5. Glucocorticoids and the stress response Flashcards
What is the stress response?
a suite of physiological and behavioral responses to a stressor that help to restore homeostasis
What are the 2 steps of the physiological stress response?
- Sympathetic nervous system
- Quick response system, within seconds
- Release of epinephrine (adrenaline) - HPA Axis (hypothalamic-pituitary-adrenal axis)
– Slower response system, minutes to hours
– Release of cortisol
What hormones are released from the adrenal cortex?
Glucocorticoids e.g. cortisol
Mineralocorticoids e.g. aldosterone
Sex hormones e.g. testosterone
What hormones are released from the adrenal medulla?
Epinephrine
Norepinephrine
Physiological consequences of the stress response: HR O2 Glucose Muscle blood Alertness GIT Immune Eyes
Immediate effects: – Increased heart rate – Increased oxygen intake – Increased blood glucose levels – Increased blood flow to muscles – Increased alertness – Inhibition of digestion, immune system – Release of endorphins – Dilation of pupils
Consequences of the stress response, beneficial?
In general, stress is beneficial in the short-term or at mild levels, but can cause major long-term problems if stress is chronic
Chronic stress is associated with which health problems?
– Heart disease – Diabetes – Ulcers – Growth problems – Compromised immune system
Link between cortisol and depression?
• Cortisol elevated in~ 50% of depressed patients
But rhythm in cortisol production (high in morning, 7-9am, low 11pm-4am)
What is the action and purpose of Dexamethasone Suppression Test?
People usually have high cortisol in the morning
• If given Dex —> HPA negative feedback turns this off, so no cortisol surge
Note: Not true of depressed patients
In pit tumour present, DEX has no effect
Depression is a symptoms of…
Cushing’s disease (in high cortisol levels)
Addison’s disease (in low cortisol)
NASA Study;
- To study the relation between elevated stress hormones and the reactivation of Epstein-Barr Virus (EBV) in astronauts.
- To study the effects of stress due to space flight on levels of neuroendocrine hormones and immune cells.
Method?
Results?
Method: • Blood samples were taken for conc of anti-vital antigens/antibodies and stress hormones: 1. Ten days before launch 2. Landing day 3. Three days after landing • Urine samples for detecting hormones.
Results:
• There was significant rise (8- to 64-fold increase) in the levels of EBV antigens in blood samples taken before, during and after the flight. (chronic stress, may have triggered the replication)
• The levels of anti-EBV antibodies continued to decrease from before to after flight.
• 11 astronauts showed evidence of EBV reactivation, and each showed increases in urinary epinephrine and norepineprine (stress hormones).
Conclusions of NASA study?
- There wasadecreaseinthevirusspecific antibodies in all the astronauts.
- Reactivation of EBV occurred in 11/28 astronauts.
- Urinary cortisol and catecholamines were elevated after flight.
- Stresses due to space flight lead to decreased virus specific T-cell immunity and reactivation of EBV.
What is the classical mode of glucocorticoid action? i.e. transactivation
Glucocorticoid
- -> GRE activation and trascription of anti-inflammatory gene
- -> Direct production of anti-inflammatory protein (so dampens down ability to make immune response)
What is the transrepression mode of glucocorticoid action?
Glucocorticoid and cytokine entry to cell
- -> TF binding site stimulated by cytokine upstream of inflammatory gene.
- -> Glucocorticoid INHIBITS transcription
- -> Inflammatory protein not produced
Name 3 main synthetic glucocorticoids used?
Predniose
Prednisolone
**Dexamethasone ** Due to high potency, few days of activity
Immunosuppressive action of glucocorticoids
- Glucocorticoids suppress cell-mediated immunity
Inhibit interleukon production e.g. IL-1,2 etc etc - Suppress humoral immunity
So B cells express less IL-2R and secrete less IL-2 - Downregulation of Fc receptors on macrophages
So phagocytosis of opsonised cells and bacteria
Glucocorticoids side effects?
- Immunosuppression
- Hyperglycemia due to gluconeogenesis, insulin resistance, impaired glucose tolerance
- Skin fragility, bruising
- Osteoporosis
- Weightgain
- Adrenal insufficiency
- Muscle breakdown
- Irregular menstruation
- CNS
- Cushing’ s syndrome
Withdrawal effects of glucocorticoids: Why does it occur? Changes for the following length of use: Less than a week? 6-10days? 11-30 days? >30 days? Monitor for...
Why does it occur?
• Excess use of high dose steroids suppress CRH and ACTH.
• Prolonged use leads to adrenal atrophy - recovery can take months
Changes for the following length of use:
Less than a week: Ok to withdraw abruptly with 1 week recovery period
6-10days: Reduce to replacement and taper 4 more days. 4 week recovery
11-30 days: Reduce to twice replacement, then by 25% every 4 days, 4 months to recover
>30 days: Reduce to twice replacement then by 25% per week, then 0800h check with cortisone. Recovery is 1 yr
Monitor for… flare-up of underlying condition
Type 1 diabetes is the main type in….
Juveniles
Pathophysiology of Type 1 diabetes?
Destruction of insulin producing beta cells in the pancreatic lymph nodes (PLN) by beta-reactive t cells
• Antigens delivered to PLN by dendritic cells
Thus PLN is site where tolerance to pancreas is first broken down
1st and 2nd stage of type 1 diabetes?
1st stage: Insulitis
Lymphocyte invasion of pancreatic islets
2nd stage:
- Overt diabetes, massive death of islet B cells
- Loss of glucose homeostasis
What is the impact of the stress response on the immune system?
- 1st few minutes – immune system is enhanced
- After about an hour of stress – immune system returns to normal
- Chronic stress suppresses immune system functioning
What is the key anti-stress hormone?
Cortisol
It helps reduce inflammation during stress, but it also acts as an immunosuppressent.
Various components of the immune system may be influenced due to cortisol.
What test was performed to investigate exam stress?
Method?
What did they find?
Conclusions?
Experiment at the Catholic University, in Korea
Method:
•Blood samples were taken on the day of the exam, and 4 weeks later.
•The students’ blood samples were monitored for the number of specific immune cells. (macrophages and other cell derived cytokines)
Results:
On the day of the exam, they found:
• Lowered levels of Interferon gamma (IFN-gamma), which is normally released by T lymphocytes and natural killer (NK) cells.
• LoweredT-helper 1 (Th1) cellular immunity.
Conclusion:
During stressful event there was a significant decrease in the number of macrophages, interferons, lymphocytes and natural killer (NK) cells.
So stress = decreased immunity
(Note for type 1 DM)
Lymphocyte access to PLN occurs during….
This timecourse is very similar to when _______ cells capable of presenting pancreatic autoantigens also appear.
Lymphocyte access to PLN occurs during infancy
This timecourse is very similar to when dendritic cells capable of presenting pancreatic autoantigens also appear.
i.e. Time of lymphocyte access to PLN = Time of dendritic cell presentation of pancreatic autoantigens
What is used to change gut permeability?
DSS, sulfated polysaccharide
Altering status of gut alters ……
Altering status of gut alters insulitis due to PLN having self antigens from both PANCREAS and GUT
What is a reason for the potential explanation for relationship between diseases Like coeliac and type 1 diabetes. Link between neonatal immune system development and gut development.?
Altering status of gut alters insulitis
Conclusion: PLN’s sample self-antigens from pancreas and also gut. Non-specific gut pertubations influence beta-reactive T cells.
Potential explanation for relationship between diseases Like coeliac and type 1 diabetes. Link between neonatal immune system development and gut development.
