a.a. IntroductionIntroduction
b.b. Causes and MechanismCauses and Mechanism
c.c. Stages and ManifestationsStages and Manifestations
d.d. Alterations of Metabolism andAlterations of Metabolism and
FunctionFunction
e.e. Pathophysiological Basis ofPathophysiological Basis of
Prevention and TreatmentPrevention and Treatment

heat loss
peripheral
thermo-sensors
deep thermo-
sensors
set point
blood vessel
skeletal muscle
heat production
balance
POAH
sweat gland
Regulation of Normal Body Temperature
POAH: preoptic anterior hypothalamus (- body’s
65

6666
FeverFever
FunctionFunction

Pyrogenic
activator
Endogenous
pyrogen (EP)
EP
producing
cell
Producing
Releasing
Process of Fever Development
67

Pyrogenic activators ( 发热激活物 ) are
substances which can activate the EP-producing
cells to produce and release endogenous
pyrogen (EP).
Concept
Pyrogenic Activators
68

Pyrogenic activators
Microbial pyrogens
Bacteria
Viruses
Other microorganisms
Non-microbial
Pyrogenic substances
Antigen-antibody
complexes
Component of
complement cascade
Steroids
Anticancer drugs
69

Substances that areSubstances that are produced by EP-producingproduced by EP-producing
cellscells under the action of pyrogenic activatorsunder the action of pyrogenic activators andand
cause the increase in the thermoregulatory setcause the increase in the thermoregulatory set
pointpoint in the hypothalamus.in the hypothalamus.
Fever-inducing cytokines (large, hydrophilicFever-inducing cytokines (large, hydrophilic
peptides).peptides).
Endogenous Pyrogens (EPs)
70

Monocytes/Macrophages
Endothelial cells
Lymphocytes
Tumor cells
Endogenous Pyrogen (EP)-
Producing Cells
71

Major Endogenous Pyrogens (EPs)
 Interleukin-1 (IL-1)Interleukin-1 (IL-1)
 Tumor necrosis factor (TNF)Tumor necrosis factor (TNF)
 Interferon (IFN)Interferon (IFN)
 Interleukin-6 (IL-6 )Interleukin-6 (IL-6 )
72

POAH
Thermoregulatory Center
Positive regulatory center:Positive regulatory center:
Located at preoptic anteriorLocated at preoptic anterior
hypothalamus (POAH)hypothalamus (POAH)
Warm-sensitive neuronsWarm-sensitive neurons
Cold-sensitive neuronsCold-sensitive neurons
Negative regulatory center:Negative regulatory center:
Medial amydaloid nucleus (MANMedial amydaloid nucleus (MAN [[ 中杏仁核中杏仁核 ])])
Ventral septal area (VSAVentral septal area (VSA [[ 腹中膈腹中膈 ])])
Arcuate nucleus (ARCArcuate nucleus (ARC [[ 弓状核弓状核 ])])
73

Routes for Endogenous Pyrogens toRoutes for Endogenous Pyrogens to
Enter Thermoregulatory CenterEnter Thermoregulatory Center
a.a. Passive transport via organum vasculosumPassive transport via organum vasculosum
laminate terminal (OVLTlaminate terminal (OVLT [[ 小丘脑终板血管器小丘脑终板血管器 ], also called], also called
supraoptic crestsupraoptic crest))
 Most importantMost important
a.a. Through stimulating vagus nerveThrough stimulating vagus nerve (( 迷走神经迷走神经 ))
b.b. Active transport across the blood brain barrierActive transport across the blood brain barrier
(BBB)(BBB)
 Important in pathological conditionsImportant in pathological conditions
EPs can not directly act on thermoregulatory center
because of BBB.
74

Central Mediators of FeverCentral Mediators of Fever
- The positive regulatory mediators- The positive regulatory mediators
Prostaglandin E2 (PGE2)Prostaglandin E2 (PGE2)
Corticotrophin-releasing hormone (CRH)Corticotrophin-releasing hormone (CRH)
Cyclic adenosine monophosphate (cAMP)Cyclic adenosine monophosphate (cAMP)
Nitric oxide (NO)Nitric oxide (NO)
NaNa++
/Ca/Ca2+2+
ratioratio
75

Prostaglandin E2 (PGE2)
PGE2 can induce fever when injected into cerebralPGE2 can induce fever when injected into cerebral
ventricles.ventricles.
Bacterial endotoxin and EP can stimulate theBacterial endotoxin and EP can stimulate the
hypothalamus to produce PGE2.hypothalamus to produce PGE2.
Cyclooxygenase inhibitor can inhibit the production ofCyclooxygenase inhibitor can inhibit the production of
PGE2.PGE2.
PGE2PGE2 ↑↑ in cerebrospinal fluid during fever.in cerebrospinal fluid during fever.
76

Arachidonic Acid Metabolism
Pain 77

Febrile CeilingFebrile Ceiling
(Fever Limit)(Fever Limit)
Upper limit of the febrile response.Upper limit of the febrile response.
Human core body temperature almost neverHuman core body temperature almost never
rises above 41 -42 during fever.℃ ℃rises above 41 -42 during fever.℃ ℃
- This phenomenon is called- This phenomenon is called febrile ceilingfebrile ceiling..
Regulated by negative fever mediators.Regulated by negative fever mediators.
78

Negative Central Regulatory MediatorsNegative Central Regulatory Mediators
•Arginine vasopressin (AVP)Arginine vasopressin (AVP) - ADH- ADH
•Lipocortin-1 (LC-1)Lipocortin-1 (LC-1)
•αα-Melanocyte stimulating hormone-Melanocyte stimulating hormone
((αα-MSH)-MSH)
79

Pyrogenic
activator
Endogenous
pyrogen (EP)
EP
producing
cell
Producing
Releasing
Pathogenesis of Fever
80

8181
FeverFever
FunctionFunction

Three stages of feverThree stages of fever
I: Fervescence stageI: Fervescence stage
II: Persistent febrile stageII: Persistent febrile stage
III: Defervescence stageIII: Defervescence stage
Stages and Manifestations of Fever
I II III
82

8383
FeverFever
FunctionFunction

Metabolic Changes During FeverMetabolic Changes During Fever
Basal metabolic rate increases by 13% with 1℃Basal metabolic rate increases by 13% with 1℃
elevation in body temperature.elevation in body temperature.
Glycolysis → Lactate ↑Glycolysis → Lactate ↑
Adipose tissue utilization → Ketone ↑, Weight lossAdipose tissue utilization → Ketone ↑, Weight loss
Glycogen degradation → Blood sugar ↑Glycogen degradation → Blood sugar ↑
Vitamin consumption ↑Vitamin consumption ↑
84

Systematic ChangesSystematic Changes
•Nervous systemNervous system
•Cardiovascular systemCardiovascular system
•Respiratory systemRespiratory system
•Digestive systemDigestive system
•Immune systemImmune system
85

Beneficial Effects of FeverBeneficial Effects of Fever
- Self defense- Self defense
Fever often increases the anti-infectionFever often increases the anti-infection
capacity of the body.capacity of the body.
The anti-tumor activity is also augmented duringThe anti-tumor activity is also augmented during
fever.fever.
EP can induce the acute phase response.EP can induce the acute phase response.
86

Chapter 5Chapter 5
StressStress
（激）应（激）应

8888
StressStress
b.b. Stress ResponsesStress Responses
c.c. Alterations of Metabolism andAlterations of Metabolism and
FunctionFunction
d.d. Stress and DiseasesStress and Diseases

What Is Stress?
A series ofA series of non-specific systemic adaptation responsesnon-specific systemic adaptation responses ofof
the body to anythe body to any strong stimulusstrong stimulus..
A state of tension that can lead to disharmony orA state of tension that can lead to disharmony or
disruption of the homeostasis of the body.disruption of the homeostasis of the body.
89

A stimulus or agent that induces stress.A stimulus or agent that induces stress.
StressorsStressors
Psychological or socio-culturalPsychological or socio-cultural
Intrinsic enrionment of the bodyIntrinsic enrionment of the body
Extrinsic factors (Physical, chemical, biological)Extrinsic factors (Physical, chemical, biological)
Threat to self-esteem ( 自尊心 ),
human relationships, accident,
etc.
Cold, heat, toxins, drugs, bacteria,
etc.
Homeostasis, disease, cancer, etc.
StressorStressor
90

EustressEustress
(( 良性激应 ))
 Preparing for Holidays
 Preparing for a job
interview, presentation,
etc.
DistressDistress
(( 劣性激应 ))
 Traffic accidentTraffic accident
 BurnBurn
 TumorTumor
Dual Effects of Stress
91

9292
StressStress
FunctionFunction

Stress ResponsesStress Responses
Cellular ResponsesCellular Responses
Heat Shock ProteinsHeat Shock Proteins
Acute Phase ProteinsAcute Phase Proteins
NeuroendocrineNeuroendocrine
ResponsesResponses
Locus ceruleus-Locus ceruleus-
norepinephrine (LC-NE)norepinephrine (LC-NE)
Hypothalamus-Hypothalamus-
pituitary-adrenal cortexpituitary-adrenal cortex
(HPA)(HPA)
93

The LC-NE System
Stressor
LC-NELC-NE
Central effects
Peripheral effectsExcitement, alert,
nervousness,
anxiety
Changes of organ
systems
NE
Sympathetic nerveSympathetic nerve
94

The HPA SystemThe HPA System
Stressor
Central effects
CRH↑
Depression,
anxiety,
anorexia
Peripheral effects
GCs↑
ACTH↑
HPA: Hypothalamus-pituitary-adrenal cortex
CRH: Corticotropin-releasing hormone
ACTH: Adrenocorticotropic hormone
GCs: Glucocorticoids
(Hypothalamus
)
(Pituitary gland)
(Adrenal cortex)
95

Cellular Responses to StressCellular Responses to Stress
In response to sustained stressors, cells arouse a series ofIn response to sustained stressors, cells arouse a series of
intracellular signal transduction and activation of certain genesintracellular signal transduction and activation of certain genes
and synthesize some protective proteins, including:and synthesize some protective proteins, including:
Heat shock proteins (HSPs)Heat shock proteins (HSPs)
Acute phase proteins (APPs)Acute phase proteins (APPs)
96

HSP Family
HSP110
Small molecule HSP
(HSP27, HSP10, etc.)
HSP90
HSP70
HSP60
HSP40
Ubiquitin
Class Intracellular location
Cytoplasm/Nucleus
Cytoplasm/ER
Cytoplasm/Nucleus/ER/Mito
Cytoplasm/Mito
Cytoplasm/ER
Cytoplasm/ER/Nucleus
Cytoplasm/Nucleus
97

Degradation
Folding/Modification
Protein
(Functional)
Translation
Poly-
peptide
mRNA
Transcription
DNA
5’ 3’
Denat
ure
HSP
HSPs: “Molecular Chaperones”
HSPs help protein:HSPs help protein:
 FoldingFolding
 RenaturationRenaturation
 TranslocationTranslocation
 DegradationDegradation 98

【【 Acute phase proteins, APPsAcute phase proteins, APPs 】】
A class of proteins whose plasma concentrationsA class of proteins whose plasma concentrations
increase (increase (positive acute phase proteinspositive acute phase proteins) during the) during the
acute phase response.acute phase response.
APPs are secretory proteins.APPs are secretory proteins.
【【 AAcute phase responsecute phase response 】】
A quick non-specific defensive response elicited inA quick non-specific defensive response elicited in
response to stress or inflammation –response to stress or inflammation – secretion ofsecretion of
proteins to plasmaproteins to plasma..
Acute Phase Proteins
99

Name Mol. Wt.
(kDa)
Peak Time
(h)
Main Functions
Group I: > 1,000-fold increase
C-reactive protein 105 6-10 Complement activation
Serum amyloid A 160 6-10 Cholesterol clearance
Group II: > 2-4-fold increase
α1-acid
glycoprotein
40 24 Promote fibroblast growth
α1-
antichymotrypsin
68 10 Inhibit cathepsin G
Haptoglobin 100 24 Inhibit cathepsins B, H, L
Fibrinogen 340 24 Coagulation, tissue repair
Group III: <2-fold increase
Ceruloplasmin 151 48-72 Inhibit free radicals
Complement C3 180 48-72 Chemotaxis, mast cell
degranulation
Common Acute Phase Proteins
100

101101
StressStress
FunctionFunction

Blood
Cardiovascular
Respiratory
↑ Viscosity ( 粘滞度 )
↑Contractibility
↑Heart rate
↑BP (→
Hypertension)
Blood redistribution
Dilation of bronchi
Nervous Excitement, anxiety,
anger
Digestive
Anorexia, gluttony (↑ appetite)
Stress ulcer
Effects of CAs on Organ Systems
102

HormoneHormone EffectEffect
ACTH
Glucagon
Thyroid hormone
Parathyroid hormone
Calcitonin
Renin
Erythropoietin
Insulin
↑
↑
↑
↑
↑
↑
↑
↓
Effects of CAs on Hormone Secretion
- a positive regulatory mechanism
103

↑↑ Metabolic rateMetabolic rate
↑↑ Breakdown of fatty acids and proteinsBreakdown of fatty acids and proteins
→→ Weight loss, weakness,Weight loss, weakness, ↓↓immunityimmunity
↓↓ Synthesis of biomoleculesSynthesis of biomolecules
↑↑ Blood sugarBlood sugar →→ HyperglycemiaHyperglycemia
Effects of CAs on MetabolismEffects of CAs on Metabolism
104

Glucagon ↑ Insulin ↓
CAs ↑
α cells of pancreas β cells of pancreas
Stressor
Sugar ↑
Stress Hyperglycemia
105

GCs: Promoting Adaptation
 Anti-insulin – ↑ blood sugar
 Enhance the effect of CAs → ↑ BP
 Enhance the metabolic rate of the body
 Stabilize the lysosome membrane
106

GCs: Adverse Effects
↓Immune response
↓ Growth and development
↓ Sex glands
↓ Protein and collagen synthesis
107

108108
StressStress
FunctionFunction

Section 4
Stress and Diseases
Stress disease
Stress-related diseases
Stress ulcer
Hypertension
Coronary heart disease
Atherosclerosis
Irritable bowel syndrome
Depression 109

Protective Mechanism of Gastric Mucosa
110

H+
H+
H+ H+
H+
H+
H+
H+
H+ H+
H+
H+
H+
Ischemia
HCO3
-
Mucus
Blood flow ↓
Stress
H+
Diffusion
Lumen
Ischemia of mucosaIschemia of mucosa – basic mechanism– basic mechanism
Diffusion of HDiffusion of H++
from lumen to mucosafrom lumen to mucosa
111
Mechanisms of Stress Ulcer
Muco
sa

Chapter 6Chapter 6
HypoxiaHypoxia
（缺）氧（缺）氧

113113
HypoxiaHypoxia
b.b. Parameters of HypoxiaParameters of Hypoxia
c.c. Classification, Etiology, andClassification, Etiology, and
MechanismMechanism
Function in the BodyFunction in the Body
TreatmentTreatment

Normal Process of Oxygen
Acquiring and Utilization
Air Lungs
Ventilation
Blood
Tissue
utilizationDiffusion
External respiration Internal respirationAir transportation
Perfusion
Oxygen supply Oxygen usage
114

115115
HypoxiaHypoxia
MechanismMechanism
TreatmentTreatment

Parameters for Evaluation of Hypoxia
PO2: Partial pressure of O2
C-O2max: O2 binding capacity
C-O2: Blood O2 content
SO2: O2 saturation
Da-vO : Difference in arterio-venous O
116

20
40
60
80
100
0 20 40 60 80 100
PO2(%)
PO2 (mmHg)
Oxygen Dissociation Curve
2,3-DPG ↑
[H+]↑ (pH ↓)
CO2 ↑
Temp ↑
2,3-DPG↓
[H+] ↓ (pH↑)
CO2↓
Temp ↓
Hb-O2 affinity?
Hb-O2 affinity?
117

The binding of 2,3-DPG prevents binding of O2.
Effect of 2,3-DPG on O2 Binding
Glycerate
2,3-Diphosphoglycerate
118

119119
HypoxiaHypoxia
MechanismMechanism
TreatmentTreatment

Types of Hypoxia
Air Lungs
① Hypotonic
Blood
Tissue
utilization
② Hemic ③ Circulatory
④ Histogenous
120

3.1 Hypotonic Hypoxia
Hypotonic hypoxia is characterized by the
decrease of PaO2 (< 60 mmHg).
Also called Hypoxic Hypoxia.
121

Etiology and Mechanism
Decreased O2 level of
inspired air
Hypoventilation
Diffusion abnormality
Venous-to-arterial shunt
(tetralogy of Fallot)
↓O2
Diffusion
abnormality
Venous-to-
arterial
shunt
Hypo-
ventilation
122

3.2 Hemic Hypoxia
Refers to decreasedRefers to decreased
quantity of Hb in the bloodquantity of Hb in the blood
or altered affinity of Hb foror altered affinity of Hb for
oxygen.oxygen.
Also calledAlso called HematogenousHematogenous
oror IsotonicIsotonic Hypoxia.Hypoxia.
123

Etiology and Mechanism
 Quantity of Hb changed (Anemia)Quantity of Hb changed (Anemia)
 Quality of Hb changedQuality of Hb changed
→ ↓→ ↓ ability of Hb to bind Oability of Hb to bind O22
 Carbon monoxide (CO) poisoningCarbon monoxide (CO) poisoning
 form Carboxyhemoglobin (HbCO)form Carboxyhemoglobin (HbCO)
 FeFe3+3+
poisoningpoisoning
 form Methemoglobin (HbFeform Methemoglobin (HbFe3+3+
))
124

3.3 Circulatory Hypoxia
Circulatory hypoxia refers to inadequateCirculatory hypoxia refers to inadequate
blood flow leading to inadequateblood flow leading to inadequate
oxygenation of the tissues.oxygenation of the tissues.
Also called Hypokinetic Hypoxia.Also called Hypokinetic Hypoxia.
125

Etiology and mechanism
Systemic circulation obstacle
Shock
Local circulation obstacle
Left heart failure
Thrombosis
Arterial stenosis (narrowing)
Tissue congestion, tissue ischemia 126

3.4 Histogenous hypoxia
Even though the amount of oxygenEven though the amount of oxygen
delivered to tissue is adequate, the tissuedelivered to tissue is adequate, the tissue
cells can not make use of the oxygencells can not make use of the oxygen
supplied to them.supplied to them.
Also called Dysoxidative Hypoxia.Also called Dysoxidative Hypoxia.
127

Mitochondrial injuryMitochondrial injury
Cyanide poisoningCyanide poisoning
ArsenideArsenide
RadiationRadiation
Bacterial toxinsBacterial toxins
Oxygen free radicalOxygen free radical
inhibit the function of the mitochondriainhibit the function of the mitochondria
Deficiency of B group vitamins (BDeficiency of B group vitamins (B22 or PP)or PP)
Coenzymes required for oxidative phosphorylation.Coenzymes required for oxidative phosphorylation.
Causes of Histogenous Hypoxia
128

Characteristic Changes of Different Types of
Hypoxia
129

Type PaO2 C-O2max Ca-O2 SaO2 Da-vO2
Hypotonic ↓ N ↓ ↓ ↓
Hemic N ↓ ↓ N ↓
Circulatory N N N N ↑
Histogenous N N N N ↓
Changes of Blood Oxygen Parameters in
Different Types of Hypoxia
130

131131
HypoxiaHypoxia
MechanismMechanism
TreatmentTreatment

Section 4. Alterations of
Metabolism and Function
Respiratory system
Circulatory system
Hematologic system
Central nervous system
Tissues and cells
132

Central respiratory failureCentral respiratory failure
- Periodic breathing- Periodic breathing
Cheyne-Stoke respirationCheyne-Stoke respiration
Biot’s breathingBiot’s breathing
High altitude pulmonary edema (HAPE)High altitude pulmonary edema (HAPE)
Clinical Manifestations
Biot’s breathing
Cheyne-StokeCheyne-Stoke
4.1 Respiratory system
133

4.2 Circulatory system
Increased cardiac output (CO) and heart rate (HR)Increased cardiac output (CO) and heart rate (HR)
Redistribution of blood flowRedistribution of blood flow
Dilation of heart and brain vesselsDilation of heart and brain vessels
Hypoxic Pulmonary Vasoconstriction (Hypoxic Pulmonary Vasoconstriction (HPV)HPV)
Capillary proliferationCapillary proliferation
Hypoxia → HIF (hypoxia-inducible factor) →Hypoxia → HIF (hypoxia-inducible factor) →
VEGF → Capillary growthVEGF → Capillary growth
134

4.3 Hematologic System
Increase in RBCs and HbIncrease in RBCs and Hb
Hypoxia → HIF → EPOHypoxia → HIF → EPO
↑↑ 2,3-DPG2,3-DPG (produced from glycolysis)(produced from glycolysis)
→→ ODC shift (left or right?)ODC shift (left or right?)
• goodgood for Ofor O22 release in the tissue;release in the tissue;
• badbad for Ofor O22 binding in the lungsbinding in the lungs
135

4.4 Central nervous system
Acute hypoxiaAcute hypoxia
HeadacheHeadache
Poor memoryPoor memory
Inability to make judgmentInability to make judgment
DepressionDepression
Chronic hypoxiaChronic hypoxia
Unable to concentrateUnable to concentrate
FatigueFatigue
DrowsinessDrowsiness
Cerebral edema and neuron injury →Cerebral edema and neuron injury →
worsen hypoxia → deathworsen hypoxia → death 136

↑↑ Ability to use of oxygenAbility to use of oxygen
(All types except histogenous hypoxia)(All types except histogenous hypoxia)
↑↑ Number and density of mitochondriaNumber and density of mitochondria
↑↑ Activity of mitochondrial enzymesActivity of mitochondrial enzymes
↑↑ GlycolysisGlycolysis
↑↑ Capillary densityCapillary density
↓↓ Metabolic stateMetabolic state
↑↑ Myoglobin (OMyoglobin (O22 reservoir)reservoir)
4.5 Tissues and Cells
137

Chapter 7Chapter 7
ShockShock
（休克）（休克）

139139
ShockShock
b.b. Pathogenesis of ShockPathogenesis of Shock
FunctionFunction
d.d. Pathophysiological Basis ofPathophysiological Basis of
TreatmentTreatment

Etiological factorsEtiological factors
Microcirculation failureMicrocirculation failure
Shock
Cell injury and organ dysfunctionsCell injury and organ dysfunctions
Effective circulatory volumeEffective circulatory volume ↓↓
140

↓↓Blood volumeBlood volume
Heart failureHeart failure
↑↑Blood vesselBlood vessel
capacitycapacity
HypovolemicHypovolemic
CardiogeniCardiogeni
cc
VasogenicVasogenic
EffectiveEffective
circulatorycirculatory
volume↓volume↓
ShockShock
General Categories of ShockGeneral Categories of Shock
141

142142
ShockShock
FunctionFunction
TreatmentTreatment

1.1. Sympathetic activationSympathetic activation rather thanrather than
sympathetic failure during shocksympathetic failure during shock
2. Essential issue of shock2. Essential issue of shock
-- Not:Not: BP↓BP↓
-- But:But: Blood flow↓ → Tissue perfusion↓Blood flow↓ → Tissue perfusion↓
Microcirculation TheoryMicrocirculation Theory
143

Pathogenesis of Shock
Microcirculation Changes
Cellular Mechanisms
Humoral Mechanisms

Three Stages of Microcirculation Changes
Stage I: Ischemic hypoxia stageStage I: Ischemic hypoxia stage
Stage II: Stagnant hypoxia stageStage II: Stagnant hypoxia stage
Stage III: Refractory stageStage III: Refractory stage

Normal Ischemic hypoxia stage
Ischemic Hypoxia Stage
Microcirculatory changes
Arteriole +++
Sphincter ++++
Venule + 146

Inflow ↓ ↓ & outflow ↓
Characteristics of MC perfusion
Arteriole +++
Sphincter ++++
Venule +
Ischemic Hypoxia Stage
Inflow < outflow
↓ Opening of true capillaries
147

148
AutoAuto BloodBlood Transfusion During Stage ITransfusion During Stage I
The “first defense line” in shockThe “first defense line” in shock

Capillary hydrostatic pressure ↓Capillary hydrostatic pressure ↓
Absorption of fluid into blood vessels ↑Absorption of fluid into blood vessels ↑
AutoAuto FluidFluid TransfusionTransfusion
AutoAuto FluidFluid Transfusion During Stage ITransfusion During Stage I
↓↓ Opening of true capillariesOpening of true capillaries
The “second defense line” in shockThe “second defense line” in shock 149

Three Stages of Microcirculation Changes
Stage I: Ischemic hypoxia stageStage I: Ischemic hypoxia stage
Stage II: Stagnant hypoxia stageStage II: Stagnant hypoxia stage
Stage III: Refractory stageStage III: Refractory stage

Change of microcirculation
Normal Stagnant hypoxia stage
Stagnant Hypoxia Stage
Arteriole +
Sphincter -
Venule +++ 151

152
ConstrictionConstriction
of Arteriolesof Arterioles
of Venulesof Venules
DilationDilation ofof
ArteriolesArterioles
of Venulesof Venules
Stage IIStage IIStage IStage I
Cell Adhesion Molecules

Inflow ↑ & outflow ↓
Characteristics of MC perfusion
Venule +++
↑ CAMs
Inflow > outflow
↑ Opening of capillary
Arteriole +
Sphincter -
153

Microcirculatory Changes
- paralyzed and collapsed
Normal Stage III
Refractory Stage
155

Mechanism for DIC Development
1) Increased blood viscosity
2) Coagulation system activated
3) Platelet aggregation and adhesion
156

Refractory Mechanisms
1) DIC1) DIC
2) Failure of vital organs2) Failure of vital organs
3) No-reflow phenomenon3) No-reflow phenomenon
Refractory Stage
157

No-Reflow Phenomenon
The failure of blood to reperfuse an ischemic area after theThe failure of blood to reperfuse an ischemic area after the
physical obstruction has been removed.physical obstruction has been removed.
Microcirculatory perfusion is not improved obviously;Microcirculatory perfusion is not improved obviously;
Blood flow in capillary is not recovered.Blood flow in capillary is not recovered.
158

Initial
Cause
Effective
Circulatory
Volume ↓
MC
Ischemia
MC
Stasis
MC
Failure
Cell damage
Organ failure
Compensatory
Decompensatory
Refractory
MODS
Stage I Stage II Stage III
Shock Pathogenesis - Summary

Cell DamageCell Damage
Cell Membrane DamageCell Membrane Damage
NaNa++
/Ca/Ca2+2+
pump dysfunctionpump dysfunction
NaNa++
/Ca/Ca2+2+
inflowinflow ，， KK++
outflowoutflow
Cellular edemaCellular edema
Lysosomal Damage
Swelling and vacuole formation
Lysosomal enzyme release
Cell autolysis
Mitochondrial DamageMitochondrial Damage
Acidosis→Respiratory enzymes ↓Acidosis→Respiratory enzymes ↓
Hypoxia→ATP↓Hypoxia→ATP↓
161

Humoral Mechanisms
Vasoactive Substances
Inappropriate Inflammatory Response

Vasoactive SubstancesVasoactive Substances
VasoconstrictorsVasoconstrictors VasodilatorsVasodilators
164
Endothelin
Angiotensin
ADH
(Vasopressin)
ANP
CAs
Histamine
5-Hydroxytryptamine
NO
PGE2
PGI2
TXA2
Bradykinin
β-endorphin

Humoral Mechanisms
Vasoactive Substances
Inappropriate Inflammatory Response
- Systemic Inflammatory Response Syndrome

An inflammatory state affecting the whole body,An inflammatory state affecting the whole body,
frequently a response of the immune system to anfrequently a response of the immune system to an
infectious or noninfectious insult.infectious or noninfectious insult.
Key IssuesKey Issues
▲▲ Disseminated activation of inflammatory cellsDisseminated activation of inflammatory cells
▲▲ Inflammatory mediator spilloverInflammatory mediator spillover
Systemic Inflammatory Response SyndromeSystemic Inflammatory Response Syndrome
(SIRS)(SIRS)
166

Development of SIRS
Causative Factor
Inflammatory Cells
Inflammatory mediators
Cascade
167

Pro-inflammatory mediatorsPro-inflammatory mediators
TNFαTNFα 、、 IL-1IL-1 、、 IL-2IL-2 、、 IL-6IL-6 、、 IL-8IL-8 、、 IFNIFN 、、 LTsLTs 、、
PAFPAF 、、 TXATXA22
Anti-inflammatory mediatorsAnti-inflammatory mediators
IL-4IL-4 、、 IL-10IL-10 、、 IL-13IL-13 、、 PGEPGE22 、、 PGIPGI22
Inflammatory MediatorsInflammatory Mediators
168

169169
ShockShock
FunctionFunction
TreatmentTreatment

Alterations of Metabolism
and Function
Metabolic Disorders
Water, Electrolytes and Acid-Base
Disturbance
Multiple Organ Dysfunction Syndrome

Organ Dysfunction During
Shock
0
10
20
30
40
50
60
70
80
90
100
Lung Liver Kidney GI Heart
Incidence
171

Multiple Organ Dysfunction SyndromeMultiple Organ Dysfunction Syndrome
(MODS)(MODS)
Pathogenesis of MODS:Pathogenesis of MODS:
 IschemiaIschemia
 HypoxiaHypoxia
 AcidosisAcidosis
 Uncontrolled inflammatory responseUncontrolled inflammatory response
- SIRS- SIRS
172

173173
ShockShock
FunctionFunction
TreatmentTreatment

2) Prevent cell damage and protect cell function
3) Block the effect of inflammatory mediators
4) Prevent onset of DIC and MOSF
1) Improve MC
Prevention & treatment according to
Pathogenesis
174

Treatment principles
Treat microcirculatory stasis
②. Volume replacement
“Infusion as much as required”
①. Acidosis correction
③. Vasoactive drugs
(Vasodilators vs. Vasoconstrictors)
175

Chapter 8Chapter 8
Disturbance of HemostasisDisturbance of Hemostasis
（凝血与抗凝血平衡紊乱）（凝血与抗凝血平衡紊乱）

177177
a.a. Coagulation and anticoagulationCoagulation and anticoagulation
homeostasishomeostasis
b.b. Disseminated intravascularDisseminated intravascular
coagulation (DIC)coagulation (DIC)

a.a. Coagulation SystemCoagulation System
b.b. Anticoagulation SystemAnticoagulation System
c.c. Fibrinolytic SystemFibrinolytic System
The Three Hemostasis Systems

The ”Classic” Coagulation System
XII XIIa
XI XIa
IX IXa
II IIa
I Ia (Fibrin)
Phospholipid, Ca++
, VIII
Phospholipid, Ca++
, V
179
Prothrombin
activator
formation
Thrombin
formation
Fibrin
formation
X Xa
Intrinsic
Fibrin net
XIIIa
VIIa VII
Tissue factor (III)
Ca++
T
F
Extrinsic
X
II: Prothrombin
I: Fibrinogen

 1.1. FromFrom body fluid (plasma)body fluid (plasma)
(1)(1) Antithrombin (AT- )Ⅲ ⅢAntithrombin (AT- )Ⅲ Ⅲ
(2)(2) Thrombomodulin (TM) - protein C systemThrombomodulin (TM) - protein C system
(3)(3) Tissue factor pathway inhibitor (TFPI)Tissue factor pathway inhibitor (TFPI)
(4) Heparin(4) Heparin
 2. From Cells2. From Cells
(1) Vascular endothelial cells (VEC)(1) Vascular endothelial cells (VEC)
(2) Monocyte-macrophage system(2) Monocyte-macrophage system
(3) Liver cells(3) Liver cells
Anticoagulation System
180

Protein S
FVIIIa
FVa
Endothelial cell
The Effect of Protein C
Thrombomodulin
Protein C
Activated
protein C
ThrombinEPCR
181
EPCR: Endothelial
↑ Release of tPA, uPA

Fibrinolytic Pathway
Plasminogen
Plasmin
Fibrin/Fibrinogen
Fibrin/Fibrinogen
degradation products (FDP)
182
Plasminogen Activator Inhibitor (PAI)
Antiplasmin
Plasminogen Activator
Tissue-type (tPA)
Urokinase-type (uPA)
Thrombin, F a, F aⅫ Ⅺ
Kallikrei
n

183183
a.a. Coagulation and anticoagulationCoagulation and anticoagulation
homeostasishomeostasis
b.b. Disseminated intravascularDisseminated intravascular
coagulation (DIC)coagulation (DIC)

Disseminated intravascular
coagulation (DIC)
a.a. ConceptConcept
b.b. CausesCauses
c.c. PathogenesisPathogenesis
d.d. Precipitating factorsPrecipitating factors
e.e. Clinic manifestationsClinic manifestations
f.f. Pathophysiological basis of prevention andPathophysiological basis of prevention and
treatment of DIC (3P, DD)treatment of DIC (3P, DD)

185
SYSTEMIC
ACTIVATION OF
COAGULATION
Intravascula
r deposition
of fibrin
Depletion of
platelets and
coagulation
factors
Thrombosis
of blood
vessels
Bleeding
Organ
failure
DEATHDEATH
Hypercoagulable state Hypocoagulable state

Causes of DIC
• Infectious diseasesInfectious diseases
• MalignancyMalignancy
• TraumaTrauma
• Obstetrical emergencyObstetrical emergency
• OthersOthers
187

Stage ofStage of
hypercoagulabilithypercoagulabilit
yy
Stage ofStage of
hypocoagulabilityhypocoagulability
Stage ofStage of
secondary fibrinolysissecondary fibrinolysis
189

Precipitating FactorsPrecipitating Factors
• Impairment of clearance mechanismImpairment of clearance mechanism
- Mononuclear phagocyte system dysfunction- Mononuclear phagocyte system dysfunction
• Liver DiseaseLiver Disease
- Synthesis of coagulation factors- Synthesis of coagulation factors ↓↓
• Hypercoagulable state of bloodHypercoagulable state of blood
- Pregnancy- Pregnancy
• Microcirculation dysfunctionMicrocirculation dysfunction
- Acidosis, plasma viscosity- Acidosis, plasma viscosity ↑↑, platelet aggregation, platelet aggregation
191

Clinical Manifestations
• BleedingBleeding
• Circulatory disturbance - shockCirculatory disturbance - shock
• Multiple organ dysfunction syndromeMultiple organ dysfunction syndrome
• Microangiopathic hemolytic anemiaMicroangiopathic hemolytic anemia
193

Anemia During DIC
195
Microangiopathic hemolytic anemia
(MAHA)
Formation of Schistocytes

Schistocyte Formation
force
Fibrin strands
RBC
RBC RBC fragments
196

• Tests for fibrinolysis
•Fibrinogen degradation products (FDP)
•D-dimer
•Plasma protamine paracoagulation test
(3P)
198
Laboratory Tests for DIC

Fbg: Fibrinogen
FM: Fibrin monomer
Fbn: Fibrin
Pln: Plasmin
3P Test:
Plasma Protamine Paracoagulation Test
Purpose: Examining the existence of FDPPurpose: Examining the existence of FDP
protamine
Dissociating
FM
Fibrin multimer
(Clot)
Fbg FM Fbn
Ⅱa
XⅢa
FDP
Pln Pln
FM—X
(Solublecomplex)
(A, B, C X,Y)
199

Fbg FM Fbn
Ⅱa XⅢa
Pln Primary
fibrinolysis
A,B,C,X,Y
+
D-Monomer
A,B,C,X,Y
+
D-Dimer
Secondary Pln
fibrinolysis
D-Dimer Test
Purpose: Examining the existence of secondary fibrinolysisPurpose: Examining the existence of secondary fibrinolysis
200

Chapter 9Chapter 9
Ischemia-Reperfusion InjuryIschemia-Reperfusion Injury
（缺血（缺血 -- 再灌注）损伤再灌注）损伤

202202
a.a. OverviewOverview
b.b. EtiologyEtiology
FunctionFunction

Ischemia
 Concept
Injury More injury
Reperfusion
“A paradox”
After prolonged ischemia, reestablishment
of blood flow (reperfusion) does not relieve
ischemic injury; On the contrary, it aggravates
the tissue injury.

204204
FunctionFunction

Coronary Artery Bypass Graft (CABG)
Percutaneous Transluminal Coronary
Angioplasty (PTCA)
Shock resuscitation (fluid infusion)
Organ transplantation
Thrombolytic therapy
Etiology
Ischemia followed by reperfusion

Factors Influencing IR Injury
a.a. Duration of ischemiaDuration of ischemia
b.b. Collateral circulationCollateral circulation
c.c. Dependency on oxygen supplyDependency on oxygen supply
d.d. Condition of reperfusionCondition of reperfusion
206

Effect of Duration of Ischemia on IRI
Ischemia
time
(min)
Reperfusion
time
(min)
Ventricular
tachycardia
(%)
Ventricula
r
fibrillation
(%)
Mortality
(%)
2 10 0 0 0
5 10 47.6 47.6 25.8
10 10 30.0 40.0 10.0
15 10 9.0 0 0
207

208208
FunctionFunction

Pathogenesis of IR Injury
a.a. Role of OFR/ROSRole of OFR/ROS
b.b. Calcium overloadCalcium overload
c.c. Activation of neutrophilsActivation of neutrophils

Free Radicals
Oxygen Free
Radicals
Reactive Oxygen
Species
Non-Free
Radicals
(Oxygen-
containing)
Non-Oxygen
Free Radicals
O2
.
OH .
LO .
1
O2
H2O2
OONO-
L .
Cl .
CH3
.
The Relationship Between
Free radicals and Reactive Oxygen Species

Mechanism of OFR Increase During IR InjuryMechanism of OFR Increase During IR Injury
a.a. Increased OFR productionIncreased OFR production
b.b. Decreased OFR clearanceDecreased OFR clearance
Role of ORF/ROS
Injurious Effects of OFRInjurious Effects of OFR

212
Generation of OFR
a.a. Xanthine oxidase pathwayXanthine oxidase pathway
b.b. Neutrophils pathwayNeutrophils pathway
c.c. Mitochondria pathwayMitochondria pathway

Xanthine Oxidase Pathway
Xanthine dehydrogenase
Xanthine oxidase (XO)
ATP↓
Ischemia
[Ca2++
]i↑
ATP
ADP
AMP
HypoxanthineXanthineO2
.
_
H2O2 + +
O2
Reperfusion
Uric acidO2
.
_
+H2O2 +
XOO2
OH.
Ca2++
-dependent
proteinase
Adenosine

214
Generation of OFR

OFROFR
Respiratory burstRespiratory burst （呼吸爆（呼吸爆
）发）发
Activation of neutrophilsActivation of neutrophils
IschemiaIschemia
Neutrophils Pathway
Oxygen consumptionOxygen consumption↑↑
ReperfusionReperfusion OO22
↑↑
Chemoattractants (CChemoattractants (C33,,
LTBLTB44))
Kill pathogenKill pathogen
Damage tissueDamage tissue

216
Generation of OFR

Generation of Endogenous OFR
O2（ 98% ） 4e
_
+4H
+
2H2O + ATP
Cytochrome
oxydase
e
_
O2
e
_
+2H
+
H2O2 OH.
e
_
+H
+
H2O
e
_
+H
+
H2O
（ 1-2% ）
_
SOD
O2
. FeFe 33 ++

Ischemia
Mitochondria Pathway
Ca2+
entering mito
ATP↓
OO22
..
__
↑↑e
_
Reperfusion
O2
OO22 +
O2（ 98%
）
4e
_
+4H
+
2H2O
Cytochrome
oxydase
e
_
O2
e
_
+2H
+
H2O2 OH.
e
_
+H
+
H2O
e
_
+H
+
H2O_
O2
.
×
(2%)

220
Clearance of OFR
a.a. Enzymatic clearanceEnzymatic clearance
SOD (Superoxide dismutase)SOD (Superoxide dismutase)
CAT (Catalase)CAT (Catalase)
b.b. Non-enzymatic clearanceNon-enzymatic clearance

Enzymatic Clearance of OFR
e
_
O2
e
_
+2H
+
H2O2
e
_
+H
+
（ 1-2% ）
_
O2
. H2O + O2
SOD CAT
Mn-SOD CuZn-SOD
Amyotrophic lateral sclerosis
(ALS)
Mutation
Stephen Hawking

222
Clearance of OFR
a.a. Enzymatic clearanceEnzymatic clearance
b.b. Non-enzymatic clearanceNon-enzymatic clearance

Non-enzymatic OFR scavengersNon-enzymatic OFR scavengers
Vitamins (Vit C, Vit E)Vitamins (Vit C, Vit E)
CeruloplasminCeruloplasmin
Dimethyl sulfoxide (DMSO)Dimethyl sulfoxide (DMSO)
AllopurinolAllopurinol
Glutathione (GSH)Glutathione (GSH)
H2O2 + 2GSH 2H2O+ GSSG

Pathogenesis of IR Injury
a.a. Role of ORF/ROSRole of ORF/ROS
b.b. Calcium overloadCalcium overload
c.c. Activation of neutrophilsActivation of neutrophils

Mechanisms of Calcium Overload
NaNa++
-Ca-Ca2+2+
exchanger dysfunctionexchanger dysfunction
Damage in cell membraneDamage in cell membrane
Damage in organelle (Mito or SR) membraneDamage in organelle (Mito or SR) membrane
Na+
-Ca2+
Exchanger
Ca2+
Pump
Ca2+
[Ca2+
]e ： 10-3
M [Ca2+
]i ： 10-7
M
Ca2+
channel
Mito
SR
Ca2+
Na +
Ca 2+
Ca 2+
SR: Sarcoplasmic reticulum

IR injuryIR injury
Activation of
Neutrophils
Chemokines
(LTs, PAF, Kinin)
Adhesion molecules ↑↑
(integrin, ICAM-1)(integrin, ICAM-1)
Activation of Neutrophils
Granzymes
(elastase,
collagenase)
OFR Cytokines

230230
FunctionFunction

OO22
••--
HH22OO22
HOClHOCl
••
OOHH
GutGut
Heart &Heart &
vesselsvessels
Lungs &Lungs &
airwaysairways
Brain &Brain &
nervesnerves
231
IR Injury to Important OrgansIR Injury to Important Organs

ArrhythmiaArrhythmia
Ventricular fibrillationVentricular fibrillation
Ventricular TachycardiaVentricular Tachycardia
Myocardial dysfunctionMyocardial dysfunction
COCO ↓↓
Myocardial stunningMyocardial stunning
 Reversible reduction of the function of heartReversible reduction of the function of heart
contraction after reperfusion.contraction after reperfusion.
 Restored after a few hours or days.Restored after a few hours or days.
Myocardial IR Injury

233233
FunctionFunction

Reduce ischemia
Control reperfusion conditions
Scavenge OFR
Relieve Ca2+
overload
Improve metabolism
- Energy supplementation
- Cell protectors
Prevention and Treatment of IR Injury

Lower pressureLower pressure
Lower flow speedLower flow speed
Lower temperatureLower temperature
Lower pHLower pH
Lower CaLower Ca2+2+
and Naand Na++
↓↓ OFR and edemaOFR and edema
↓↓ CaCa2+2+
overloadoverload
↓↓ metabolism →↓ energymetabolism →↓ energy
consumptionconsumption
Control Reperfusion ConditionsControl Reperfusion Conditions

Pathophysiology review pt_i

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