Stress and Stress-related Diseases Jianzhong Sheng MD PhD
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Transcript of Stress and Stress-related Diseases Jianzhong Sheng MD PhD
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
StressStress
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
StressStress
■■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
StressStress
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