CH0576: The Biology of Disease - Dr Rosemary Bassrosemary.bass@northumbria.ac.uk

Biology of Stress & Disease

Copyrighted work available under Creative Commons by-nc-nd 2.0 UK

Summary of Lecture

Evolution of ideas about stress:-Physiological-Psychological

Causes & consequences of stress

Definitions

Any condition: Physical or Emotional can be a potential stressor

Stress (Biological) Interruption to Homeostasis

Psychological (emotional) stress

Exacerbate many disease states

Stress is a relatively modern concept

Coronary artery diseaseCancer

HypertensionStroke

Rheumatoid arthritisImmunosuppression

UlcersIrritable bowel

ImpotenceType 2 diabetes

Chronic fatigue syndromeDepression

Disease States/Conditions Exacerbated by Stress

Potential Stressors:

● Infection● Noise● Pain● Malnutrition● Exercise● Heat● Cold● Trauma● Obesity● Age● Drugs

● Surgery● Doctors● Anxiety● Depression● Anger● Fear

Environmental

MindHealth outcomes

Healthy Individual

Transient Effect

Return to Steady state

Elevated stress

response

Expression of Disease/illness

Coping strategy

Symptomatic individuals – ineffective coping strategy to stressor – Exacerbate illness

How Stress Affects the Heart

Acute emotional stress/trauma can cause:

•MI if have underlying CHD

•Left ventricle dysfunction especially in older women – sudden chest pain, shortness of breath

•Ventricle Dysrhythmias leading to cardiac death

Hans-Selye-1974

Stress: General adaptation syndrome (GAS)

Stressors – Ovarian steroid injections(cold, surgical injury, restraint,)

Same generalized pattern of hormonal and physiological response

GAS or “stress response”

1936 – experiments on rats

(humans, monkeys the same)

•Can impact on general health as long term stress changes way body functions.

•Evidence causes epigenetic changes – which affects next generation if in germ cells

•Epigenetic alterations = chemical modification of DNA associated histones which alters transcription

STRESS

3 phases:

1) Alarm stage (CNS arousal, fight or flight response, SNS)

2) Resistance (adaptation) stage (Period of stress longer than a few hours) – Long term metabolic adjustments

3) Exhaustion Stage (Breakdown of homeostatic regulation)

GAS = Physiological Stress Response

1) 3)2)Normal

ResistanceLevel

Selye defined 3 components of physiologic stress:

1)Exogenous/endogenous stressor initiating the disturbance

2)Chemical/physical disturbance produced by the stressor

3)Body’s adaptational response to the disturbance

Psychological Mediators of Stress(Not just all physiologic)

1950’s - Activation of adrenal cortex‘Psychological stressors’ e.g. stressful interview techniques or exams

1960’s – Changes in plasma cortisol levelsElevated – watching war filmsDecreased – watching Disney nature films

1970’s – Presence or absence of Stress response – psychologic factors influence GAS:‘discomfort’, ‘unpleasantness’, ‘suddenness’

Biology of Disease Exam

Increased heart rate, dry mouth (sympathetically

mediated)eg. of reactive response

Animal hears sound stimulus

Autonomic: Small increase in BP

Behavioural: Cessation Movement - Short

Sound plus short electric shock

Autonomic: Dramatic increase in BP

Behavioural: Cessation Movement - Long

Stimulus, No shock

Autonomic: Dramatic increase in BP

Behavioural: Cessation Movement - Long

Conditioned

Bilateral amygdalectomy abolishes conditioned response – Amygdala (limbic system) – learning response to fearful stimulus

Psychological Mediators of Stress: Anticipatory response (conditioned fear)

Limbic System

•First described by Broca in 1878

•Thought to be involved in emotions especially relating to survival, primative behavioural responses

•Located on top of brain stem & is an extension of the olfactory system(Amygdala, parahippocampal gyrus, hippocampus, fornix, mamillary body of the hypothalamus, thalamus, cingulate gyrus, septal area, habenula)

Modern Concepts of the “Limbic system”

Evidence from lesion studies in animals and humans as well

as pathology in humans

● Orbital and medial prefrontal cortex

● Ventral parts of the basal ganglia

● Mediodorsal nucleus of the thalamus

● Amygdala

Hippocampus/Mammillary body are now thought to have

little or no role in emotional behaviour

Purves et al Neuroscience

Conditioned Fear : Clinical correlations:

Anxiety (stress) disorders – typesPanic Disorder - frequent panic attacks, discrete periods with sudden onset of intense fearful feelings, fear of dying etc.

Agoraphobia - Anxiety about and/or avoidance of unfamiliar places or situations

Obsessive compulsive disorder – Obsessions causing marked anxiety or distress-repetitive behaviours (e.g. checking gas taps over and over).

Generalized anxiety disorder – 6 months or more of persistent anxiety/worry

Phobia’s – Anxiety induced by objects/animals e.g. spiders or social situations

Post-traumatic stress disorder – re-experiencing of a traumatic event, increased arousal and avoidance of triggers

Neural recognition of real or predicted stressors and physiological response:

•Stress response initiated by CNS & endocrine system(CRH-corticotrophin releasing hormoneACTH – adrenocorticotrophin releasing hormone)

•Initiation different if stressor is real or perceived

•Real stress starts a response in the limbic system or specific sensory system

•Perceived stress starts a response in the limbic system (as nothing real to start a response through a sensory system)

Neural recognition of real or predicted stressors and physiological response:

Adapted from Fig 10-1 (McCance and Huether)

Limbic system Brainstem(locus coeruleus)

Sympathetic nervous system

Norepinephrine secretion

Adrenal medulla(80% Epinephrine

20% NE)

Paraventricular nucleus of

Hypothalamus

Sensory Cortex

Stressor Anterior Pituitary

Adrenal cortex

(Cortisol)

HypothalamusAnterior PituitaryStress

Adrenal Gland

CRH

ACTH

CortisolCatecholaminesAdrenaline (epinephrine)Noradrenaline (norepinephrine)

Physiological Stress response: Alarm phase

Adr, NA

Stressor (exercise, thermal

changes, acute emotional stress)

General sympathetic

activation

● Increased mental alertness● Increased field of view● Upregulation of energy use by cells● Mobilisation of glycogen (skeletal muscle and liver)● Redistribution of blood flow(away from gut/skin)● Reduced digestive activity● Reduced urine production● Increased sweating● Increased heart rate● Increased respiratory rate

Physiological Effect:

Adr/NA

b1, b2, b3

Adrenoceptors(G-protein coupled

receptors)Elevated

Sympathetic Activity

(“fight or flight”

Physiological Effects: Receptor Stimulation

NB. Other receptor subtypes e.g. a1 different downsteam signalling effects

Physiological Consequences of Adrenergic Receptor Stimulation:

a1 – Increased glycogenolysis (breakdown); smooth muscle

contraction (blood vessels and urinary tract)

a2 – Smooth muscle relaxation (G.I. tract), Insulin secretion

– Primarily SNS mediated (NA)

b1 – Lipolysis, myocardial contraction (increased rate/force)

b2 – hepatic gluconeogenesis, glycogenolysis, increased glucagon

secretion, Smooth muscle relaxation (bronchi, skeletal muscle BV, G.I. tract)

- Primarily hormonally mediated Adr from Adrenal medulla

Physiological Stress response: Resistance Phase

Hypothalamus

Anterior pituitary

ACTH

Releasing Factors

Adrenal Cortex

Mineralocorticoid

Growth Hormone

Cortisol

SNS

Renin

Angiotensin

Glucagon

Conservation of salts and water

Elevated blood glucose

● Mobilisation of energy reserves for most tissues (lipolysis, skeletal muscle proteins)● Glucose conservation for brain

Long-term metabolic adjustments

Sagittal Section Through Adrenal Gland

Mineralocorticoids

Aldosterone

Effects salt (mineral) balance

Influences how kidneys handle sodium, potassium & H+

Aldosterone is stimulated by angiotensin II

Na+ & H2O retention

K+ & H+ excretion in urine

Glucocorticoids

Cortisol (& corticosterone)Regulation of metabolismRate protein catabolism conversion of amino acids→ glucose lipolysisStress response – make nutrients available for ATP productionRaises BP by vasoconstrictionImmune systemAnti-inflammatory effects reduced (skin cream)

reduce release of histamine from mast cells decrease capillary permeability depress phagocytosis

Pathological consequences of elevated cortisol: Cushing Syndrome

http://www.csrf.net/

Prognosis Good: e.g.removal of tumours results in re-establishment of normal homeostatic levels, patients loose weight etc.

Common symptoms:•Increased & abnormal fat deposition: Moon face/buffalo hump•Hypertension•Hirsutism•May develop type 2 diabetes •Commonly caused by tumours of the adrenal gland or pituitary•Excess ACTH (glucocorticoid hypersecretion)•Muscle weakness•Oedema•Loss of muscle & bone mass•Corticosteriod mediated elevation of sympathetic nervous activity

C - Central obesity, Cervical fat pads, Collagen fibre weakness

U - Urinary free cortisol & glucose

S – Stretch marks, Suppressed immunity

H - Hypercortisolism, Hypertension, Hyperglycaemia, Hirsutism

I - Increased administration of corticosteroids

N – Neoplasia

G - Glucose intolerance, Growth retardation

Adrenalin and Cortisol are part of the body’s stress response and are under negative

feedback

Target cells for cortisolRespond to cortisol

Neural Inputs

Hypothalamus CRH secretion

Anterior pituitary ACTH secretion

Adrenal cortex Cortisol secretion

Plasma CRH

Plasma ACTH

Plasma cortisol

-ve

-ve

Long LoopFeedback

Pathological consequences of elevated Cortisol: Stress, inflammation, obesity and diabetes.

Refer to pg 319: McCance and Huether: Directed reading and Padgett DA, Glaser, R: Trends Immunol 24 (8):444-8, 2003

Increased Cortisol

Obesity

Food Intake(stress

influenced?) Plasma: Increased

Glucose/FFA

Pancreatic B-Cell DestructionType 2 Diabetes

ROS

NF-kB activation

Proinflammatory cytokines

TNFa, IL6, CRP

Emotional stress

Smoking

Infection

Insulin Signalling

Genetic factors

Genetic factors

Interference

Stress and the immune system: Role of Cortisol

Glucocorticoids (Cortisol) used therapeutically as Anti-inflammatory and immunosuppressive agents

Cortisol - suppress activity of Th1 cells (lymphocytes – secrete cytokines)

- decrease in cellular immunity and pro-inflammatory response

Action on Th2 cells Stimulation

- increase in humoral immunity (secreted antibodies) and anti-inflammatory response

Overall response is a balance between effects on both cell classes

Noradrenaline and adrenaline mediate similar effects

Activity switch from TH1 to TH2 is called TH2 shift

Exhaustion Phase: Collapse of Vital Systems

Final Phase of GAS

Outcome if corrective

actions not in place

Possible causes:

● Exhaustion of fuel reserves – lipids● Failure of electrolyte balance● Collapse of Glucocorticoid production● Cumulate structural/functional damage to organs – cardiac failure

E.g. Aldosterone (resistance phase)

- Conservation of Na+ but K+ excretion

K+ declines lead to malfunction of neurons and muscle fibres (important for AP generation and contraction)

Effects of Stress on other hormones: Female Sex hormones

Cortisol Suppresses LH, estradiol and progesterone production

Stress Inhibition of female reproductive

system

- Suppression of GnRH (elevated levels of CRH)

- Suppressed GnRH, LH and E2 via cortisol

-Target tissue resistance to E2 induced by cortisol

Consequences:

● Amenorrhea or dysmenorrhea● Dyspareunia● If in long term: Atrophy of vaginal cells, vaginal prolapse, osteoporosis

Effects of Testosterone in the Male

Required for initiation & maintenance of spermatogensis

Decreases GnRH secretion via hypothalamus

Induces differentiation of male accessory reproductive organs

Inhibits LH secretion via anterior pituitary

Induces male secondary sex characteristics

Stimulates protein anabolism, bone growth and ultimate cessation of bone growth

Required for sex drive

Stimulates erythropoeitin secretion

Effects of Stress on other hormones: Testosterone

Produced by leydig cells

Libido, sperm production, male secondary sexual characteristics, anabolic

Stress cause a marked fall in testosterone levels

Stressors: marathon running, mountain climbing, work stress, ageing.

Elevated Cortisol may inhibit production

Effects of Stress on other hormones: Endorphins

•Stressful stimuli cause endorphin release

•Injury, extreme exercise, haemorrhage etc.

•Haemorrhage – release of beta endorphins inhibit BP increases

•Modulate BP instability

•Dancing, combat and sport.

•Increased endorphin production – feeling of excitement, insensitivity to pain

•Endorphins released from anterior pituitary in response to CRH (from hypothalamus)

Prolactin

Unique anterior pituitary hormone

Major function to stimulate mammary gland development & milk production

Does this by direct effects

Not by stimulating the release of another hormone

Effects of Stress on other hormones: Prolactin

Stress leads to increased synthesis and release of prolactin

Lactation and breast

development

Anterior pituitary

Widespread receptor distribution

Liver, kidney, intestine etc.

Stressful stimuli:Gastroscopy, pelvic examination, surgery, exams, parachute jumping.

Stronger stimulus required than for cortisol.

May also be involved in immune function prl receptors on lymphocytes

Prolactin

Anterior pituitary

Hypothalamus

Dopamine

Prolactin Plasma Levels

-ve

Short-loop feedback

X

Effects of Stress on other hormones: Oxytocin

Promotion of ‘tend’ and ‘befriend’ response

Oxytocin: Childbirth, lactation

Implicated in stress reduction

Animal experiments● Elevated Oxytocin ● Decreased HPA (hypothalamus-pituitary-adrenal ) activity & reduced anxiety

Vasopressin, with testosterone has opposite response – enhances fight or flight – increased stress

Oxytocin may work in concert with oestrogens to mediate calming response in stressful situations

Gender difference: Evidence for lower physiological stress response in women?

Oxytocin

Primarily a neurotransmitter in the brain, but can act as a hormone when secreted into blood stream by the posterior pituitary

Levels of oxytocin during pregnancy

Used to induce labour

“Love hormone”

Oxytocin Receptor

G-protein coupled receptor – intracellular signalsExpressed by myoepithelium of mammary glandExpressed by endometrium & myometrium of uterus – levels increase during pregnancy

SENSOR

EFFECTOR

HYPOTALAMUSCONTROL CENTER

Example:

PITUITARY GLAND

Oxytocin is part of a positive feedback mechanism

Uterine contractions

OXYTOXIN

Neural

electrical

impulses

DELIVERY!

Ageing and Stress:

Stress – Age syndrome

Lower adaptive reserve and coping

● Neuronal Loss: Alterations in excitability of Limbic system and HPA

● Rise in ‘Stress’ hormones- Catecholamine- ACTH- Cortisol

● Decreased sex hormone levels

● Increased Free radical damage (ROS)

● Depression of immune function

● Protein loss, muscle wasting, decrease in available fuel reserves

Summary of Lecture•Links between disease & stress (including stress disorders )

•Different forms of stress

•GAS – General Adaptation Syndrome & how ideas have subsequently changed

•Limbic system

•CNS & Endocrine system in stress

•How stress affects hormones

References – Stress or Endocrine chapters in:

Hadley, M.C. & Levine J.E. (2007). Endocrinology. 6th Edit, Pearson International.

McCance, K. L. & Huether, S. E. (2006). Pathophysiology. (The Biologic Basis for Disease in Adults and Children). 5th Edit. Elsevier Mosby.

Marieb, E. N. (2009) Essentials of Human Anatomy & Physiology. 9th Edit, Pearson International

Purves, D et al (2008). Neuroscience. 4th Edit. Sinauer.

Tortora G. J. & Derrickson B.(2006). Principles of Anatomy and Physiology. 11th Edit, Wiley.

Unglaub Silverthorn D. (2007) Human Physiology (An integrated approach), 4th Edit, Pearson International.