Stress and Stress-related DiStress and Stress-related Diseasesseases

Jianzhong Sheng MD PhDJianzhong Sheng MD PhD

StressStress

Teaching contents Overview Neuroendocrine response Cellular and humoral responses Effects of stress on the body Stress and diseases Pathophysiological basis of prevention a

nd treatment

StressStress

Basic concepts of stressBasic concepts of stress

■ ■ StressStress

■ ■ StressorStressor

■ ■ Classification of stress responseClassification of stress response

■ ■ Significance of stressSignificance of stress

StressStress

11 ．． StressStress

Stress is defined as a state of tension that can lead to Stress is defined as a state of tension that can lead to disharmony or threaten the homeostasis of body.disharmony or threaten the homeostasis of body.

StimulatingStimulatingS

pecific

Sp

ecific resp

onses

respon

ses

NecrosisNecrosis

PyogenesisPyogenesis

AcidosisAcidosis

Nonspecific responsesNonspecific responses

Anxiety

Anxiety

Dread

Dread

Blood re-

Blood re-

distributiondistribution

Heart rate

Heart rate

increasesincreases

StressStress

Surgery

Burn

Infection

Hypoxia

Trauma

Noise

No relation with the No relation with the characteristics of characteristics of the stimulithe stimuli

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22 ．． StressorStressor

The stimuli or agents that induce stress are termed The stimuli or agents that induce stress are termed stressor.stressor.

Stressor

Stressor

Psychological or social factorsPsychological or social factors

Intrinsic factorsIntrinsic factors

External factorsExternal factors （（ Physical, chemical, biologicaPhysical, chemical, biologicall ））

Threat to self esteem, relationships with other people.

Cold, heat, toxins, drugs, bacteria.

Homeostasis, disease, cancer.

StressStress

44 ．． Significance of stressSignificance of stress

■ ■ Stress that is healthy, or gives one a feeling of fulfillmen that is healthy, or gives one a feeling of fulfillment or other positive feelings is termed eustress.t or other positive feelings is termed eustress. ((Fight or flight Fight or flight response)response)

■ ■ Stress that is harmful to our body and induces diseases is termed distress..

Psychological stressPsychological stress

33 ．． Classification of stress responseClassification of stress response

Stress responseStress response Physical stressPhysical stress

Physical, chemicalPhysical, chemical

Psychological or socio-culturalPsychological or socio-cultural

StressStress

Eustress or positive stress occurs whe

n your level of stress is high enough to

motivate you to move into action to ge

t things accomplished.

What is eustress?

StressStress

What is distress?

Distress or negative stress occurs

when your level of stress is either

too high or too low and your body

and/or mind begin to respond

negatively to the stressors.

StressStress

4. General adaptation syndrome,GAS

Stress is also called general adaptation syndrome (GAS)Stress is also called general adaptation syndrome (GAS)

Alarm stage

Resistance stage

Exhaustion stage

The body is prepared for The body is prepared for

fighting against the threats or fighting against the threats or

challenges on homeostasis.challenges on homeostasis.

The ACTH-glucocorticoids take tThe ACTH-glucocorticoids take the major role in this stage. The ihe major role in this stage. The increased catecholamines fall doncreased catecholamines fall down soon.wn soon.

The resources are depleted The resources are depleted and the signs of “wear and and the signs of “wear and tear” or systemic damage tear” or systemic damage appears.appears.

Organisms become Organisms become

increasingly vulnerable to increasingly vulnerable to

health problem.health problem.

The resources are The resources are

depleteddepleted

CharacteristicCharacteristic SignificanceSignificance

StressStress

Response is quick and short. TResponse is quick and short. The sympathetic-adrenal medulla he sympathetic-adrenal medulla axis catecholamines axis catecholamines

Body’s responses in the stressBody’s responses in the stress

StressStress

StressorsStressors

Cell,Humors Cell,Humors

HSPHSP

Neuro-endocrineNeuro-endocrine

CA, GCCA, GC

Changes in functions and metabolism of organs and systems

Teaching contents Overview Neuroendocrine response Cellular and humoral responses Effects of stress on the body Stress and diseases Pathophysiological basis of prevention a

nd treatment

StressStress

1. Neuroendocrine Responses to Stress1. Neuroendocrine Responses to Stress ））

Ne

uroe

nd

ocrine R

esp

onse

sN

eu

roen

docrine

Re

spo

nses

Locus Ceruleus (LC)-norepinephrine (NE) –Locus Ceruleus (LC)-norepinephrine (NE) –sympathetic/Adrenal Medulla Axissympathetic/Adrenal Medulla Axis

CatecholaminesCatecholamines↑↑

HPAHPA excitementexcitement

GlucocorticoidsGlucocorticoids↑↑

StressStress

Rest hormonal responses to stressRest hormonal responses to stress

ACTHACTHadrenocorticotropic adrenocorticotropic

hormonehormone

LC LC The central integratiThe central integrating site for the automoming site for the automomic nervous system responc nervous system respon

se to stressorsse to stressors

Adrenal MedullaAdrenal Medulla

StressorStressor

CRHCRH

GCGC

Cerebral cortexCerebral cortex

Limbic systemLimbic system

Paraventricular nucleuParaventricular nucleus of the hypothalamuss of the hypothalamus

（（ PVNPVN ））

Social Social Psychological Psychological

StressStress

CatecholaminesCatecholamines

Adrenal cortexAdrenal cortex

PituitaryPituitary

StressStress

Emotion

►►LLocus ceruleusocus ceruleus - Norepinephrine - Norepinephrine （（ LC-NELC-NE ））1. LC-NE—sympathetic/Adrenal Medulla Axis1. LC-NE—sympathetic/Adrenal Medulla Axis

2. 2. Effects of CNS (Effects of CNS (Afferent pathwaysAfferent pathways of LC)

■■Inducing exitement, alertness, anxiety, etc.Inducing exitement, alertness, anxiety, etc.

■■The PVN activation initiates the HPA axis for more The PVN activation initiates the HPA axis for more

profound stress responses.profound stress responses.

StressStress

3. 3. Effects of peripheral Effects of peripheral ((Efferent pEfferent p

athwaysathways of LC)

■■Rapidly Increasing the levels of

CA, Ad, NE and dopamineCA, Ad, NE and dopamine

4. 4. The effects of The effects of CA at high level on the bodyCA at high level on the body

（（ Functional and metabolic responses of bodyFunctional and metabolic responses of body ））

StressStress

■■Cardiovascular SystemCardiovascular System

Stress CAStress CA Heart rate , Cardiac contractility , Heart rate , Cardiac contractility , Cardiac output↑Cardiac output↑

PeripheralPeripheral resistance↑ ↑ Blood supply redistribution Blood supply redistribution Blood supply in some important organs Blood supply in some important organs

■■Respiration System Respiration System

Stress Respiratory rate , Inspiration , Blood carrying Stress Respiratory rate , Inspiration , Blood carrying O2 , O2 supply O2 , O2 supply

StressStress

The levels of CA in blood during stress (times)

Stress NE Adrenin

Hypoxia, Anoxia 10 － 20 4 － 5

hemorrhagic shock 50 10

■■MetabolismMetabolism

Stress CA↑ Stress CA↑ receptor in A cell (+)A cell (+) Glucagon Glucagon ↑↑

receptor inreceptor in B cell (+)B cell (+)

Insulin↓ Blood glucose↑ Insulin↓ Blood glucose↑ glycogenolysis, lipoclasisglycogenolysis, lipoclasis

Matching the demand of energy in tissuesMatching the demand of energy in tissues

pancreas

Cortisol

HSP90

R RHSP90

R R

R

HSP90HSP90

R

GC GC

GRE

Inflammation medium

mRNA

Anti-inflammation of GCStressStress

Disadvantage to the bodyDisadvantage to the body

StressStress

■■The changes of other hormonesThe changes of other hormones

CA ACTH, GH, TCA ACTH, GH, T33/T/T44, renin secretion, renin secretion

■■Consistent constriction of viscera blood vesselsConsistent constriction of viscera blood vessels

Erosion Erosion and and hemorrhage in gastrointestinal hemorrhage in gastrointestinal mucosamucosa

■■Vasoconstraction and Heart rateVasoconstraction and Heart rate↑ ↑ Heart Load↑ Heart Load↑

HypertensionHypertension

■■Over-exhaustion of Over-exhaustion of

the energy in the bodythe energy in the body

■■CACA↑ ↑ Thrombin formationThrombin formation

peripheral sensors peripheral sensors (The body stress (The body stress

responses)responses)

PVN

Pituitary

Adrenal Cortex

GC↑

CRH↑

ACTH↑

► ► Hypothalamic-pituitary-adrenalHypothalamic-pituitary-adrenal （（ HPAHPA ））

1.1.Essence of cellEssence of cell

HPAHPA axis including axis including PVN, Pituitary and Adrenal Cortex. PVN, Pituitary and Adrenal Cortex. PVN is the central site in this system.PVN is the central site in this system.

StressStress

Locus ceruleus –

adrenal medulla

Emotional stressEmotional stress

Amygdaloid nucleus,

hippocampi,

limbic system

2. 2. Effects of CNSEffects of CNS

PVNLimbic system

Interegrating information

Stressors

CRH↑CRH↑

ADH↑ADH↑

antidiuretic hormoneantidiuretic hormone

StressStress

●●Suitable Suitable CRHCRH↑↑ AdaptationAdaptation↑↑ ExcitementExcitement↑↑HappyHappy↑↑memorymemory↑↑

●●Over Over CRHCRH↑↑ Adaptation anxiety,Adaptation anxiety, dumps, dumps, inappetenceinappetence

Pituitory

ACTH↑ACTH↑

①

Sympthetic-adrenal medulla excitement

CA↑CA↑

β-endorphine↑β-endorphine↑③amygdaloid

nucleus

②

Adrenal Cortex

GC↑GC↑

3. 3. PeripheralPeripheral effectseffects

StressStress

● ● Proteolysis, gluconeogenesis Proteolysis, gluconeogenesis

● ● Effects of Effects of CA, CA, GlucagonGlucagon

● ● Sensitivity of cardiovascular Sensitivity of cardiovascular

system to CAsystem to CA (Permitting) (Permitting)

●●Stabling lysoomeStabling lysoome

●●Anti-inflammation Anti-inflammation

AdvantageAdvantage

4. Physiological significance of GC4. Physiological significance of GC↑ ↑ GC>25-37mg/dGC>25-37mg/d ））

●●Immune Immune Infection Infection

● ● Growing slowly Growing slowly

●●Inhibiting sexual gland axis and Inhibiting sexual gland axis and thyroid thyroid

●●Dystropy Dystropy

●●Over proteolysis negative Over proteolysis negative nitrogen balance nitrogen balance

DisadvantageDisadvantage

Hormone Secreted from ChangeHormone Secreted from Change

-Endorphine)-Endorphine) Pituitary etc Pituitary etc ↑↑

ADH Hypothalamus (ventricular nuclear) ADH Hypothalamus (ventricular nuclear) ↑↑

Growth hormone Adrenal pituitary Acute↑, Chronic↓Growth hormone Adrenal pituitary Acute↑, Chronic↓

AldAld （（ Aldehyde) Adrenal cortex Aldehyde) Adrenal cortex ↑↑

Glucagons Glucagons Cell in pancreatic islet ↑ Cell in pancreatic islet ↑

Prolactin adrenal pituitary Prolactin adrenal pituitary ↑↑

Insulin β Insulin β Cell in pancreatic isletCell in pancreatic islet ↓↓

TRH Hypothalamus TRH Hypothalamus ↓↓

TSH Pituitary TSH Pituitary ↓↓

T3T3 、、 T4 Thyroid gland T4 Thyroid gland ↓↓

GhRH GhRH HypothalamusHypothalamus ↓↓

►► Rest hormonal responses to stressRest hormonal responses to stress StressStress

Teaching contents Overview Neuroendocrine response Cellular and humoral responses Effects of stress on the body Stress and diseases Pathophysiological basis of prevention a

nd treatment

StressStress

Stress responses of cellsStress responses of cellsCell-humour responses to stressCell-humour responses to stress

In responses of cellular-molecular level to more stressors (mainly non-psychogenic stressors), cells arouse a series of intracellular signal transduction and activation of correlative gene and synthesize some protective proteins, which mainly are heat shock proteins and acute phase proteins.

StressStress

【【 Acute phase proteins, APPAcute phase proteins, APP 】】

APP have been defined as one whose plasma concentration increases (positive acute phase proteins) or decreases (negative acute phase proteins) during the acute phase responses.

【【 AAcute phase responsecute phase response 】】（（ APRAPR ）。）。

► ►Acute phase proteins

The acute phase response is a quickly mobilized, non-specific defensive response elicited in response of the host to infection, tissue injury or inflammation, etc..

StressStress

22 ．． Effects of APPEffects of APP

■■αα11Antitrypsin↑Antitrypsin↑

■■Fibrinogen ↑Fibrinogen ↑

StressStress thrombinogenthrombinogen↑↑, profibrinolysinprofibrinolysin↑↑, fibrinogenfibrinogen↑↑, factor factor ⅧⅧ↑↑

■■Complement C3↑Complement C3↑

■■transport protein ↑transport protein ↑ （（ haptoglobin, haptoglobin, transferrintransferrin ））

1. 1. Origin of APPOrigin of APP

■■APPAPP are mainly produced by liver. Ventricular endothelial are mainly produced by liver. Ventricular endothelial cells, monocytes and cells, monocytes and fibroblasts fibroblasts can produce small amount of can produce small amount of APP.APP.

Hepatocytes synthesize APP when being stimulated by IL-Hepatocytes synthesize APP when being stimulated by IL-11 、、 TNF-TNF- and IL-6 and IL-6

StressStress

33. Function of . Function of APPAPP

■■Inhibiting proteinase activity and decreasing tissue injuryInhibiting proteinase activity and decreasing tissue injury

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■■Other: Serum amyloid protein A Other: Serum amyloid protein A restorationrestoration

of of injured cellsinjured cells

■■Inhibiting Inhibiting free radical productionfree radical production

■■Blocking Blocking pathogene spread pathogene spread

■■Cleaning foreign matters and Cleaning foreign matters and necrotic tissue; Promoting phagnecrotic tissue; Promoting phag

ocyte functionsocyte functions

■■Non-specific inducers Non-specific inducers

■■Existing in most of cellsExisting in most of cells

■■Conservative structures Conservative structures

1. Biological characteristics of 1. Biological characteristics of HSP

►► Heat shock proteinHeat shock protein ，， HSPHSP

【【 Concept of Concept of HSPHSP 】】 Heat shock proteins are a family of stress proteins whose Heat shock proteins are a family of stress proteins whose synthesis is upregulated in response to a variety of synthesis is upregulated in response to a variety of environmental insults such as “heat stress”.environmental insults such as “heat stress”.

StressStress

22. . Funcation and classification of HSPFuncation and classification of HSP

■■Classification with MWClassification with MW

HSP110HSP110 、、 HSP90HSP90 、、 HSP70HSP70 、、 HSP60 and Small MW HSP HSP60 and Small MW HSP etc.etc.

Environment stressHeat shockFree radical

Heavy metal Pathological state

FeverInflammationIschemiaTraumaVirusAntineoplastic

Growth factorDevelopment and differentiationOncogene

Other

HSPHSE

HSF

HSF

Factors inducing HSP production

heat-shock element (HSE)

StressStress

▲▲inducible inducible HSPHSP

Functions: Repairing or removing injured proteins; RepairFunctions: Repairing or removing injured proteins; Repair

ing pre-ribosomal RNA; Protecting cells; Promoting toleraing pre-ribosomal RNA; Protecting cells; Promoting tolera

nce of cells to stressors.nce of cells to stressors.

▲▲Structural Structural HSPHSP

Functions: Folding and translocation of new synthesized prFunctions: Folding and translocation of new synthesized pr

oteins. Also called “oteins. Also called “Molecular chaperone”Molecular chaperone” 。。

■ ■ Classification with biological functionClassification with biological function

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33 ． ． Basic structure and function of HSPBasic structure and function of HSP

■■Basic structure of Basic structure of HSPHSP7070

ATPase (High reservation regioATPase (High reservation region)n)

Alterable regionAlterable region

Proteinase sensitity siteProteinase sensitity site

NN- 450 AA - 450 AA residuesresidues 200 AA 200 AA residuesresidues -C-C

N-terminalN-terminal ：： Having ATPase activity;Having ATPase activity;

C-terminalC-terminal ： ： Being alterable. Combining with injured proteins aBeing alterable. Combining with injured proteins and recovering their correct folding (needing ATP to supply energnd recovering their correct folding (needing ATP to supply energy. y.

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■ ■ The function of The function of HSPHSP

▲▲Repairing the damaged proteins Repairing the damaged proteins ，， maintain the normal maintain the normal

function of cells, increasing the torlerance of cells to stressor. function of cells, increasing the torlerance of cells to stressor. (in(in

duced HSPduced HSP7070))

▲▲Regulating Regulating NaNa++-K-K++-ATP activity-ATP activity 。。

▲▲Combining with monomer of Combining with monomer of STF, inhibiting the STF, inhibiting the

formation of HSTFformation of HSTF trimertrimer ，， inhibiting HSP production.inhibiting HSP production.

StressStress

soluble tuberculosis factor (STF)

Teaching contents Overview Neuroendocrine response Cellular and humoral responses Effects of stress on the body Stress and diseases Pathophysiological basis of prevention a

nd treatment

StressStress

Central nervous system Cardiovascular system Digestive system Immune system The blood system Urogenital system

Effects of stress on the body

Function alteration

StressStress

■■Change in Change in glycometabolismglycometabolism

StressStress insulin↓, insulin↓, CA, CA, glucagon, glucagon, GH, GCGH, GC↑↑

GlycogenolysisGlycogenolysis ↑ ↑ Stress diabetesStress diabetes

■■High metabolism rateHigh metabolism rate

Sever stressSever stress CA, GC CA, GC↑ catabolism↑ catabolism ↑ loss of weight, ↑ loss of weight, weak, immuneweak, immune↓↓

1. Effects on metabolism1. Effects on metabolism

【【 CharacteristicsCharacteristics 】】 Metabolism rate↑, Metabolism rate↑, dialysisdialysis ↑↑, synthesis , synthesis ↓↓

■■Changes in lipid metabolism Changes in lipid metabolism

■■Changes in protein metabolismChanges in protein metabolism

StressStress

22. Changes in different systems. Changes in different systems

■■Change of CNSChange of CNS

▲▲ LC-NE axis activated inducing excitement, anxiety, angry.LC-NE axis activated inducing excitement, anxiety, angry.

▲▲ HPA axis suitable excitement helpful to good emotion and HPA axis suitable excitement helpful to good emotion and

study.study.

▲▲ HPA axis over excitement or less inducing function HPA axis over excitement or less inducing function

problems of CNS, (problems of CNS, (dumps, anorexia, suicide)dumps, anorexia, suicide)

■■Change of cardiovascular systemChange of cardiovascular system

■■Change of gastrointestinalChange of gastrointestinal

StressStress

■■Change of immunity Change of immunity

▲▲Acute stress responseAcute stress response

Stress WBC, activityStress WBC, activity↑↑ ，， APsAPs↑↑

GCGC 、、 CACA↑↑

ImmuneImmune↓↓

StressStress

▲▲Psychological stress Psychological stress

Lonely life, Lonely life, dumpsdumps, death of relatives, death of relatives

ImmuneImmune↓↓

DiseasesDiseases

■■Change of bloodChange of blood

Acute stressAcute stress peripheral bloodperipheral blood

WBC 、 Platelet↑ ， blood coagulation↑

AdvantageAdvantage ：： anti-infection, anti-injury, anti-anti-infection, anti-injury, anti-bleedingbleeding

disadvantagedisadvantage ：： promoting formation of thrombus promoting formation of thrombus and DIC (and DIC (Disseminated intravascular coagulationDisseminated intravascular coagulation))

StressStress

■■Change of kidney and procreationChange of kidney and procreation

Na+ Na+ discharge ↓specific gravity of urine discharge ↓specific gravity of urine

Paramenia, amenorrhea, latex Paramenia, amenorrhea, latex ↓↓

Teaching contents Overview Neuroendocrine response Cellular and humoral responses Effects of stress on the body Stress and diseases Pathophysiological basis of prevention a

nd treatment

StressStress

Stress and diseaseStress and disease

►►Stress ulcerStress ulcer

11 ．． ConceptConcept

StressStress

This patient with no Helicobacter infection got this ulcer during a period of severe somatic stress due to a heart disease.

Stress ulcer is the term given to mucosal damage or lesions of the esophagus, sto-mach or duodenum in critically ill or stress- ed otherwise healthy patients.

22 ．． Mechanisms of digestive ulcerMechanisms of digestive ulcer

■■Mucosa ischemia

SympatheticSympathetic--adrenal medulla (+) ↑ adrenal medulla (+) ↑

Vasoconstiction in stomach, Vasoconstiction in stomach, duodenumduodenum

Mucosa ischemia

[[HCO3-]HCO3-]↓ ↓ , , mucus ↓ Mucosa regeneration mucus ↓ Mucosa regeneration ↓↓

Gastric mucosa barrier damagedGastric mucosa barrier damaged

H+ enters mucosaH+ enters mucosa ↑↑ Entered H+ removing Entered H+ removing ↓↓

HH++ accumulation in mucosa (Stress ulcer)accumulation in mucosa (Stress ulcer)

StressStress

■■Increased the production and secretion of glucocorticoids Increased the production and secretion of glucocorticoids

GC induces the dialysis of proteins more than the synthesis, GC induces the dialysis of proteins more than the synthesis,

resulting in the decreased resistance of gastric muca to impairing resulting in the decreased resistance of gastric muca to impairing

factors and hydrogen ion. factors and hydrogen ion.

■■Other factorsOther factors

▲▲AcidosisAcidosis

▲▲Bile acid Bile acid and and lysolecithinlysolecithin

Severe stress Severe stress fluids of fluids of duodenum entering stomach bduodenum entering stomach b

ile acid ile acid and and lysolecithinlysolecithin↑ Anti-injury ability of mucosa↑ Anti-injury ability of mucosa ↓↓

stress ulcerstress ulcer

StressStress

►► Essential hypertensionEssential hypertension

11 ．． The excitement of sympathetic-adrenal medulla systemThe excitement of sympathetic-adrenal medulla system

StressStress

Emotion

Noises

Exertion

Tension

Stressor Stressor

HypothalamusHypothalamus

Sympathetic impulse↑Sympathetic impulse↑

Adrenal catecholamines↑Adrenal catecholamines↑

VasoconstrictionVasoconstriction

ReninRenin Angiotensin ⅡAngiotensin Ⅱ↑↑

Ald ↑Ald ↑

Retention of water and sodiumRetention of water and sodium

Elevated arterial pressureElevated arterial pressureHypertensionHypertension

Aldosterone (ald)

【【 The mechanisms of inhibiting immune by GCThe mechanisms of inhibiting immune by GC 】】

●●Inhibiting WBC Inhibiting WBC chemiotaxis, chemiotaxis,

●●Blocking LCBlocking LC DNA synthesis and DNA synthesis and mitosismitosis , peripheral peripheral LCLC

numbernumber

●●Impairing B cells, Impairing B cells, Inhibiting cellular and humeral immuneInhibiting cellular and humeral immune

StressStress

Teaching contents Overview Neuroendocrine response Cellular and humoral responses Effects of stress on the body Stress and diseases Pathophysiological basis of prevention a

nd treatment

StressStress

QuestionsQuestions

11 ．． The major characteristics of stress responsesThe major characteristics of stress responses ？？

22 ．． The significance of increased CA, GC levels in stress?The significance of increased CA, GC levels in stress? 。。

33 ．． What are changed in the metabolisms of the body duriWhat are changed in the metabolisms of the body duri

ng stressng stress ？ ？

44 ．． The characteristics and mechanisms of stress ulcerThe characteristics and mechanisms of stress ulcer ？？

55 ．． What is heat shock proteins (HSP)What is heat shock proteins (HSP) ？？

StressStress