Pathophysiology review pt_i

Dept. of PathologyDept. of PathologyMedical CollegeMedical College

Hunan Normal UniversityHunan Normal University(( 湖南师范大学医学院病理学教研室湖南师范大学医学院病理学教研室 )) 1

Chapter 2Chapter 2Water and Electrolytes Water and Electrolytes Balance and ImbalanceBalance and Imbalance（水和电解质代谢紊乱）（水和电解质代谢紊乱）

2

Water and Electrolytes Water and Electrolytes Balance and ImbalanceBalance and Imbalance

Physiological Basis of Water and Sodium Physiological 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

Plasma5%

Interstitial15%

ICF40%

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 (bound Tissue constituent (bound HH22O)O)

5

Intake (ml/day)

Output(ml/day)

Drinking 1000-1500Food 700Metabolism 300

Urine 1000-1500(min: 500)

Lungs 400Skin 500Stool 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 ：① Composition of electrolytes different between ICF and ECF② Osmotic balance between ICF and ECF③ 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 and Participation 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%

Bone40%

ECF: Extracellular fluidICF: Intracellular fluid

Serum [NaSerum [Na++] 130~150 mmol/L] 130~150 mmol/L9

10

Water and Electrolytes Water and Electrolytes Balance and ImbalanceBalance and Imbalance




11

Regulation of Body FluidsTwo 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 KinasePKa = 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 Balance Water and Electrolytes Balance and Imbalanceand Imbalance




ECF↓Hypovolemic

ECF ↑Hypervolemic

ECF N

Serum Na+ ↓ Hyponatremia

Hypovolemichyponatremia

(Hypotonic dehydration)

Hypervolemic hyponatremia

(Water intoxication)

Normovolemic hyponatremia

Serum Na+ ↑ Hypernatremia

Hypovolemic hypernatremia

(Hypertonicdehydration)

Hypervolemic hypernatremia

(Salt intoxication)

Normovolemic hypernatremia

Serum Na+ N Hypovolemia(Isotonic

dehydration)

Hypervolemia(Edema)

Classification of Water and Sodium Metabolic Disorders

16

Pla s

ma

ISF ICFPl

asm

aISF ICF

Different Types of Water and Sodium Disorders

Pla s

ma

ISF ICF

ISF ICFPlasma

Extracellular

Intracellular

17

ECF↓Hypovolemic

ECF ↑Hypervolemic

ECF N

Serum Na+ ↓ Hyponatremia

Hypovolemichyponatremia(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

①②

③④

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 Balance Water and Electrolytes Balance and Imbalanceand Imbalance


Disorder of Potassium MetabolismDisorder of Potassium Metabolism


Potassium (K+): Distribution and Normal Functions

ECFICF

(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/L30

31

Physiological Functions of K+

Cell metabolismRegulation of osmosis and pHGeneration of resting potential

Generation of Resting Potential

← Resting Potential= K+ potential

At resting:Plasma membrane permeabilityK + >> Na+

32

33

Serum K+ conc. < 3.5 mmol/L

Disturbance of Disturbance of Potassium MetabolismPotassium Metabolism

Hypokalemia ( 低钾血症 )

Serum K+ conc. > 5.5 mmol/LHyperkalemia ( 高钾血症 )

Changes of ECG in Hyperkalemia

Delayed repolorization

Flat T waveU waveSuppressed ST

Speeded repolorization

Peaked T waveShortened Q-T

34



Chapter 3Chapter 3Acid-Base Balance and Acid-Base Balance and

ImbalanceImbalance（酸碱平衡紊乱）（酸碱平衡紊乱）

3636

Acid-Base Balance and Acid-Base Balance and Imbalance Imbalance

①① Acid-base homeostasisAcid-base homeostasis②② Parameters of acid-base balanceParameters of acid-base balance③③ 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 acids38

2. Regulation of Acid-Base Balance2. Regulation of Acid-Base Balance

Buffer Systems

BloodCellsBone

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

DigestionAbsorption

Metabolism

41

4242




1. pH

pH < 7.35: AcidosispH > 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 24241.21.2

= 6.1 + 1.3 = 7.444

2. PaCO2

Partial pressure of carbon dioxide (CO2) in plasma (artery)

Significance: respiratory parameterNormal 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”

37~38C 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 airPaCO2 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, BB Buffer Base, BB

Meaning: BB － Metabolic alkalosisBB － 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, BEThe 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 ，， AG AG 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 meaningUndetermined

AG = Na+ - (Cl- + HCO-3)

= 140 - (104 + 24) = 12 mmol/L (10 ~ 14 mmol/L)

51

5252




pH

Acidosis

Respiratory[HCO3

-]↓ H2CO3↑Metabolic

Alkalosis

[HCO3-]↑ H2CO3 ↓

Metabolic Respiratory

Types of Acid-Base Types of Acid-Base DisturbanceDisturbance

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

Respiratory acidosis

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

Respiratory acidosis

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

Equation ： predict PaCO2 = 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

Equation ： predict PaCO2 = 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

Respiratory alkalosis

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

Respiratory alkalosis

61

Changes of Blood Gas ParametersChanges of Blood Gas Parameters

pHpH PaCOPaCO22-- HHCOCO33

-- ABAB SBSB BBBB BEBE

AcidosisAcidosisMetabolic Metabolic ↓↓ ↓↓ ↓↓↓↓ ↓↓ ↓↓ ↓↓ ↓↓

RespiratoryRespiratory ↓↓ ↑↑↑↑ ↑↑ ↑↑ ↑↑ ↑↑ ↑↑

AlkalosisAlkalosisMetabolic Metabolic ↑↑ ↑ ↑ ↑↑↑↑ ↑↑ ↑↑ ↑↑ ↑↑

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

①① IntroductionIntroduction②② Causes and MechanismCauses and Mechanism③③ Stages and ManifestationsStages and Manifestations④④ Alterations of Metabolism and Alterations of Metabolism and

FunctionFunction⑤⑤ Pathophysiological Basis of Pathophysiological 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 thermostat)

65

6666

FeverFever




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).

ConceptPyrogenic Activators

68

Pyrogenic activators

Microbial pyrogensBacteriaVirusesOther microorganisms

Non-microbial

Pyrogenic substances

Antigen-antibody complexesComponent of complement cascadeSteroids Anticancer drugs

69

Substances that are Substances that are produced by EP-producing produced by EP-producing cellscells under the action of pyrogenic activators under the action of pyrogenic activators and and cause the increase in the thermoregulatory set cause the increase in the thermoregulatory set pointpoint in the hypothalamus. in the hypothalamus.

Fever-inducing cytokines (large, hydrophilic Fever-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 anterior Located at preoptic anterior hypothalamus (POAH)hypothalamus (POAH)

Warm-sensitive neuronsWarm-sensitive neuronsCold-sensitive neurons Cold-sensitive neurons

Negative regulatory center:Negative regulatory center:Medial amydaloid nucleus (MAN Medial amydaloid nucleus (MAN [[ 中杏仁核中杏仁核 ])])

Ventral septal area (VSA Ventral septal area (VSA [[ 腹中膈腹中膈 ])])

Arcuate nucleus (ARC Arcuate nucleus (ARC [[ 弓状核弓状核 ])])73

Routes for Endogenous Pyrogens to Routes for Endogenous Pyrogens to Enter Thermoregulatory CenterEnter Thermoregulatory Center

①① Passive transport via organum vasculosum Passive transport via organum vasculosum laminate terminal (OVLT laminate terminal (OVLT [[ 小丘脑终板血管器小丘脑终板血管器 ], also called ], also called

supraoptic crest supraoptic crest) ) Most importantMost important

②② Through stimulating vagus nerve Through stimulating vagus nerve (( 迷走神经迷走神经 ) )

③③ Active transport across the blood brain barrier Active transport across the blood brain barrier (BBB)(BBB) Important in pathological conditionsImportant in pathological conditions

④④ Through generation of PGE2 – BBB-permeableThrough generation of PGE2 – BBB-permeable

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 cerebral PGE2 can induce fever when injected into cerebral ventricles.ventricles.

Bacterial endotoxin and EP can stimulate the Bacterial endotoxin and EP can stimulate the hypothalamus to produce PGE2.hypothalamus to produce PGE2.

Cyclooxygenase inhibitor can inhibit the production of Cyclooxygenase inhibitor can inhibit the production of PGE2.PGE2.

PGE2 PGE2 ↑ ↑ 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 never Human 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 Negative Central Regulatory MediatorsMediators

•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




Three stages of feverThree stages of feverI: Fervescence stage I: Fervescence stage

II: Persistent febrile stage II: Persistent febrile stage

III: Defervescence stage III: Defervescence stage

Stages and Manifestations of Fever

I II III

82

8383

FeverFever




Metabolic Changes During Metabolic Changes During FeverFeverBasal 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 Fever Beneficial Effects of Fever - Self defense- Self defense

Fever often increases the anti-infection Fever often increases the anti-infection capacity of the body.capacity of the body.

The anti-tumor activity is also augmented during The 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（应激）（应激）

8888

StressStress

①① IntroductionIntroduction②② Stress ResponsesStress Responses③③ Alterations of Metabolism and Alterations of Metabolism and

FunctionFunction④④ Stress and DiseasesStress and Diseases

What Is Stress?

A series of A series of non-specific systemic adaptation responses non-specific systemic adaptation responses of of the body to any the body to any strong stimulusstrong stimulus. .

A state of tension that can lead to disharmony or A 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.

Stressors

Stressors

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(( 良性应激 ))

Preparing for Holidays

Preparing for a job interview, presentation, etc.

DistressDistress(( 劣性应激 ))

Traffic accidentTraffic accident

BurnBurn

TumorTumor

Dual Effects of Stress

91

9292

StressStress



Stress Responses Stress Responses

Cellular ResponsesCellular ResponsesHeat Shock Proteins Heat Shock Proteins

Acute Phase ProteinsAcute Phase Proteins

Neuroendocrine Neuroendocrine ResponsesResponses

Locus ceruleus-Locus ceruleus-norepinephrine (LC-NE) norepinephrine (LC-NE)

Hypothalamus-Hypothalamus-pituitary-adrenal cortex pituitary-adrenal cortex (HPA)(HPA)

93

The LC-NE SystemStresso

r

LC-NELC-NE

Central effects

Peripheral effects

Excitement, alert,

nervousness, anxiety

Changes of organ systems

NE

Sympathetic nerveSympathetic nerve

94

The HPA SystemThe HPA SystemStressor

Central effects

CRH↑

Depression, anxiety, anorexia

Peripheral effects

GCs↑

ACTH↑

HPA: Hypothalamus-pituitary-adrenal cortex

CRH: Corticotropin-releasing hormoneACTH: 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 of In response to sustained stressors, cells arouse a series of

intracellular signal transduction and activation of certain genes intracellular 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

HSP70HSP60HSP40

Ubiquitin

Class Intracellular locationCytoplasm/Nucleus

Cytoplasm/ER

Cytoplasm/Nucleus/ER/MitoCytoplasm/MitoCytoplasm/ER

Cytoplasm/ER/Nucleus

Cytoplasm/Nucleus

97

Degradation

Folding/Modification

Protein(Functional)

Translation

Poly-peptide

mRNA

TranscriptionDNA

5’ 3’

Denature

HSP

HSPs: “Molecular Chaperones”

HSPs help protein:HSPs help protein: Folding Folding RenaturationRenaturation Translocation Translocation DegradationDegradation 98

【【 Acute phase proteins, APPsAcute phase proteins, APPs 】】 A class of proteins whose plasma concentrations A 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 in A quick non-specific defensive response elicited in response to stress or inflammation – response to stress or inflammation – secretion of secretion of proteins to plasmaproteins to plasma. .

Acute Phase Proteins

99

Name Mol. Wt. (kDa)

Peak Time (h)

Main Functions

Group I: > 1,000-fold increaseC-reactive protein 105 6-10 Complement activationSerum amyloid A 160 6-10 Cholesterol clearance

Group II: > 2-4-fold increase1-acid glycoprotein

40 24 Promote fibroblast growth

1-antichymotrypsin

68 10 Inhibit cathepsin G

Haptoglobin 100 24 Inhibit cathepsins B, H, LFibrinogen 340 24 Coagulation, tissue repair

Group III: <2-fold increaseCeruloplasmin 151 48-72 Inhibit free radicalsComplement C3 180 48-72 Chemotaxis, mast cell

degranulation

Common Acute Phase Proteins

100

101101

StressStress



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 sugar Blood sugar →→ Hyperglycemia Hyperglycemia

Effects of CAs on MetabolismEffects of CAs on Metabolism

104

Glucagon Insulin

CAs

cells of pancreas 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



Section 4Stress and Diseases

Stress disease

Stress-related diseases

Stress ulcer

HypertensionCoronary heart diseaseAtherosclerosisIrritable bowel syndromeDepression 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 mucosa Ischemia of mucosa – basic mechanism– basic mechanismDiffusion of HDiffusion of H++ from lumen to mucosa from lumen to mucosa

111

Mechanisms of Stress Ulcer

Mucosa



Chapter 6Chapter 6

HypoxiaHypoxia（缺氧）（缺氧）

113113

HypoxiaHypoxia①① IntroductionIntroduction②② Parameters of HypoxiaParameters of Hypoxia③③ Classification, Etiology, and Classification, Etiology, and

MechanismMechanism④④ Alterations of Metabolism and Alterations of Metabolism and

Function in the BodyFunction in the Body⑤⑤ Pathophysiological Basis of Pathophysiological Basis of

TreatmentTreatment

Normal Process of Oxygen Acquiring and Utilization

Air LungsVentilation

Blood Tissue utilization Diffusion

External respiration Internal respirationAir transportation

Perfusion

Oxygen supply Oxygen usage

114

115115




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-vO2: Difference in arterio-venous O2

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

Glycerate2,3-Diphosphoglycerate

118

119119




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 decreased Refers to decreased quantity of Hb in the blood quantity of Hb in the blood or altered affinity of Hb for or altered affinity of Hb for oxygen.oxygen.

Also called Also called HematogenousHematogenous or or IsotonicIsotonic Hypoxia. Hypoxia.

123

Etiology and Mechanism

Quantity of Hb changed (Anemia)Quantity of Hb changed (Anemia)

Quality of Hb changed Quality 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+ poisoning poisoning

form Methemoglobin (HbFeform Methemoglobin (HbFe3+3+) ) 124

3.3 Circulatory Hypoxia

Circulatory hypoxia refers to inadequate Circulatory hypoxia refers to inadequate

blood flow leading to inadequate blood flow leading to inadequate

oxygenation of the tissues.oxygenation of the tissues.

Also called Hypokinetic Hypoxia.Also called Hypokinetic Hypoxia.

125

Etiology and mechanismSystemic circulation obstacle

Shock

Local circulation obstacleLeft heart failure

ThrombosisArterial stenosis (narrowing)

Tissue congestion, tissue ischemia 126

3.4 Histogenous hypoxia

Even though the amount of oxygen Even though the amount of oxygen delivered to tissue is adequate, the tissue delivered to tissue is adequate, the tissue cells can not make use of the oxygen cells can not make use of the oxygen supplied to them.supplied to them.

Also called Dysoxidative Hypoxia.Also called Dysoxidative Hypoxia.

127

Mitochondrial injuryMitochondrial injuryCyanide poisoningCyanide poisoningArsenideArsenideRadiationRadiationBacterial toxinsBacterial toxinsOxygen 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 (B2 2 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




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-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-DPG 2,3-DPG (produced from glycolysis)(produced from glycolysis)

→→ ODC shift (left or right?)ODC shift (left or right?)

• goodgood for O for O22 release in the tissue; release in the tissue;

• badbad for O for O22 binding in the lungs binding in the lungs

135

4.4 Central nervous systemAcute hypoxiaAcute hypoxia

HeadacheHeadachePoor memoryPoor memoryInability to make judgmentInability to make judgmentDepressionDepression

Chronic hypoxiaChronic hypoxiaUnable to concentrateUnable to concentrateFatigueFatigueDrowsinessDrowsinessCerebral 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

↑ ↑ Glycolysis Glycolysis

↑ ↑ Capillary density Capillary density

↓ ↓ Metabolic state Metabolic state

↑ ↑ Myoglobin (OMyoglobin (O22 reservoir) reservoir)

4.5 Tissues and Cells

137



Chapter 7Chapter 7

ShockShock（休克）（休克）

139139

ShockShock

①① IntroductionIntroduction②② Pathogenesis of ShockPathogenesis of Shock③③ Alterations of Metabolism Alterations of Metabolism

and Functionand Function④④ Pathophysiological Basis of Pathophysiological Basis of

TreatmentTreatment

Etiological factorsEtiological factors

Microcirculation failureMicrocirculation failure

Shock

Cell injury and organ dysfunctionsCell injury and organ dysfunctions

Effective circulatory volume Effective circulatory volume ↓↓

140

↓↓Blood volume Blood volume

Heart failureHeart failure

↑↑Blood vessel Blood vessel capacitycapacity

HypovolemHypovolemicic

CardiogeCardiogenicnic

VasogeniVasogenicc

Effective Effective

circulatory circulatory

volume↓volume↓

ShocShockk

General Categories of General Categories of ShockShock

141

142142

ShockShock



TreatmentTreatment

1. 1. Sympathetic activationSympathetic activation rather than rather than sympathetic failure during shocksympathetic failure during shock

2. Essential issue of shock 2. 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 perfusionArteriole +++Sphincter ++++

Venule +

Ischemic Hypoxia Stage

Inflow < outflow

↓ Opening of true capillaries

147

148

Auto Auto BloodBlood Transfusion During Stage I Transfusion 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 ↑

Auto Auto FluidFluid Transfusion Transfusion

Auto Auto 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






Change of microcirculation

Normal Stagnant hypoxia stage

Stagnant Hypoxia Stage

Arteriole +Sphincter -

Venule +++ 151

152

Constriction Constriction of Arteriolesof Arterioles

Constriction Constriction of Venulesof Venules

DilationDilation of of ArteriolesArterioles

ConstrictionConstriction of Venulesof Venules

Stage IIStage IIStage IStage I

Cell Adhesion Molecules


Inflow ↑ & outflow ↓

Characteristics of MC perfusionVenule +++ ↑ 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 the The 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



Cellular Mechanisms

Humoral Mechanisms

Cell DamageCell Damage

Cell Membrane DamageCell Membrane DamageNaNa++/Ca/Ca2+2+ pump dysfunctionpump dysfunctionNaNa++/Ca/Ca2+2+ inflowinflow ，， KK++ outflowoutflowCellular edemaCellular edema

Lysosomal DamageSwelling and vacuole formationLysosomal enzyme releaseCell autolysis

Mitochondrial DamageMitochondrial DamageAcidosisAcidosis→→Respiratory enzymes Respiratory enzymes ↓ ↓ HypoxiaHypoxia→→ATPATP↓↓

161



Cellular Mechanisms

Humoral Mechanisms

Humoral Mechanisms

Vasoactive Substances

Inappropriate Inflammatory Response

Vasoactive SubstancesVasoactive SubstancesVasoconstrictorsVasoconstrictors VasodilatorsVasodilators

164

Endothelin

Angiotensin

ADH (Vasopressin)

ANP

CAs

Histamine

5-Hydroxytryptamine

NO

PGE2PGI2TXA2

Bradykinin

-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 an frequently 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 SIRSCausative Factor

Inflammatory Cells

Inflammatory mediators

Cascade

167

Pro-inflammatory mediatorsPro-inflammatory mediatorsTNFαTNFα 、、 IL-1IL-1 、、 IL-2IL-2 、、 IL-6IL-6 、、 IL-8IL-8 、、 IFNIFN 、、 LTsLTs 、、 PAFPAF 、、 TXATXA22

Anti-inflammatory mediatorsAnti-inflammatory mediatorsIL-4IL-4 、、 IL-10IL-10 、、 IL-13IL-13 、、 PGEPGE22 、、 PGIPGI22

Inflammatory MediatorsInflammatory Mediators

168

169169

ShockShock



TreatmentTreatment

Alterations of Metabolism and

FunctionMetabolic Disorders

Water, Electrolytes and Acid-Base Disturbance

Multiple Organ Dysfunction Syndrome

Organ Dysfunction During Shock

0102030405060708090

100

Lung Liver Kidney GI Heart

Inci

denc

e

171

Multiple Organ Dysfunction Multiple Organ Dysfunction Syndrome (MODS)Syndrome (MODS)

Pathogenesis of MODS:Pathogenesis of MODS: Ischemia Ischemia HypoxiaHypoxia Acidosis Acidosis Uncontrolled inflammatory responseUncontrolled inflammatory response

- SIRS- SIRS

172

173173

ShockShock



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 principlesTreat 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 Disturbance of HemostasisHemostasis（凝血与抗凝血平衡紊乱）（凝血与抗凝血平衡紊乱）

177177

Disturbance of HemostasisDisturbance of Hemostasis

①① Coagulation and Coagulation and anticoagulation homeostasisanticoagulation homeostasis

②② Disseminated intravascular Disseminated intravascular coagulation (DIC)coagulation (DIC)

①① Coagulation SystemCoagulation System

②② Anticoagulation SystemAnticoagulation System

③③ 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++TF

Extrinsic

X

II: ProthrombinI: Fibrinogen

1. 1. From From 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

ThrombomodulinProtein C

Activatedprotein C

ThrombinEPCR

181

EPCR: Endothelial protein C receptor

↑ Release of tPA, uPA

Fibrinolytic Pathway

Plasminogen

Plasmin

Fibrin/Fibrinogen

Fibrin/Fibrinogendegradation products (FDP)

182

Plasminogen Activator Inhibitor (PAI)

Antiplasmin

Plasminogen Activator Tissue-type (tPA)

Urokinase-type (uPA)

Thrombin, F a, ⅫF aⅪ

Kallikrein

183183

Disturbance of HemostasisDisturbance of Hemostasis

①① Coagulation and Coagulation and anticoagulation homeostasisanticoagulation homeostasis

②② Disseminated intravascular Disseminated intravascular coagulation (DIC)coagulation (DIC)

Disseminated intravascular

coagulation (DIC)①① ConceptConcept

②② Causes Causes

③③ PathogenesisPathogenesis

④④ Precipitating factorsPrecipitating factors

⑤⑤ Clinic manifestations Clinic manifestations

⑥⑥ Pathophysiological basis of prevention and Pathophysiological basis of prevention and

treatment of DIC (3P, DD)treatment of DIC (3P, DD)

185

SYSTEMIC ACTIVATION OF COAGULATION

Intravascular 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• Others Others

187









Stage of Stage of hypercoagulabilityhypercoagulability

Stage of Stage of hypocoagulabilityhypocoagulability

Stage of Stage of secondary fibrinolysissecondary fibrinolysis

189









Precipitating FactorsPrecipitating Factors• Impairment of clearance mechanism Impairment 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










• BleedingBleeding

• Circulatory disturbance - shockCirculatory disturbance - shock

• Multiple organ dysfunction syndrome Multiple organ dysfunction syndrome

• Microangiopathic hemolytic anemiaMicroangiopathic hemolytic anemia

193


194

Anemia During DIC

195

Microangiopathic hemolytic anemia

(MAHA)

Formation of Schistocytes

Schistocyte Formation

force

Fibrin strandsRBC

RBC RBC fragments

196









• Tests for fibrinolysis

• Fibrinogen degradation products (FDP)

• D-dimer

• Plasma protamine paracoagulation test

(3P)

198

Laboratory Tests for DIC

Fbg: FibrinogenFM: Fibrin monomerFbn: FibrinPln: Plasmin

3P Test: Plasma Protamine Paracoagulation TestPurpose: Examining the existence of FDP Purpose: Examining the existence of FDP

protamine

Dissociating FMFibrin multimer

(Clot)

Fbg FM FbnⅡ a

XⅢa

FDPPln Pln

FM—X(Soluble complex)

(A, B, C X,Y)

199

Fbg FM FbnⅡ a XⅢa

Pln Primary fibrinolysis

A,B,C,X,Y+

D-Monomer

A,B,C,X,Y+

D-Dimer

Secondary Pln fibrinolysis

D-Dimer TestPurpose: Examining the existence of secondary fibrinolysis Purpose: Examining the existence of secondary fibrinolysis

200



Chapter 9Chapter 9

Ischemia-Reperfusion Ischemia-Reperfusion InjuryInjury（缺血（缺血 -- 再灌注损伤）再灌注损伤）

202202

Ischemia-Reperfusion InjuryIschemia-Reperfusion Injury

①① OverviewOverview②② EtiologyEtiology③③ Pathogenesis Pathogenesis ④④ Alterations of Metabolism and FunctionAlterations of Metabolism and Function⑤⑤ Pathophysiological Basis of Prevention Pathophysiological Basis of Prevention

and Treatmentand Treatment

Ischemia

Concept

Injury More injuryReperfusion

“A paradox”

After prolonged ischemia, reestablishment of blood flow (reperfusion) does not relieve ischemic injury; On the contrary, it aggravates the tissue injury.

204204




Coronary Artery Bypass Graft (CABG)

Percutaneous Transluminal Coronary Angioplasty (PTCA)

Shock resuscitation (fluid infusion)

Organ transplantation

Thrombolytic therapy

EtiologyIschemia followed by reperfusion

Factors Influencing IR Injury

①①Duration of ischemia Duration of ischemia

②②Collateral circulationCollateral circulation

③③Dependency on oxygen supplyDependency on oxygen supply④④Condition of reperfusionCondition of reperfusion

206

Effect of Duration of Ischemia on IRI

Ischemia time(min)

Reperfusion time(min)

Ventricular

tachycardia

()

Ventricular

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


①① OverviewOverview②② EtiologyEtiology③③ PathogenesisPathogenesis④④ Alterations of Metabolism and FunctionAlterations of Metabolism and Function⑤⑤ Pathophysiological Basis of Prevention Pathophysiological Basis of Prevention


Pathogenesis of IR Injury

①① Role of OFR/ROSRole of OFR/ROS

②② Calcium overloadCalcium overload

③③ 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 .

1O2 H2O2

OONO-

L .

Cl . CH3

.

The Relationship Between Free radicals and Reactive Oxygen Species

Mechanism of OFR Increase During IR Injury Mechanism of OFR Increase During IR Injury

①① Increased OFR productionIncreased OFR production

②② Decreased OFR clearanceDecreased OFR clearance

Role of ORF/ROS

Injurious Effects of OFRInjurious Effects of OFR

212

Generation of OFR

①① Xanthine oxidase pathwayXanthine oxidase pathway

②② Neutrophils pathwayNeutrophils pathway

③③ Mitochondria pathwayMitochondria pathway

Xanthine Oxidase Pathway

Xanthine dehydrogenase

Xanthine oxidase (XO)

ATP

Ischemia

[Ca2++]i↑

ATP

ADP

AMP

Hypoxanthine XanthineO2._H2O2 + +

O2

ReperfusionUric acidO2

._

+ H2O2 +

XOO2

OH.

Ca2++-dependent proteinase

Adenosine

214

Generation of OFR




OFR OFR

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 + ATPCytochrome

oxydase

e_

O2e

_+2H+

H2O2 OH.e

_+H+

H2O

e_+H+

H2O（ 1-2% ）

_

SODO2. Fe Fe 3 3

Ischemia

Mitochondria Pathway

Ca2+ entering mito

ATP

OO22.._ _

e_

Reperfusion O2

OO22 +O2（ 98

% ）4e

_+4H

+

2H2OCytochrome oxydase

e_

O2e

_+2H+

H2O2 OH.e

_+H+

H2O

e_+H+

H2O_O2.

×

(2%)




Role of ORF/ROS


220

Clearance of OFR

①① Enzymatic clearanceEnzymatic clearance

SOD (Superoxide dismutase)SOD (Superoxide dismutase)

CAT (Catalase)CAT (Catalase)

②② Non-enzymatic clearanceNon-enzymatic clearance

Enzymatic Clearance of OFR

e_

O2e

_+2H+

H2O2e

_+H+

（ 1-2% ）_O2. H2O + O2

SOD CAT

Mn-SOD CuZn-SOD

Amyotrophic lateral sclerosis(ALS)

Mutation

Stephen Hawking

222

Clearance of OFR

①① Enzymatic clearanceEnzymatic clearance

②② Non-enzymatic clearanceNon-enzymatic clearance

Non-enzymatic OFR scavengers Non-enzymatic OFR scavengers

Vitamins (Vit C, Vit E)Vitamins (Vit C, Vit E)

CeruloplasminCeruloplasmin

Dimethyl sulfoxide (DMSO)Dimethyl sulfoxide (DMSO)

Allopurinol Allopurinol

Glutathione (GSH)Glutathione (GSH)

H2O2 + 2GSH 2H2O + GSSG




Role of ORF/ROS


Injurious Effects of OFR


①① Role of ORF/ROSRole of ORF/ROS



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 ： 10-3M [Ca2+]i ： 10-7M

Ca2+ channel

MitoSR

Ca2+

Na +

Ca 2+

Ca 2+

SR: Sarcoplasmic reticulum


①① Role of ORF/ROSRole of ORF/ROS



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




OO22--

HH22OO22

HOClHOClOOHH

GutGut

Heart & Heart & vesselsvessels

Lungs &Lungs &airwaysairways

Brain &Brain &nervesnerves

231

IR Injury to Important OrgansIR Injury to Important Organs

ArrhythmiaArrhythmiaVentricular fibrillationVentricular fibrillationVentricular TachycardiaVentricular Tachycardia

Myocardial dysfunctionMyocardial dysfunctionCO CO ↓↓Myocardial stunningMyocardial stunning

Reversible reduction of the function of heart Reversible 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




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 Na and Na++

↓ ↓ OFR and edemaOFR and edema

↓ ↓ CaCa2+2+ overload overload

↓ ↓ metabolism →↓ energy metabolism →↓ energy consumptionconsumption

Control Reperfusion ConditionsControl Reperfusion Conditions

Education

Pathophysiology review pt_i