Stress and Stress-related Diseases Jianzhong Sheng MD PhD

1. Stress Stress and Stress-related Diseases Jianzhong Sheng MD PhD

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

3. Basic concepts of stress ■ Stress ■ Stressor ■ Classification of stress response ■ Significance of stress Stress

4. Necrosis Burn Stimulating Surgery Specific responses Infection Pyogenesis Hypoxia Acidosis Nonspecific responses Trauma Noise Blood re-distribution Heart rate increases Dread Stress Anxiety Stress 1．Stress Stress is defined as a state of tension that can lead to disharmony or threaten the homeostasis of body. No relation with the characteristics of the stimuli

5. Stress 2．Stressor The stimuli or agents that induce stress are termed stressor. Stressor External factors（Physical, chemical, biological） Cold, heat, toxins, drugs, bacteria. Intrinsic factors Homeostasis, disease, cancer. Psychological or social factors Threat to self esteem, relationships with other people.

6. 4．Significance of stress ■ Stress that is healthy, or gives one a feeling of fulfillment or other positive feelings is termed eustress.(Fight or flight response) ■ Stress that is harmful to our body and induces diseases is termed distress. Stress 3．Classification of stress response Physical, chemical Stress response Physical stress Psychological stress Psychological or socio-cultural

7. Stress What is eustress? Eustressor positive stress occurs when your level of stress is high enough to motivate you to move into action to get things accomplished.

8. Stress What is distress? Distressor 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.

9. Response is quick and short. The sympathetic-adrenal medulla axis catecholamines Stress 4.General adaptation syndrome,GAS Stress is also called general adaptation syndrome (GAS) Characteristic Significance The body is prepared for fighting against the threats or challenges on homeostasis. Alarm stage The ACTH-glucocorticoids take the major role in this stage. The increased catecholamines fall down soon. Organisms become increasingly vulnerable to health problem. Resistance stage The resources are depleted The resources are depleted and the signs of “wear and tear” or systemic damage appears. Exhaustion stage

10. Neuro-endocrine CA, GC Cell,Humors HSP Changes in functions and metabolism of organs and systems Stress Body’s responses in the stress Stressors

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

12. Stress 1. Neuroendocrine Responses to Stress） Locus Ceruleus (LC)-norepinephrine (NE) –sympathetic/Adrenal Medulla Axis Neuroendocrine Responses Catecholamines↑ HPAexcitement Glucocorticoids↑ Rest hormonal responses to stress

13. Emotion Stressor CRH Adrenal Medulla Catecholamines GC Stress ►Locus ceruleus - Norepinephrine （LC-NE） 1. LC-NE—sympathetic/Adrenal Medulla Axis Social Psychological Stress Cerebral cortex Limbic system Paraventricular nucleus of the hypothalamus（PVN） LC The central integrating site for the automomic nervous system response to stressors Pituitary ACTH adrenocorticotropic hormone Adrenal cortex

14. Stress 2. Effects of CNS (Afferent pathways of LC) ■Inducing exitement, alertness, anxiety, etc. ■The PVN activation initiates the HPA axis for more profound stress responses. 3. Effects of peripheral (Efferent pathways of LC) ■Rapidly Increasingthe levels ofCA, Ad, NE and dopamine

15. ■Cardiovascular System Stress CAHeart rate , Cardiac contractility , Cardiac output↑ Peripheral resistance↑ Blood supply redistribution Blood supply in some important organs ■Respiration System Stress Respiratory rate , Inspiration , Blood carrying O2 , O2 supply Stress 4. The effects of CA at high level on the body （Functional and metabolic responses of body）

16. ■Metabolism Stress CA↑  receptor in A cell (+)Glucagon ↑  receptor inB cell (+) Insulin↓ Blood glucose↑ glycogenolysis, lipoclasis Matching the demand of energy in tissues pancreas The levels of CA in blood during stress (times) Stress NE Adrenin Hypoxia, Anoxia 10－20 4－5 hemorrhagic shock 50 10 Stress

17. GC GC R HSP90 R HSP90 HSP90 HSP90 R R R R Stress Anti-inflammation of GC Cortisol Inflammation medium GRE mRNA

18. ■The changes of other hormones CA ACTH, GH, T3/T4, renin secretion ■Consistent constriction of viscera blood vessels Erosion and hemorrhage in gastrointestinal mucosa ■Vasoconstraction and Heart rate↑ Heart Load↑ Hypertension ■Over-exhaustion of the energy in the body ■CA↑ Thrombin formation Stress Disadvantage to the body

19. Stress ► Hypothalamic-pituitary-adrenal（HPA） 1.Essence of cell HPAaxis including PVN, Pituitary and Adrenal Cortex. PVN is the central site in this system. CRH↑ ACTH↑ GC↑ Amygdaloid nucleus, hippocampi, limbic system Locus ceruleus– adrenal medulla PVN Pituitary peripheral sensors (The body stress responses) Emotional stress Adrenal Cortex

20. Stressors ② amygdaloid nucleus ADH↑ antidiuretic hormone Stress 2. Effects of CNS PVN Limbic system Interegrating information ③ CRH↑ β-endorphine↑ ① Pituitory CA↑ ACTH↑ Adrenal Cortex Sympthetic-adrenal medulla excitement GC↑ 3. Peripheraleffects ●Suitable CRH↑Adaptation↑Excitement↑Happy↑memory↑ ●Over CRH↑Adaptation anxiety,dumps, inappetence

21. Advantage Disadvantage ●Immune Infection ● Growing slowly ●Inhibiting sexual gland axis and thyroid ●Dystropy ●Over proteolysis negative nitrogen balance ● Proteolysis, gluconeogenesis ● Effects of CA, Glucagon ● Sensitivity of cardiovascular system to CA(Permitting) ●Stabling lysoome ●Anti-inflammation Stress 4. Physiological significance of GC↑ GC>25-37mg/d）

22. Stress ►Rest hormonal responses to stress Hormone Secreted from Change -Endorphine)Pituitary etc ↑ ADH Hypothalamus (ventricular nuclear) ↑ Growth hormone Adrenal pituitary Acute↑, Chronic↓ Ald（Aldehyde) Adrenal cortex ↑ Glucagons  Cell in pancreatic islet ↑ Prolactin adrenal pituitary ↑ Insulin β Cell in pancreatic islet↓ TRH Hypothalamus ↓ TSH Pituitary ↓ T3、T4 Thyroid gland ↓ GhRH Hypothalamus↓

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

24. Stress Stress responses of cells Cell-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.

25. Stress ►Acute phase proteins 【Acute phase response】（APR）。 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.. 【Acute 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.

26. 2．Effects of APP ■α1Antitrypsin↑ ■Fibrinogen ↑ Stressthrombinogen↑, profibrinolysin↑, fibrinogen↑, factor Ⅷ↑ ■Complement C3↑ ■transport protein ↑（haptoglobin, transferrin） Stress 1. Origin of APP ■APPare mainly produced by liver. Ventricular endothelial cells, monocytes and fibroblastscan produce small amount of APP. Hepatocytes synthesize APP when being stimulated by IL-1、TNF- and IL-6

27. Stress 3. Function of APP ■Inhibiting proteinase activity and decreasing tissue injury ■Blocking pathogene spread ■Cleaning foreign matters and necrotic tissue; Promoting phagocyte functions ■Inhibiting free radical production ■Other: Serum amyloid protein A restorationof injured cells

28. Stress ► Heat shock protein，HSP 【Concept of HSP】 Heat shock proteins are a family of stress proteins whose synthesis is upregulated in response to a variety of environmental insults such as “heat stress”. 1. Biological characteristics of HSP ■Non-specific inducers ■Existing in most of cells ■Conservative structures 2. Funcation and classification of HSP ■Classification with MW HSP110、HSP90、HSP70、HSP60 and Small MW HSP etc.

29. Stress Factors inducing HSP production Heat shock Free radical Heavy metal Environment stress Pathological state Fever Inflammation Ischemia Trauma Virus Antineoplastic HSF HSF HSE HSP Growth factor Development and differentiation Oncogene Other heat-shock element (HSE)

30. Stress ■ Classification with biological function ▲Structural HSP Functions: Folding and translocation of new synthesized proteins. Also called “Molecular chaperone”。 ▲inducible HSP Functions: Repairing or removing injured proteins; Repairing pre-ribosomal RNA; Protecting cells; Promoting tolerance of cells to stressors.

31. 3． Basic structure and function of HSP N- 450 AA residues 200 AA residues-C Stress ■Basic structure of HSP70 ATPase (High reservation region) Alterable region Proteinase sensitity site N-terminal：Having ATPase activity; C-terminal： Being alterable. Combining with injured proteins and recovering their correct folding (needing ATP to supply energy.

32. ■ The function of HSP ▲Repairing the damaged proteins ，maintain the normal function of cells, increasing the torlerance of cells to stressor. (induced HSP70) ▲Regulating Na+-K+-ATP activity。 ▲Combining with monomer of STF, inhibiting the formation of HSTFtrimer，inhibiting HSP production. Stress soluble tuberculosis factor (STF)

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

34. Stress Effects of stress on the body Function alteration • Central nervous system • Cardiovascular system • Digestive system • Immune system • The blood system • Urogenital system

35. Stress 1. Effects on metabolism 【Characteristics】Metabolism rate↑, dialysis↑, synthesis ↓ ■High metabolism rate Sever stress CA, GC↑ catabolism↑ loss of weight, weak, immune↓ ■Change in glycometabolism Stressinsulin↓, CA, glucagon, GH, GC↑ Glycogenolysis↑ Stress diabetes ■Changes in lipid metabolism ■Changes in protein metabolism

36. 2. Changes in different systems ■Change of CNS ▲LC-NE axis activated inducing excitement, anxiety, angry. ▲HPA axis suitable excitement helpful to good emotion and study. ▲HPA axis over excitement or less inducing function problems of CNS, (dumps, anorexia, suicide) Stress ■Change of cardiovascular system ■Change of gastrointestinal

37. Stress ■Change of immunity ▲Acute stress response Stress WBC, activity↑ GC、CA↑ Immune↓ ▲Psychological stress Lonely life, dumps, death of relatives Immune↓ Diseases

38. WBC、Platelet↑，blood coagulation↑ ■Change of kidney and procreation Na+discharge ↓specific gravity of urine Paramenia, amenorrhea, latex ↓ Stress ■Change of blood Acute stressperipheral blood Advantage：anti-infection, anti-injury, anti-bleeding disadvantage：promoting formation of thrombus and DIC (Disseminated intravascular coagulation)

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

40. This patient with no Helicobacter infection got this ulcer during a period of severe somatic stress due to a heart disease. Stress Stress and disease ►Stress ulcer 1．Concept 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.

41. Stress 2．Mechanisms of digestive ulcer ■Mucosa ischemia Sympathetic-adrenal medulla (+) ↑ Vasoconstiction in stomach, duodenumMucosa ischemia [HCO3-]↓ , mucus ↓ Mucosaregeneration ↓ Gastric mucosa barrier damaged H+ enters mucosa↑Entered H+ removing ↓ H+accumulation in mucosa (Stress ulcer)

42. Stress ■Increased the production and secretion of glucocorticoids GC induces the dialysis of proteins more than the synthesis, resulting in the decreased resistance of gastric muca to impairing factors and hydrogen ion. ■Other factors ▲Acidosis ▲Bile acidand lysolecithin Severe stress fluids of duodenum entering stomach bile acidand lysolecithin↑ Anti-injury ability of mucosa↓ stress ulcer

43. Emotion Noises Exertion Tension Stressor Hypothalamus Sympathetic impulse↑ Ald ↑ Renin Angiotensin Ⅱ ↑ Adrenal catecholamines↑ Retention of water and sodium Vasoconstriction Hypertension Elevated arterial pressure Stress ►Essential hypertension 1．The excitement of sympathetic-adrenal medulla system Aldosterone (ald)

44. Stress 【The mechanisms of inhibiting immune by GC】 ●Inhibiting WBC chemiotaxis, ●Blocking LCDNA synthesis and mitosis , peripheral LCnumber ●Impairing B cells,Inhibiting cellular and humeral immune

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

46. Stress Questions 1．The major characteristics of stress responses？ 2．The significance of increased CA, GC levels in stress?。 3．What are changed in the metabolisms of the body during stress？ 4．The characteristics and mechanisms of stress ulcer？ 5．What is heat shock proteins (HSP)？